Background: Hepatocellular carcinoma (HCC) accounts for the majority of liver cancer, with the incidence and mortality rates increasing every year. Despite the improvement of clinical management, substantial challenges remain due to its high recurrence rates and short survival period. This study aimed to identify potential diagnostic and prognostic biomarkers in HCC through bioinformatic analysis.Methods: Datasets from GEO and TCGA databases were used for the bioinformatic analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were carried out by WebGestalt website and clusterProfiler package of R. The STRING database and Cytoscape software were used to establish the protein-protein interaction (PPI) network. The GEPIA website was used to perform expression analyses of the genes. The miRDB, miRWalk, and TargetScan were employed to predict miRNAs and the expression levels of the predicted miRNAs were explored via OncomiR database. LncRNAs were predicted in the StarBase and LncBase while circRNA prediction was performed by the circBank. ROC curve analysis and Kaplan-Meier (KM) survival analysis were performed to evaluate the diagnostic and prognostic value of the gene expression, respectively.Results: A total of 327 upregulated and 422 downregulated overlapping DEGs were identified between HCC tissues and noncancerous liver tissues. The PPI network was constructed with 89 nodes and 178 edges and eight hub genes were selected to predict upstream miRNAs and ceRNAs. A lncRNA/circRNA-miRNA-mRNA network was successfully constructed based on the ceRNA hypothesis, including five lncRNAs (DLGAP1-AS1, GAS5, LINC00665, TYMSOS, and ZFAS1), six circRNAs (hsa_circ_0003209, hsa_circ_0008128, hsa_circ_0020396, hsa_circ_0030051, hsa_circ_0034049, and hsa_circ_0082333), eight miRNAs (hsa-miR-150-5p, hsa-miR-19b-3p, hsa-miR-23b-3p, hsa-miR-26a-5p, hsa-miR-651-5p, hsa-miR-10a-5p, hsa-miR-214-5p and hsa-miR-486-5p), and five mRNAs (CDC6, GINS1, MCM4, MCM6, and MCM7). The ceRNA network can promote HCC progression via cell cycle, DNA replication, and other pathways. Clinical diagnostic and survival analyses demonstrated that the ZFAS1/hsa-miR-150-5p/GINS1 ceRNA regulatory axis had a high diagnostic and prognostic value.Conclusion: These results revealed that cell cycle and DNA replication pathway could be potential pathways to participate in HCC development. The ceRNA network is expected to provide potential biomarkers and therapeutic targets for HCC management, especially the ZFAS1/hsa-miR-150-5p/GINS1 regulatory axis.

Immunotherapy shows promising therapeutic efficacy against various types of cancer, but most fail to respond. Preclinical studies have suggested that concomitant medications, such as statins, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, metformin and beta-blockers, might affect clinical outcomes if used with immune checkpoint inhibitors (ICIs), but their clinical roles are conflicting. This meta-analysis investigates the effect of these concomitant medications on outcomes in patients treated with ICIs. A search was conducted for all reports published until 31 March 2021 in PubMed, Web of Science, Cochrane Library, EMBASE and conference proceedings. Studies were included if they investigated the association between the concomitant use of these medications and progression-free survival (PFS) or overall survival (OS) during ICI treatment. A total of 3331 patients from 13 eligible studies were included. Among them, five articles on statins, six studies evaluating NSAIDs, five studies employing low-dose aspirin, eight studies on metformin and four articles on beta-blockers were included. The concomitant use of statins during ICI treatment was correlated with improved OS and PFS. Low-dose aspirin was associated with better PFS instead of OS. No significant association was demonstrated between the concurrent use of NSAIDs, beta-blockers and metformin and OS or PFS. The concomitant use of statins and low-dose aspirin during ICI treatment showed a positive impact on treatment outcomes. The concurrent use of NSAIDs, beta-blockers and metformin is not significantly associated with clinical benefits. The effect of these medications in different cancer patients treated with ICI is needed to be further validated.

