Long Non-coding RNA PCED1B Antisense RNA 1 Promotes Cell Proliferation and Invasion in Hepatocellular Carcinoma by Regulating the MicroRNA-34a/CD44 Axis.

OBJECTIVE: This study aimed to examine the role of long non-coding RNA PCED1B antisense RNA 1 (PCED1B-AS1) in the development of hepatocellular carcinoma (HCC). METHODS: A total of 62 pairs of HCC tissues and adjacent non-tumor tissues were obtained from 62 HCC patients. The interactions of PCED1B-AS1 and microRNA-34a (miR-34a) were detected by dual luciferase activity assay and RNA pull-down assay. The RNA expression levels of PCED1B-AS1, miR-34a and CD44 were detected by RT-qPCR, and the protein expression level of CD44 was determined by Western blotting. The cell proliferation was detected by cell proliferation assay, and the cell invasion and migration by transwell invasion assay. The HCC tumor growth after PCED1B-AS1 was downregulated was determined by in vivo animal study. RESULTS: PCED1B-AS1 was highly expressed in HCC tissues, which was associated with poor survival of HCC patients. Furthermore, PCED1B-AS1 interacted with miR-34a in HCC cells, but they did not regulate the expression of each other. Additionally, PCED1B-AS1 increased the expression level of CD44, which was targeted by miR-34a. The cell proliferation and invasion assay revealed that miR-34a inhibited the proliferation and invasion of HCC in vitro, while CD44 exhibited the opposite effects. Furthermore, PCED1B-AS1 suppressed the role of miR-34a. Moreover, the knockdown of PCED1B-AS1 repressed the HCC tumor growth in nude mice in vivo. CONCLUSION: PCED1B-AS1 may play an oncogenic role by regulating the miR-34a/CD44 axis in HCC.

Bone mineral density as an individual prognostic biomarker in NSCLC patients treated with immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) have left a deep impression in the treatment of non-small cell lung cancer (NSCLC), however, not all patients benefit from it. The purpose of this study was to investigate the prognostic value of baseline bone mineral density (BMD) derived from chest computed tomography (CT) scans in NSCLC patients treated with ICIs. Methods: This study included patients with advanced NSCLC who underwent ICI treatment at the Wuhan Union Hospital from March 2020 to October 2022. Baseline BMD was evaluated at non-contrast chest CT at the level of first lumbar vertebra. Patients were divided into BMD-lower group and BMD-higher group according to the optimal cutoff value calculated by X-tile software. Baseline characteristics of the two groups were compared and variables between the two groups were balanced by propensity score matching (PSM) analysis. We calculated the objective response rate (ORR) and disease control rate (DCR) of the two groups and analyzed overall survival (OS) and progression-free survival (PFS) using BMD and other clinical indexes through Cox regression models and Kaplan-Meier survival curves. Results: A total of 479 patients were included in this study, and all patients were divided into BMD-lower group (n=270) and BMD-higher group (n=209). After PSM analysis, each group consisted of 150 patients. ORR (43.3% vs. 43.5% before PSM, P = 0.964; 44.7% vs. 44.7% after PSM, P = 1.000) and DCR (91.1% vs. 94.3% before PSM, P = 0.195; 93.3% vs. 96.7% after PSM, P =0.190) were similar in two groups. There was no statistically significant relationship between BMD degree and PFS before (16.0 months vs. 18.0 months, P = 0.067) and after PSM analysis (17.0 months vs. 19.0 months, P = 0.095). However, lower BMD was associated with shorter OS both before (20.5 months vs. 23.0 months, P< 0.001) and after PSM analysis (20.0 months vs. 23.0 months, P = 0.008). Conclusion: Lower baseline BMD is associated with worse clinical outcomes in NSCLC patients treated with ICIs. As a reliable and easily obtained individual prognostic biomarker, BMD can become a routine detection indicator before immunotherapy.

Non-small cell lung cancer and immune checkpoint inhibitor therapy: does non-alcoholic fatty liver disease have an effect?

