Lizhu Lin

Abstract Background Cholangiocarcinoma refers to an epithelial cell malignancy with poor prognosis. Yinchenhao decoction (YCHD) showed positive effects on cancers, and associations between YCHD and cholangiocarcinoma remain unclear. This study aimed to screen out the effective active components of Yinchenhao decoction (YCHD) using network pharmacology, estimate their potential targets, screen out the pathways, as well as delve into the potential mechanisms on treating cholangiocarcinoma. Methods By the traditional Chinese medicine system pharmacology database and analysis platform (TCMSP) as well as literature review, the major active components and their corresponding targets were estimated and screened out. Using the software Cytoscape 3.6.0, a visual network was established using the active components of YCHD and the targets of cholangiocarcinoma. Based on STRING online database, the protein interaction network of vital targets was built and analyzed. With the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server, the gene ontology (GO) biological processes and the Kyoto encyclopedia of genes and genomes (KEGG) signaling pathways of the targets enrichment were performed. The AutoDock Vina was used to perform molecular docking and calculate the binding affinity. The PyMOL software was utilized to visualize the docking results of active compounds and protein targets. In vivo experiment, the IC 50 values and apoptosis rate in PI-A cells were detected using CCK-8 kit and Cell Cycle Detection Kit. The predicted targets were verified by the real-time PCR and western blot methods. Results 32 effective active components with anti-tumor effects of YCHD were sifted in total, covering 209 targets, 96 of which were associated with cancer. Quercetin, kaempferol, beta-sitosterol, isorhamnetin, and stigmasterol were identified as the vital active compounds, and AKT1, IL6, MAPK1, TP53 as well as VEGFA were considered as the major targets. The molecular docking revealed that these active compounds and targets showed good binding interactions. These 96 putative targets exerted therapeutic effects on cancer by regulating signaling pathways (e.g., hepatitis B, the MAPK signaling pathway, the PI3K-Akt signaling pathway, and MicroRNAs in cancer). Our in vivo experimental results confirmed that YCHD showed therapeutic effects on cholangiocarcinoma by decreasing IC 50 values, down-regulating apoptosis rate of cholangiocarcinoma cells, and lowering protein expressions. Conclusions As predicted by network pharmacology strategy and validated by the experimental results, YCHD exerts anti-tumor effectsthrough multiple components, targets, and pathways, thereby providing novel ideas and clues for the development of preparations and the treatment of cholangiocarcinoma.

384950 Background: Tislelizumab is a humanized immunoglobulin G4 anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb). At the interim analysis (median follow-up, 10.0 months), RATIONALE-309 met its primary endpoint, as first-line tislelizumab + chemotherapy significantly improved PFS, as assessed by an independent review committee (IRC), in patients with recurrent/metastatic nasopharyngeal cancer (RM NPC) compared with placebo + chemotherapy. Tislelizumab + chemotherapy had an acceptable safety profile, comparable to placebo + chemotherapy (Yang Y, et al. ESMO-IO Virtual Congress, 2021. Oral presentation 121O). Here, we report an updated analysis of PFS, PFS after next line of treatment (PFS2), and overall survival (OS) with an extended median follow-up of 15.5 months. Methods: A total of 263 eligible patients with RM NPC were randomly assigned 1:1 to receive tislelizumab 200 mg intravenously (IV) or placebo on day 1, plus gemcitabine (1 g/m 2 IV day 1, day 8), plus cisplatin (80 mg/m 2 day 1) every 3 weeks for 4–6 cycles, followed by tislelizumab or placebo every 3 weeks until disease progression, unacceptable toxicity, or withdrawal. After IRC-confirmed disease progression, patients in the placebo arm could crossover to receive tislelizumab monotherapy. The primary endpoint was IRC-assessed PFS. Secondary endpoints included IRC-assessed objective response rate and duration of response, investigator-assessed PFS and PFS2, and OS. Biomarker analysis was an exploratory endpoint. Results: At an updated data cut-off (September 30, 2021), IRC-assessed PFS was consistent with the interim data analysis and demonstrated significant improvement for tislelizumab + chemotherapy versus placebo + chemotherapy (median PFS, 9.6 vs. 7.4 months, respectively; hazard ratio [HR], 0.50; 95% CI, 0.37, 0.68). Median PFS2 and OS were not reached for the tislelizumab + chemotherapy arm and were 13.9 months and 23.0 months for the placebo + chemotherapy arm, respectively. The HRs were 0.38 (95% CI, 0.25, 0.58) for PFS2 and 0.60 (95% CI, 0.35, 1.01) for OS. The association of tumor microenvironment features by gene-expression analysis with clinical benefit will be presented. Conclusions: Tislelizumab + chemotherapy showed consistent, clinically meaningful improvement in PFS compared with placebo + chemotherapy in this updated analysis. Clinically meaningful improvements in PFS2 and OS were also observed for the tislelizumab + chemotherapy arm. This is the first report of PFS2 benefit for an anti–PD-1 mAb in combination with chemotherapy in the first-line treatment setting of RM NPC. These results support the use of tislelizumab + chemotherapy as first-line therapy for RM NPC. Clinical trial information: NCT03924986.

OBJECTIVE: We conducted this study to evaluate the efficacy and safety of traditional Chinese medicine (TCM) in advanced non-small cell lung cancer (NSCLC) patients who underwent chemotherapy. DESIGN: This was a prospective, open-label, randomized controlled trial. NSCLC patients at stage IIIA, IIIB, or IV were randomly assigned to either TCM plus chemotherapy or chemotherapy alone. The comprehensive TCM treatment consisted of Kang Ai injection, herbal decoction, and Zhenqifuzheng capsules. The primary endpoint was quality of life (QOL) measured by the Functional Assessment of Cancer Therapy-Lung version 4.0. The secondary endpoints were chemotherapy completion rate, tumor response, and adverse events. All assessments were done at baseline, the third week, and the sixth week. RESULTS: Thirty-nine participants were randomly assigned to the treatment group and 36 to the control group. The QOL scores were significantly improved in the treatment group compared with those of the control group in social well-being (cycle 1, P = .048; cycle 2, P = .015), emotional well-being (cycle 1, P = .047; cycle 2, P = 4.29E-05), and functional well-being (cycle 1, P = .030; cycle 2, P = .003), while the QOL scores in the above 3 domains declined in the control group (P < .05). Both groups had a decline in the physical well-being score (cycle 1, P = .042; cycle 2, P = .017) and lung cancer symptom score (cycle 1, P = .001; cycle 2, P = .001) after 2 courses of intervention. The deterioration in physical well-being and lung cancer symptoms was noticeably smaller in the treatment group (P < .05). There were significant differences between the 2 groups in social well-being, emotional well-being, functional well-being, lung cancer symptom domain, and the total score (P < .05). Patients in the treatment group had a significantly lower incidence of platelet reduction than the control group (P = .028) after 2 cycles of treatment. No significant difference in nonhematological adverse events (AEs) was observed. CONCLUSION: This study illustrated that comprehensive TCM treatment could promote the QOL of NSCLC patients, alleviate symptoms, and reduce the AEs caused by chemotherapy, verifying the synergistic and attenuating effects of TCM in NSCLC patients undergoing chemotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry (www.chictr.org.cn): ChiCTR-TRC-13003637.