Background: Immunotherapy has shown promising therapeutic efficacy in various cancers but not gliomas. Circulating lymphocytes play critical roles in cancer control and responses to immune checkpoint inhibitors. Treatment-related lymphopenia has been associated with poor survival in patients with various tumors. This meta-analysis evaluated the risk and impact of lymphopenia in patients with glioma.Methods: The PubMed, Embase, Web of Science, and Cochrane Library databases were comprehensively searched. Eligible studies were included if they reported the incidence and risk factors of lymphopenia and the impact of lymphopenia on survival. Stata 16.0 was used for this meta-analysis.Results: A total of 21 studies were included in the final systematic review and 20 were included in the quantitative analysis. The overall incidence of grade III/IV lymphopenia was 31.6% [95% confidence interval (CI), 22.3–40.8%]. Pooled results based on pathology of glioma revealed that the incidence in astrocytoma and astrocytoma oligodendroglioma patients was 20.2% (95% CI:5.9–34.4%), and the incidence in glioblastoma patients was 27.6% (95% CI:16.2–38.9%). Lymphopenia was associated with poor overall survival (hazard ratio, 1.99; 95% CI, 1.74–2.27; P< 0.001) compared to no lymphopenia. Brain receiving radiation dose of 20 or 25 Gy, female sex, older age, lower baseline lymphocyte count, and dexamethasone dose > 2 mg instead of baseline use were risk factors for lymphopenia.Conclusions: Treatment-related lymphopenia was associated with decreased survival in patients with glioma. Optimization of chemoradiation regimens, particularly in patients with concurrent risk factors, can reduce lymphopenia and potentially improve survival in the era of immunotherapy.

The combination of transcatheter arterial chemoembolisation (TACE) and thermal ablation versus TACE alone for hepatocellular carcinoma (Review)

This meta‐analysis was performed to assess the relationship between Lenvatinib use for malignancy and hypertension (HTN). A total of 2483 patients met inclusion criteria. The relative risk (RR) for all‐grade and high‐grade (≧3) HTN were 2.61 (p ≦ .001) and 3.35 (p≦ .001), respectively, for Lenvatinib compared with other multitarget tyrosine kinase inhibitors or placebo. The cumulative incidence of all‐grade and high‐grade HTN was 70% and 34%, respectively. The studies with median treatment duration (TD) longer than 7.4 months demonstrated a higher incidence of high‐grade HTN than studies with shorter TD (34% vs 28%). The incidence of all levels of HTN increased with TD (68% vs 49%). Trials with median progression‐free survival (PFS) longer than nine months had a higher incidence of both all‐grade (37% vs 28%) and high‐grade (71% vs 48%) HTN. Lenvatinib, a drug commonly used in cancer treatment, is a risk factor for the development of HTN. A longer duration of Lenvatinib treatment was associated with higher frequency of HTN. Further investigation for Lenvatinib of the association between the occurrence of HTN and prognosis will be warranted.

Objective To describe and analyze the predictive models of the prognosis of patients with hepatocellular carcinoma (HCC) undergoing systemic treatment. Design Systematic review. Data sources PubMed and Embase until December 2020 and manually searched references from eligible articles. Eligibility criteria for study selection The development, validation, or updating of prognostic models of patients with HCC after systemic treatment. Results The systematic search yielded 42 eligible articles: 28 articles described the development of 28 prognostic models of patients with HCC treated with systemic therapy, and 14 articles described the external validation of 32 existing prognostic models of patients with HCC undergoing systemic treatment. Among the 28 prognostic models, six were developed based on genes, of which five were expressed in full equations; the other 22 prognostic models were developed based on common clinical factors. Of the 28 prognostic models, 11 were validated both internally and externally, nine were validated only internally, two were validated only externally, and the remaining six models did not undergo any type of validation. Among the 28 prognostic models, the most common systemic treatment was sorafenib (n = 19); the most prevalent endpoint was overall survival (n = 28); and the most commonly used predictors were alpha-fetoprotein (n = 15), bilirubin (n = 8), albumin (n = 8), Child–Pugh score (n = 8), extrahepatic metastasis (n = 7), and tumor size (n = 7). Further, among 32 externally validated prognostic models, 12 were externally validated > 3 times. Conclusions This study describes and analyzes the prognostic models developed and validated for patients with HCC who have undergone systemic treatment. The results show that there are some methodological flaws in the model development process, and that external validation is rarely performed. Future research should focus on validating and updating existing models, and evaluating the effects of these models in clinical practice. Systematic review registration PROSPERO CRD42020200187.