BACKGROUND: Immunotherapy based on the application of immune checkpoint inhibitors (ICIs) is one of the standard treatments for advanced non-small cell lung cancer (NSCLC). Non-alcoholic fatty liver Disease (NAFLD) has demonstrated predictive value for response to immunotherapy in non-lung cancer types. Our study investigated the effect of NAFLD on the efficacy of real-life use of ICIs for patients with stage III / IV NSCLC. METHODS: The clinical and imaging data of patients with stage III / IV NSCLC who were first admitted to Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from March 2020 to July 2022 were retrospectively collected to ensure that they underwent at least one CT scan before treatment. A total of 479 patients were divided into the NAFLD group (Liver/Spleen density ratio ≤ 1) and the non-NAFLD group (Liver/Spleen density ratio > 1) by measuring the baseline liver and spleen CT value. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) of the patients were obtained. RESULTS: A total of 118 patients with NAFLD and 361 patients without NAFLD were included in the study. Patients with NAFLD tended to have higher BMI and higher total bilirubin compared to patients without NAFLD. The median duration of follow-up in the study was 22 m (IQR, 17-29 m). Both of 2 groups had a higher DCR (94% vs. 92%, p = 0.199) and ORR (38.1% vs. 44.9%, p = 0.452) respectively. There was no difference in efficacy between the two groups. In univariate analysis, NAFLD had no significant effect on PFS (p = 0.785) and OS (p = 0.851). Surprisingly, the presence of hypertension was observed to be associated with a higher OS (HR 1.471 95%CI 1.018-2.127, p = 0.040). Besides, based on multivariate analysis, lactic dehydrogenase was associated with PFS (HR 1.001 95%CI 1.000,1.002, p = 0.037) and OS (HR 1.002, 95%CI 1.001-1.003, p < 0.001). CONCLUSIONS: Among patients with NSCLC, NAFLD did not result in changes in survival or disease progression after immune checkpoint inhibitor therapy.

Prognosis stratification of cancer patients treated with immune checkpoint inhibitors through lung immune prognostic index: a meta-analysis and systematic review.

BACKGROUND: Although numerous studies have reported the prognostic value of the lung immune prognostic index (LIPI) in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs), the prognostic value of the LIPI in a pancancer setting remains unclear. METHODS: A comprehensive search was conducted until July 2023 across the PubMed, Embase, Web of Science, and Cochrane Library databases to identify relevant studies evaluating the prognostic value of the LIPI in cancer patients treated with ICIs. The outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). We described and compared the pooled outcomes by stratifying the patients based on different groupings of LIPI (good vs. intermediate [0 vs. 1], good vs. poor [0 vs. 2], and good vs. intermediate / poor [0 vs. 1 + 2]). RESULTS: A total of 9959 patients in 35 studies were included. A higher score of LIPI was associated with impaired OS. The pooled HRs were 1.69 (95% CI: 1.55-1.85, p < 0.001; 0 vs. 1), 3.03 (95% CI: 2.53-3.63, p < 0.001; 0 vs. 2), and 2.38 (95% CI: 1.97-2.88, p < 0.001; 0 vs. 1 + 2). A higher LIPI score was associated with shorter PFS. The pooled HRs were 1.41 (95% CI: 1.31-1.52, p < 0.001; 0 vs. 1), 2.23 (95% CI: 1.87-2.66, p < 0.001; 0 vs. 2), and 1.65 (95% CI: 1.46-1.86, p < 0.001; 0 vs. 1 + 2). Similarly, a higher LIPI score was associated with a lower ORR. The pooled ORs were 0.63 (95% CI: 0.54-0.75, p < 0.001; 0 vs. 1) and 0.38 (95% CI: 0.29-0.50, p < 0.001; 0 vs. 2). A higher LIPI score was associated with a lower DCR. The pooled ORs were 0.47 (95% CI: 0.35-0.61, p < 0.001; 0 vs. 1) and 0.19 (95% CI: 0.12-0.30, p < 0.001; 0 vs. 2). CONCLUSION: In patients with NSCLC or other solid tumours, the lung immune prognostic index could robustly stratify the clinical outcomes into three groups among the patients who receive ICIs. LIPI is a low-cost, simple, accessible, and accurate prognostic tool in a pancancer setting and it may contribute to the evaluation of risk stratification in patients treated with ICIs.

The impact of pulmonary artery to ascending aorta diameter ratio progression on the prognosis of NSCLC patients treated with immune checkpoint inhibitors.

