Integration of meta-analysis and network pharmacology analysis to investigate the pharmacological mechanisms of traditional Chinese medicine in the treatment of hepatocellular carcinoma.

Background: This study will explore the therapeutic value of traditional Chinese medicine (TCM) in Hepatocellular Carcinoma (HCC) through meta-analysis, combined with network pharmacology analysis. Methods: The results of randomized controlled trials on TCM and HCC were retrieved and summarized from multiple databases. The effective active com-pounds and target genes of the high-frequency TCM were obtained using the TCMSP database, and disease targets of HCC were acquired through the public disease database. The network pharmacology analysis was used to get the core genes and investigate the potential oncogenic molecular mechanism. Results: A total of 14 meta-analysis studies with 1,831 patients suggested that therapy combined TCM is associated with better clinical efficacy and survival prognosis, as well as avoiding many adverse events. A total of 156 compounds, 247 herbal target genes and 36 core genes were identified. The function analysis suggested above genes may participate development in HCC through regulating some pathways, such as HIF-1 pathway and PD-L1 immune-related pathway. Conclusion: TCM, as a novel, safe, and effective multi-mechanism therapy, holds greater value in the treatment of HCC.

Efficacy and safety of consolidation chemotherapy after adjuvant therapy in stage IB-IIA cervical cancer patients with risk factors: a retrospective single-center study.

Objective: Accumulated evidence has suggested a relatively high recurrence rate in early-stage cervical cancer (CC) patients with risk factors. This study aimed to assess the efficacy and safety of consolidation chemotherapy following adjuvant therapy (concurrent chemoradiotherapy (CCRT) or radiotherapy (RT) alone) in stage IB-IIA CC patients with risk factors. Methods: A total of 237 stage IB-IIA CC patients who received radical surgery between January 2014 and December 2021 were included in the retrospective study. According to the types of adjuvant therapies, the patients were classified into the control group (CCRT or RT alone) and the study group (consolidation chemotherapy following CCRT or RT alone). The propensity score matching (PSM) was used to balance baseline characteristics between the two groups. The primary end points of the study were disease-free survival (DFS) and overall survival (OS). Results: For the entire cohort, no significant difference was observed in the DFS or OS between the study and control group, which was also confirmed in the PSM cohort (n=124). The multivariate analysis identified the high-risk factor type was an independent adverse prognostic factor for the patients. In patients with high risk factors, consolidation chemotherapy following adjuvant therapy was significantly associated with better clinical outcomes and identified as an independent prognostic favorable factor. Moreover, this association remained statistically significant in high-risk patients with ≥2 metastatic lymph nodes. In patients with intermediate risk factors, consolidation chemotherapy following adjuvant therapy was unrelated to DFS or OS. The safe assessment demonstrated consolidation chemotherapy following adjuvant therapy was significantly correlated with higher rates of ≥ grade 3 hematologic toxicities in both the global and subgroup analysis stratified by risk factor type. Conclusion: Consolidation chemotherapy after adjuvant therapy provided survival benefits in stage IB-IIA CC patients with high risk factors, particularly those with ≥2 metastatic lymph nodes. However, related hematologic toxicities should be alerted in patient management. The actual efficacy and safety of consolidation chemotherapy still need to be investigated in more well-designed clinical trials.

A novel investigation into the negative impact of opioid use on the efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer patients.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) have effectively improved the clinical outcome of advanced non-small cell lung cancer (NSCLC). Opioids are commonly used for pain relief in cancer patients. This study aims to clarify the prognostic impact of opioid use in advanced NSCLC patients receiving ICI therapy. METHODS: A systematic literature review was carried out using online databases before July 2023. The meta-analysis was used to clarify the correlation of opioid use with the overall survival (OS) or progression-free survival (PFS) of ICI-treated NSCLC patients, both of which were determined using hazard ratios (HRs) coupled with 95 % confidence intervals (CIs). Then, an independent cohort enrolling 181 NSCLC patients was utilized for validation. Finally, a comprehensive bioinformatics analysis based on TCGA cohort was performed to investigate the prognostic significance of opioid target genes (OTGs) and their correlation with immune infiltration in NSCLC patients. RESULTS: A total of 8 studies enrolling 1174 patients were included in the meta-analysis. Opioid use was negatively associated with worse PFS (HR = 2.16, 95 %CI: 1.26-3.71) and OS (HR = 2.02, 95 %CI: 1.54-2.63) in ICI-treated NSCLC patients. The retrospective validation confirmed the above result and identified opioid use as an independent unfavorable predictor for PFS and OS in both the entire cohort and ICI subgroup. The bioinformatic analysis identified 14 prognostic OTGs (CYP17A1, PDYN, PYCARD, FGA, NTSR1, FABP1, HPCA, PENK, PDGFB, LIN7A, FKBP5, TYMS, CACNA1H and LDHA), most of which were correlated with immune infiltration in NSCLC. A risk model was constructed based on 14 OTGs and found to effectively stratify the clinical outcome in both the training and validation set, independent of age, gender and TNM staging system. The model was also significantly correlated with infiltration of activated dendritic cells, neutrophils and tumor infiltrating lymphocytes. Finally, a nomogram was constructed based on the model, age, gender and TNM stage, which could predict well the 1-, 3- and 5-year survival of NSCLC patients. CONCLUSION: Opioid use is correlated with the poor clinical outcome in ICI-treated NSCLC patients. Precise pain management is highly advocated and opioids are recommended to be cautiously used in these patients. OTGs have the potential to be prognostic biomarkers for NSCLC patients and their role in tumor immunity needs to be further investigated.