Background The association between Glasgow Prognostic Score (GPS) and the modified Glasgow Prognostic Score (mGPS) and clinical outcomes in patients receiving immune checkpoint inhibitors (ICIs) remains controversial. Thus, this meta‐analysis aimed to examine the prognostic performance of GPS and mGPS in patients treated with ICIs. Methods Eligible studies were retrieved from searches of EMBASE, PubMed, Web of Science, and Cochrane Library until July 2021. The hazard ratio (HR) and 95% confidence intervals (CIs) were pooled by using fixed‐effect or random‐effects model to evaluate the influence of GPS/mGPS on overall survival (OS) and progression‐free survival (PFS). Results A total of 1164 patients were included. Overall, mGPS score of 2 and 1 were related to inferior OS ( p < 0.001) and PFS ( p < 0.001). Subgroup analyses showed no significant association between mGPS score of 1 and OS in patients with non‐small cell lung cancer (NSCLC), while this score was significantly associated with poor PFS in patients with NSCLC and head and neck squamous cell carcinoma. Higher GPS (score of 1 or 2) were associated with poor clinical outcomes (OS: p < 0.001; PFS: p = 0.036). Subgroup analysis showed high GPS levels were linked to worse OS in patients with NSCLC and gastric cancer, but not for PFS in these patients. Regarding test time point, GPS was related to worse OS and PFS in pre‐treatment GPS group, but not in post‐treatment GPS group. Conclusion GPS and mGPS showed great potential to predict survival in patients treated with ICIs. Large and perspective trial are warranted to further validate these findings.

Background: In patients with stage 0-A (as per Milan criteria) hepatocellular carcinoma (HCC) imageguided ablation is less invasive and requires shorter hospitalization than resection, but long-term prognosis is poorer. This meta-analysis was conducted to investigate whether liver stiffness measurement (LSM) could be used to predict prognosis in HCC patients after tumor ablation. Methods: A literature search was conducted for all studies published till July 2020 in PubMed, Web of Science, Cochrane Library and EMBASE. Studies were included if they investigated the association between pretreatment LSM and prognosis in HCC patients treated with ablation. Subgroup analysis, meta-regression, publication bias assessment and sensitivity were conducted. Results: Eight studies (with a total of 1276 HCC patients) were included in this meta-analysis. All patients were treated with radiofrequency ablation. Pooled results showed that high pretreatment LSM were associated with poor overall survival (OS) (hazard ratio [HR] ¼ 4.31, 95% confidence interval [CI]: 2.27-8.20, p < .001) and recurrence-free survival (RFS), regardless of whether LSM was considered as a categorical variable (HR ¼ 2.63, 95% CI ¼ 1.63-4.22, p < .001) or as a continuous variable (HR ¼ 1.02, 95% CI ¼ 1.01-1.04, p ¼ .003). Among studies treating LSM value as a categorical variable, liver stiffness measured using acoustic radio force impulse (ARFI) or transient elastography (TE) was significantly associated with RFS, but not liver stiffness measured using two-dimensional shear wave elastography (SWE). Conclusions: High baseline LSM value appears to be associated with poor prognosis in HCC patients treated with radiofrequency ablation.