Background: Immunotherapy, represented by immune checkpoint inhibitors (ICIs), is a major breakthrough in cancer treatment. Studies have reported that the use of ICIs is associated with an increase in the pulmonary artery to ascending aorta diameter (PAD/AoD) ratio. However, the impact of PAD/AoD ratio progression on the prognosis of patients is unclear. Methods: This retrospective cohort study included patients with stage III or IV non-small cell lung cancer (NSCLC) treated with ICIs at the Wuhan Union Hospital between March 1, 2020, and September 1, 2022. The baseline and post-treatment PAD/AoD ratios of patients were evaluated through chest CT scans. The primary outcome of this study was overall survival (OS), while the secondary outcomes included progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR). Results: The PAD/AoD ratio increased after the initiation of ICIs (from 0.75 to 0.78; P < 0.001). A total of 441 patients were divided into severe group (n=221) and non-severe group (n=220) according to the median increase of PAD/AoD ratio (1.06). Compared with the non-severe group, the severe group had a lower DCR (87.8% vs. 96.0%, P = 0.005) and ORR (87.5% vs. 96.0%, P = 0.063). Over the entire duration of follow-up (median 22.0 months), 85 (38.5%) patients in the severe group and 30 (7.3%) patients in the non-severe group died. An increased PAD/AoD ratio was associated with shorter PFS (Hazard ratio (HR): 1.48 [95% CI, 1.14 to 1.93]; P = 0.003) and OS (HR: 3.50 [95% CI, 2.30 to 5.30]; P < 0.001). Similar results were obtained across subgroups. Conclusions: ICI treatment exacerbates an increase in the PAD/AoD ratio in patients with cancer, and greater increase in the PAD/AoD ratio was associated with a worse prognosis. PAD/AoD ratio could be a biomarker to stratify prognosis of NSCLC patients treated with ICIs.

Ablation alone is noninferior to radiotherapy plus ablation in the patients with early-stage hepatocellular carcinoma: a population-based study.

Recently, the efficacy of two low-invasive treatments, ablation, and radiotherapy, has been fully compared for the patients with the early-stage hepatocellular carcinoma (HCC). However, the comparison between radiotherapy plus ablation and ablation alone has been less frequently reported. Data from the Surveillance, Epidemiology, and End Results (SEER) database were searched for early-stage HCC patients treated with ablation plus radiotherapy or ablation alone. The outcome measures were overall survival (OS) and cancer-specific survival (CSS). The propensity score matching (PSM) was used to reduce selection bias. We included 240 and 6619 patients in the radiotherapy plus ablation group and ablation group before the PSM. After PSM, 240 pairs of patients were included. The median OS (mOS) and median CSS (mCSS) of patients receiving ablation alone were longer than that of receiving radiotherapy plus ablation (mOS: 47 vs. 34 months, P = 0.019; mCSS: 77 vs. 40 months, P = 0.018, after PSM) before and after PSM. The multivariate analysis indicated that radiotherapy plus ablation independent risk factor for OS and CSS before PSM, but the significance disappeared after PSM. The detailed subgroup analyses indicated ablation alone brought more benefit in very early-stage HCC and older patients. In addition, we found different types of radiotherapy might lead to different outcomes when combined with ablation. In conclusion, ablation alone is noninferior to radiotherapy plus ablation in patients with early-stage HCC. The additional radiation prior to ablation may bring survival benefits in the patients with higher tumor stage. However, due to the risk of selection bias in that study, the results should be interpreted cautiously.

Immune checkpoint inhibitors in cancer: the increased risk of atherosclerotic cardiovascular disease events and progression of coronary artery calcium.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have contributed to a significant advancement in the treatment of cancer, leading to improved clinical outcomes in many individuals with advanced disease. Both preclinical and clinical investigations have shown that ICIs are associated with atherosclerosis and other cardiovascular events; however, the exact mechanism underlying this relationship has not been clarified. METHODS: Patients diagnosed with stages III or IV non-small cell lung cancer (NSCLC) at the Wuhan Union Hospital from March 1, 2020, to April 30, 2022, were included in this retrospective study. Coronary artery calcium (CAC) volume and score were assessed in a subset of patients during non-ECG-gated chest CT scans at baseline and 3, 6, and 12 months after treatment. Propensity score matching (PSM) was performed in a 1:1 ratio to balance the baseline characteristics between the two groups. RESULTS: Overall, 1458 patients (487 with ICI therapy and 971 without ICI therapy) were enrolled in this cardiovascular cohort study. After PSM, 446 patients were included in each group. During the entire period of follow-up (median follow-up 23.1 months), 24 atherosclerotic cardiovascular disease (ASCVD) events (4.9%) occurred in the ICI group, and 14 ASCVD events (1.4%) in the non-ICI group, before PSM; 24 ASCVD events (5.4%) occurred in the ICI group and 5 ASCVD events (1.1%) in the non-ICI group after PSM. The CAC imaging study group comprised 113 patients with ICI therapy and 133 patients without ICI therapy. After PSM, each group consisted of 75 patients. In the ICI group, the CAC volume/score increased from 93.4 mm3/96.9 (baseline) to 125.1 mm3/132.8 (at 12 months). In the non-ICI group, the CAC volume/score was increased from 70.1 mm3/68.8 (baseline) to 84.4 mm3/87.9 (at 12 months). After PSM, the CAC volume/score was increased from 85.1 mm3/76.4 (baseline) to 111.8 mm3/121.1 (12 months) in the ICI group and was increased from 74.9 mm3/76.8 (baseline) to 109.3 mm3/98.7 (12 months) in the non-ICI group. Both cardiovascular events and CAC progression were increased after the initiation of ICIs. CONCLUSIONS: Treatment with ICIs was associated with a higher rate of ASCVD events and a noticeable increase in CAC progression.