Identification of C-PLAN index as a novel prognostic predictor for advanced lung cancer patients receiving immune checkpoint inhibitors.

Objective: Increasing studies have highlighted the potential utility of non-invasive prognostic biomarkers in advanced lung cancer patients receiving immune checkpoint inhibitor (ICI) based anti-cancer therapies. Here, a novel prognostic predictor named as C-PLAN integrating C-reactive protein (CRP), Performance status (PS), Lactate dehydrogenase (LDH), Albumin (ALB), and derived Neutrophil-to-lymphocyte ratio (dNLR) was identified and validated in a single-center retrospective cohort. Methods: The clinical data of 192 ICI-treated lung cancer patients was retrospectively analyzed. The pretreatment levels of CRP, PS, LDH, ALB and dNLR were scored respectively and then their scores were added up to form C-PLAN index. The correlation of C-PLAN index with the progression-free survival (PFS) or overall survival (OS) was analyzed by a Kaplan-Meier model. The multivariate analysis was used to identify whether C-PLAN index was an independent prognostic predictor. Results: A total of 88 and 104 patients were included in the low and high C-PLAN index group respectively. High C-PLAN index was significantly correlated with worse PFS and OS in ICI-treated lung cancer patients (both p<0.001). The multivariate analysis revealed high C-PLAN index was an independent unfavorable factor affecting PFS (hazard ratio (HR)=1.821; 95%confidence interval (CI)=1.291-2.568) and OS (HR=2.058, 95%CI=1.431-2.959). The high C-PLAN index group had a significantly lower disease control rate than the low C-PLAN index group (p=0.024), while no significant difference was found for objective response rate (p=0.172). The subgroup analysis based on clinical features (pathological type, therapy strategy, TNM stage and age) confirmed the prognostic value of C-PLAN index, except for patients receiving ICI monotherapy or with age ranging from 18 to 65 years old. Finally, a nomogram was constructed based on C-PLAN index, age, gender, TNM stage and smoking status, which could predict well the 1-, 2- and 3-year survival of ICI-treated lung cancer patients. Conclusion: The C-PLAN index has great potential to be utilized as a non-invasive, inexpensive and reliable prognostic predictor for advanced lung cancer patients receiving ICI-based anti-cancer therapies.

An Up-To-Date Investigation Into the Correlation Between Proton Pump Inhibitor Use and the Clinical Efficacy of Immune Checkpoint Inhibitors in Advanced Solid Cancers: A Systematic Review and Meta-Analysis.

Background: Although immune checkpoint inhibitors (ICIs) have revolutionized the current anticancer therapies, a considerable proportion of patients are found to hardly benefit from these drugs. Accumulating studies have demonstrated that concomitant proton pump inhibitor (PPI) use may affect the clinical efficacy of ICIs; however, their results are inconsistent. In this study, based on updated evidence, we aimed to perform a meta-analysis to clarify the prognostic significance of PPI use in advanced solid cancer patients receiving ICI therapy. Methods: Eligible literature was searched using PubMed, Cochrane Library, Web of Science, EMBASE, and other network resources before July 2021. Clinical outcome was evaluated using overall survival (OS) and progression-free survival (PFS). The correlation of PPI use with OS or PFS was determined based on hazard ratios (HRs) and 95% confidence intervals (CIs). Results: A total of 17 studies enrolling 9,978 ICI-treated cancer patients were included in our meta-analysis. The global analysis demonstrated that PPI use was significantly correlated with worse OS [HR = 1.29 (1.10-1.50)] instead of PFS [HR = 1.19 (0.98-1.44)] in solid cancer patients receiving ICI therapy. In a subgroup analysis, the negative correlation of PPI use with ICI efficacy was significant in patients with non-small cell lung cancer [PFS, HR = 1.27 (1.10-1.47)] and urothelial carcinoma [OS, HR = 1.55 (1.31-1.84), PFS, HR = 1.52 (1.13-2.06)] and mixed cohorts containing multiple cancer types [OS, HR = 1.40 (1.16-1.69)], while an opposite result was observed in the PFS of patients with melanoma [HR = 0.48 (0.25-0.90)]. Moreover, the unfavorable prognostic impact of PPI use was also significant in patients over 65 years old [OS, HR = 1.28 (1.05-1.55), PFS, HR = 1.32 (1.12-1.56)] or those receiving anti-PD-1 [OS, HR = 1.37 (1.04-1.79)] or anti-PD-L1 therapies (OS, HR = 1.49 (1.30-1.69), PFS, HR = 1.34 (1.20-1.50). Finally, PPI use was significantly correlated with a worse prognosis in patients receiving PPIs 30 days before and/or after ICI initiation (OS, HR = 1.38 (1.18-1.62), PFS, HR = 1.23 (1.06-1.43)). Conclusion: Although our global analysis revealed PPI use was not correlated with the PFS of ICI-treated patients, considering the results of our subgroup analysis, PPIs should be still cautiously used shortly before or during ICI therapy. Furthermore, more clinical validations and related mechanism investigations are of great necessity to clarify the clinical correlation of PPI use with ICI efficacy. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], PROSPERO [No. CRD42021243707].