Application and development of Deuterium Metabolic Imaging in tumor glucose metabolism: visualization of different metabolic pathways.

Cancer metabolism has emerged as a pivotal area of research recently. The ability to visualize and comprehend the metabolic processes of cancer holds immense clinical value, particularly in the diagnosis of malignant tumors and the assessment of treatment responses. Deuterium Metabolic Imaging (DMI), as a robust, simple, and versatile MR spectroscopic imaging tool, demonstrates promise in tumor diagnosis and treatment efficacy assessment. This review explored the latest developments and applications of DMI in oncology across various tumor metabolic axes, with a specific emphasis on its potential for clinical translation. DMI offers invaluable insights into tumor biology, treatment responses, and prognostic outcomes. Notably, DMI can identify early responses to immunotherapy, a prominent area of current research interest. In conclusion, DMI harbors the potential to evolve into a convenient and efficient imaging technique in clinical practice, thereby advancing precision medicine and improving the diagnosis and evaluation of cancer treatments.

Association of the pretreatment lung immune prognostic index with immune checkpoint inhibitor outcomes in patients with advanced hepatocellular carcinoma.

OBJECTIVE: To evaluate whether the pretreatment Lung Immune Prognostic Index (LIPI) is associated with outcomes in advanced hepatocellular carcinoma (HCC) patients under ICI. METHODS: A two-center retrospective study of patients with HCC treated with immune checkpoint inhibitors (ICIs) between January 2018 and January 2021 was performed. Based on pretreatment derived neutrophils/ (leukocytes minus neutrophils) ratio (dNLR) greater than 3 and a lactate dehydrogenase (LDH) level greater than the normal value, patients were stratified into three groups (good LIPI:0 risk factor, intermediate LIPI: 1 risk factor, and poor LIPI: 2 risk factors). The primary endpoints were overall survival (OS) and progression-free survival (PFS). The second endpoints were disease control rate (DCR) and objective response rate (ORR). RESULTS: In the pooled cohort (n = 224), 80 (35.7%) had a good LIPI (zero factor), 91 (40.6%) had intermediate LIPI (one factor), and 53 (23.7%) had poor LIPI (two factors). The median follow-up was 25.1 months. Median OS was 16.8 months, 12.5 months, and 9.5 months for the good, intermediate, and poor LIPI groups, respectively (P < 0.0001). Median PFS was 11.8 months, 7.8 months, and 4.0 months for the good, intermediate, and poor LIPI groups, respectively (P < 0.0001). Multivariate analysis indicated that the intermediate LIPI and poor LIPI both were independently associated with OS, PFS, and ORR, DCR (P < 0.05), as risk factors. CONCLUSION: Pretreatment LIPI was correlated with worse outcomes for ICIs suggesting that LIPI could be promising biomarker for advanced HCC patients under ICIs.

Network-Based Method to Investigate the Promoted Cell Apoptosis Mechanisms of Oridonin in OSCC through the RNA-Transcriptome.

The morbidity of oral cancer is high in the world. Oridonin is a traditional Chinese medicine that can effectively inhibit oral squamous cell carcinoma (OSCC) growth, but its mechanism remains unclear. Our previous data showed that oridonin inhibited CAL-27 cell proliferation and promoted apoptosis. Herein, we explored the mechanism and target of oridonin in human OSCC through RNA sequencing and integration of multiple bioinformatics analysis strategies. Differences in gene expression can be analyzed with RNA sequencing. Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), gene set enrichment analysis (GSEA), Disease Ontology (DO), and other enrichment analyses were used to evaluate differentially expressed genes (DEGs). Protein-protein interaction (PPI) networks were built via the STRING database. It was found that tumor necrosis factor (TNF) signaling pathway, cytokine-cytokine receptor interaction, and nuclear factor-kappa B (NF-kappaB) signaling pathway were associated with the therapeutic effects of oridonin in OSCC. Three key genes (BIRC3, TNFSF10, and BCL6) were found to associate with cell apoptosis in OSCC cells treated with oridonin. Quantitative PCR assays verified the expression of apoptosis-related DEGs: TNFSF10, BIRC3, AIFM2, BCL6, BCL2L2, and Bax. Western blots were employed for verifying proteins expression associated with DEGs: cleaved caspase 3, Bax, Bcl-w, anti-cIAP2, and anti-TRAIL. In conclusion, our findings reveal the molecular pathways and targets by which oridonin can treat and induce cytotoxic effects in OSCC: by affecting the signaling including TNF, NF-κB, and cytokine-cytokine receptor interaction and by regulating the key gene BIRC3, TNFSF10, and BCL6. It should be noted that further clinical trial validation is very necessary. Combined with current research trends, our existing research may provide innovative research drugs for the treatment of OSCC.

Gain-of-Function p53N236S Mutation Drives the Bypassing of HRasV12-Induced Cellular Senescence via PGC-1α.

One of the key steps in tumorigenic transformation is immortalization in which cells bypass cancer-initiating barriers such as senescence. Senescence can be triggered by either telomere erosion or oncogenic stress (oncogene-induced senescence, OIS) and undergo p53- or Rb-dependent cell cycle arrest. The tumor suppressor p53 is mutated in 50% of human cancers. In this study, we generated p53N236S (p53S) mutant knock-in mice and observed that p53S heterozygous mouse embryonic fibroblasts (p53S/+) escaped HRasV12-induced senescence after subculture in vitro and formed tumors after subcutaneous injection into severe combined immune deficiency (SCID) mice. We found that p53S increased the level and nuclear translocation of PGC-1α in late-stage p53S/++Ras cells (LS cells, which bypassed the OIS). The increase in PGC-1α promoted the biosynthesis and function of mitochondria in LS cells by inhibiting senescence-associated reactive oxygen species (ROS) and ROS-induced autophagy. In addition, p53S regulated the interaction between PGC-1α and PPARγ and promoted lipid synthesis, which may indicate an auxiliary pathway for facilitating cell escape from aging. Our results illuminate the mechanisms underlying p53S mutant-regulated senescence bypass and demonstrate the role played by PGC-1α in this process.

Association between sarcopenia and clinical outcomes in patients with hepatocellular carcinoma: an updated meta-analysis.

Although numerous studies have reported the association between sarcopenia and the prognosis of hepatocellular carcinoma (HCC) patients, there is lack of a newer and more comprehensive meta-analysis. Herein, a comprehensive literature search was performed on PubMed, Web of Science, the Cochrane Library, and Embase databases to identify relevant studies published up to February 2022. The outcomes were overall survival (OS), recurrence, progression-free survival, tumor response, severe postoperative complications, and toxicity of drugs. A total of 57 studies involving 9790 HCC patients were included in the meta-analysis. The pooled prevalence of sarcopenia in HCC patients was 41.7% (95% CI 36.2-47.2%). Results demonstrated that sarcopenia was significantly associated with impaired OS (HR: 1.93, 95% CI 1.73-2.17, P < 0.001), higher risk of tumor recurrence (HR: 1.75, 95% CI 1.56-1.96, P < 0.001), lower objective response rate (OR: 0.37 95% CI 0.17-0.81, P = 0.012), and more drug-related adverse events (OR: 2.23, 95% CI 1.17-4.28, P = 0.015) in HCC patients. The subgroup analyses revealed that the OS of patients at the early stage of tumor was more severely affected by sarcopenia than for patients at other stages. Moreover, the presence of cirrhosis and Child Pugh class B increased the hazard of mortality from sarcopenia. This study has shown that sarcopenia is highly associated with poor prognosis in HCC patients. In addition, cirrhosis and poor liver functional reserve increase the danger of sarcopenia. OS was more impaired in HCC patients with sarcopenia at early stage of tumor than at other tumor stages.

Evaluation of Transarterial Chemoembolization Protocol with Drug-Eluting Beads in Combination with Lipiodol for Hepatocellular Carcinoma: A Single-Center Controlled Study.

Objectives: To evaluate the efficacy and safety of transarterial chemoembolization (TACE) with drug-eluting beads (DEB-TACE) and lipiodol (DEB-Lipiodol TACE) in the treatment of unresectable hepatocellular carcinoma (HCC) patients. Materials and Methods: The medical records of consecutive unresectable HCC patients who underwent DEB-TACE or DEB-Lipiodol TACE from June 2016 to July 2021 were retrospectively evaluated. Therapeutic response, overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were compared among the groups. Results: Three hundred and twenty-seven patients were enrolled in the study, including 293 patients in the DEB-TACE group and 34 patients in the DEB-Lipiodol TACE group. The objective response rate in the DEB-Lipiodol TACE group was 17.6%, significantly higher than that in the DEB-TACE group (5.8%, P=0.011). Similarly, DEB-Lipiodol TACE group also had a higher disease control rate (91.2% vs 68.6%, P=0.006). Median OS was 13 months (95% CI: 11.0 months and 15.0 months) and 22 months (95% CI: 17.3 months and 26.7 months) in the DEB-TACE group and DEB-Lipiodol TACE group, respectively (P=0.041). Meanwhile, median PFS was 7 months (95% CI: 5.2 months and 8.8 months) in the DEB-TACE group and 12 months (95% CI: 7.9 months and 16.1 months) in the DEB-Lipiodol TACE group (P=0.174). There was no statistically significant difference in AEs incidence among the two groups (P > 0.05). Conclusions: DEB-Lipiodol TACE was safe, well tolerated, and had a better efficacy compared with DEB-TACE in unresectable HCC patients.

Focus on the Dynamics of Neutrophil-to-Lymphocyte Ratio in Cancer Patients Treated with Immune Checkpoint Inhibitors: A Meta-Analysis and Systematic Review.

Background: A number of studies have reported an association between the dynamics of neutrophil-to-lymphocyte ratio (NLR) and clinical efficacy in patients treated with immune checkpoint inhibitors (ICIs), but there is still a lack of a meta-analysis or systematic review. Methods: PubMed, Embase, Web of Science, and the Cochrane Library were searched until September 2022 for studies reporting on the association between the change in NLR after ICI treatment and clinical outcomes. Outcome measures of interest included: change in NLR before and after treatment, overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Results: A total of 4154 patients in 38 studies were included. The pooled percentage of patients with increased NLR was 49.7% (95CI%: 43.7−55.8%). Six studies discussing the change in NLR in patients with different tumor responses all showed that the NLR level in patients without response to immunotherapy may increase after ICI treatment. The upward trend in NLR was associated with shorter OS (pooled HR: 2.05, 95%CI: 1.79−2.35, p < 0.001) and PFS (pooled HR: 1.89, 95%CI: 1.66−2.14, p < 0.001) and higher ORR (pooled OR: 0.27, 95%CI: 0.19−0.39, p < 0.001), and downward trend in NLR was associated with longer OS (pooled HR: 0.49, 95%CI: 0.42−0.58, p < 0.001) and PFS (pooled HR: 0.55, 95%CI: 0.48−0.63, p < 0.001) and lower ORR (pooled OR: 3.26, 95%CI: 1.92−5.53, p < 0.001). In addition, post-treatment high NLR was associated with more impaired survival than baseline high NLR (pooled HR of baseline high NLR: 1.82, 95%CI: 1.52−2.18; pooled HR of post-treatment high NLR: 2.93, 95%CI: 2.26−3.81), but the NLR at different time points may have a similar predictive effect on PFS (pooled HR of baseline high NLR: 1.68, 95%CI: 1.44−1.97; pooled HR of post-treatment high NLR: 2.00, 95%CI: 1.54−2.59). Conclusions: The NLR level of tumor patients after ICI treatment is stable overall, but the NLR level in patients without response to immunotherapy may increase after ICI treatment. Patients with an upward trend in NLR after ICI treatment were associated with worse clinical outcomes; meanwhile, the downward trend in NLR was associated with better clinical outcomes. Post-treatment high NLR was associated with more impaired survival than baseline high NLR.

Safety and efficacy of lenvatinib combined with camrelizumab plus transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: A two-center retrospective study.

Objectives: To compare the safety and efficacy of lenvatinib (LEN) combined with camrelizumab plus transcatheter arterial chemoembolization (TACE-LEN-C) and TACE combined with LEN (TACE-LEN) in patients with unresectable hepatocellular carcinoma (uHCC). Methods: Eighty-three patients with uHCC treated with TACE-LEN-C or TACE-LEN from September 2018 to May 2021 were enrolled in this retrospective study. Overall survival (OS), progression-free survival (PFS), local tumor response, and adverse events (AEs) were evaluated. Univariate and multivariate analyses were used to determine the factors affecting survival. Results: There were 31 patients in the TACE-LEN-C group and 52 patients in the TACE-LEN group. The median follow-up period was 14.2 months (range 7.2-25.2 months) in the whole study. The combination of triple therapy was found to significantly prolong the PFS (12.5 months vs. 6.6 months, P<0.001) and OS (18.9 months vs. 13.9 months, P<0.001. In terms of tumor response, the combination demonstrated a higher objective response rate (71% vs. 42.3% by the modified Response Evaluation Criteria in Solid Tumors, P=0.023) without a statistically significant difference in the disease control rate (93.5% in TACE-LEN-C, 80.8% in TACE-LEN, P=0.195). In the multivariate analysis, two independent factors affecting PFS were identified: number of tumors and treatment. Three independent factors affected OS: number of tumors, Barcelona Clinic Liver Cancer (BCLC) stage, and treatment. All the AEs were tolerable. Conclusion: TACE-LEN-C is a safe and effective treatment for patients with uHCC, and could be a potential treatment option.

An Overview of Hepatocellular Carcinoma After Insufficient Radiofrequency Ablation.

Radiofrequency ablation (RFA) is a commonly used treatment for hepatocellular carcinoma (HCC), however, various complex conditions in clinical practice may lead to insufficient radiofrequency ablation (IRFA), allowing residual HCC to survive. In clinical practice and laboratory models, IRFA plays an important role in rapid tumor progression. Therefore, targeting the residual HCC and avoiding IRFA were worthwhile methods. A deeper understanding of IRFA is required; IRFA contributes to the improvement of proliferative activity, migration rates, and invasive capacity, and this may be due to the involvement of multiple complex processes or proteins, including epithelial mesenchymal transitions (EMTs), cancer stem cells (CSCs), autophagy, heat shock proteins (HSPs), changes of non-tumor cells and extracellular matrix, altered immune microenvironment, hypoxia-inducible factors (HIFs), growth factors, epigenetic alterations, and metabolic reprogramming. We focus on the processes of the above mechanisms and possible therapeutic approach, with a review of the literature. Additionally, we recapitulated the construction methods of various experimental models of IRFA (in vivo and in vitro).

Transarterial chemoembolization combined with camrelizumab for recurrent hepatocellular carcinoma.

PURPOSE: To evaluate the efficacy and safety of transarterial chemoembolization (TACE) combined with camrelizumab (hereafter, TACE-camrelizumab) in the treatment of patients with recurrent hepatocellular carcinoma (R-HCC) after curative resection. PATIENTS AND METHODS: R-HCC patients who underwent TACE plus camrelizumab or TACE-alone from January 2016 to August 2021 were retrospectively evaluated. Patients were assessed for tumor response, progression-free survival, survival rates and adverse events. RESULTS: Seventy-one patients were included in this study, including 20 patients in the TACE- camrelizumab group and 51 patients in the TACE-alone group. The objective response rate was 56.9% in the TACE-alone group and 40% in the TACE-camrelizumab group at 3 months (P = 0.201). The disease control rates were 84.3% in TACE-alone group and 80% in TACE-camrelizumab group at 3 months (P = 0.663). The progression-free survival (PFS) of the TACE-alone group was slightly longer than those of the TACE- camrelizumab group (9 months vs. 6 months). However, there were no statistically significant differences in the median PFS (P = 0.586). Similarly, there were no significant differences in the half-year and one-year survival rates (P = 0.304, P = 0.430). Multivariate analysis revealed that Neutrophil-to-lymphocyte ratio (NLR) was associated with PFS significantly. 75% patients developed at least one type of AEs related to camrelizumab in TACE-camrelizumab group, and no patients developed severe AEs. CONCLUSION: Comparing with TACE-Alone, the efficacy of TACE-camrelizumab for patients with R-HCC was similar. Meanwhile, the results of this study also indicated that TACE is still a better choice for patients with R-HCC.

Efficacy of Drug-Eluting Beads Transarterial Chemoembolization Plus Camrelizumab Compared With Conventional Transarterial Chemoembolization Plus Camrelizumab for Unresectable Hepatocellular Carcinoma.

OBJECTIVES: The purpose of this study was to compare the efficacy and safety of drug-eluting beads transarterial chemoembolization plus camrelizumab (D-TACE-C) with conventional transarterial chemoembolization plus camrelizumab (C-TACE-C) in the treatment of patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This was a retrospective study that evaluated the consecutive medical records of patients with unresectable HCC who had undergone D-TACE-C or C-TACE-C from April 2020 to August 2021. Efficacy of treatment was evaluated using tumor response, progression-free survival (PFS) and survival rates. The adverse events were recorded. RESULTS: A total of 54 patients were included in this study, including 27 patients who had received D-TACE-C treatment, and 27 patients who had received C-TACE-C treatment. The median PFS and DCR in the D-TACE-C group were significantly longer than those for the C-TACE-C group (PFS: 10 vs. 3 months, P=.017; DCR: 70.4% vs. 40.7%, P = .028). Cox regression analysis showed that D-TACE-C was the only protective factor for PFS. The 6-month and 12-month survival rates in D-TACE-C group and C-TACE-C group were 85.2% versus 79.4% (P = .646) and 65.2% versus 65.1% (P = .903), respectively. Reactive cutaneous capillary endothelial proliferation was the most common adverse event associated with the treatment. There was no significant difference in the adverse events related to TACE and camrelizumab between the two groups. No treatment-related deaths occurred in this study. CONCLUSIONS: D-TACE-C is a safe and well-tolerated treatment, and may produce better PFS and tumor response in patients with unresectable HCC than C-TACE-C.

Prognostic impact of sarcopenia in patients with hepatocellular carcinoma treated with PD-1 inhibitor.

Background: Sarcopenia is a progressive generalized loss of skeletal muscle mass commonly observed in advanced stages of cancer. Objective: To assess the relationship between sarcopenia and the prognosis of patients with hepatocellular carcinoma (HCC) treated with a programmed cell death 1 (PD-1) inhibitor. Design: This is a retrospective study. Methods: This study included patients with HCC treated with camrelizumab between 1 March 2020 and 1 December 2021. The skeletal muscle area at the L3 vertebra middle level was used to calculate the skeletal muscle index. Propensity score matching (PSM) analysis was used to balance the variables between the two groups. Results: In all, 97 patients with HCC were included in the study, with 46 and 51 patients in the sarcopenia group and the non-sarcopenia group, respectively. The baseline characteristics of albumin, Child-Pugh class, albumin-bilirubin score, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio were significantly different between the two groups. In total, 26 patients from each group (n = 52) were selected after the PSM analysis. The progression-free survival (PFS) in the non-sarcopenia group was significantly longer than that in the sarcopenia group before and after PSM analysis (6.5 versus 4.8 months, p = 0.038). In addition, the disease control rate was similar before and after PSM analysis (57.7% versus 69.2%, p = 0.388). The objective response rate in the non-sarcopenia group tended to be higher than that in the sarcopenia group (11.5% versus 30.8%, p = 0.090, after PSM), but no statistically significant difference was found. The median overall survival (OS) in the non-sarcopenia group tended to longer than it in the sarcopenia group before PSM without significant differences (16.3 versus 11.3 months, p = 0.090) and the median OS was similar between the two groups after PSM (16.3 versus 16.8 months, p = 0.735). Conclusions: HCC patients with sarcopenia tended to have higher levels of inflammation and lower levels of albumin than patients without sarcopenia. Sarcopenia is associated with a shorter PFS in HCC patients treated with PD-1 inhibitor.

Role of long intergenic non-protein coding RNA 01857 in hepatocellular carcinoma malignancy via the regulation of the microRNA-197-3p/anterior GRadient 2 axis.

OBJECTIVE: This study investigates the differential expression and the mechanism of long intergenic non-protein coding RNA (LINC) 01857 in hepatocellular carcinoma (HCC) proliferation and apoptosis. METHODS: LINC01857 expression in HCC tissues and cells was evaluated. In addition, gain-of and loss-of functions were carried out to assess HCC cell proliferation and apoptosis. After that, LINC01857 subcellular localization was predicted and verified. Additionally, the binding relations between LINC01857 and microRNA (miRNA)-197-3p and between miR-197-3p and anterior GRadient 2 (AGR2) were detected and confirmed. Besides, HCC cell proliferation and apoptosis were assessed after silencing LINC01857 or overexpressing AGR2. Next, levels of key factors in the AKT and ERK pathways were measured. Additionally, xenograft transplantation was also conducted to confirm the effect of LINC01857 in HCC. RESULTS: LINC01857 was overexpressed in HCC. Silencing LINC01857 leads to a blockage in HCC cell proliferation but improved apoptosis. LINC01857 could competitively bind to miR-197-3p and thus upregulate AGR2. miR-197-3p was poorly expressed in HCC, while AGR2 was overexpressed. Mechanistically, downregulated miR-197-3p or overexpressed AGR2 were observed to attenuate the effect of the LINC01857 knockdown on suppressing cell proliferation and enhancing apoptosis. Moreover, LINC01857 activated the AKT and ERK pathways through the manipulation of the miR-197-3p/AGR2 axis in HCC. CONCLUSION: The results of this study indicated that LINC01857 was highly expressed in HCC, and it could improve HCC cell proliferation and reduce apoptosis via competitively binding to miR-197-3p, promoting AGR2 and upregulating the AKT and ERK pathways.