[Atezolizumab therapy in Chinese patients with locally advanced or metastatic solid tumors: An open-label, phase â study].

OBJECTIVE: To evaluate pharmacokinetics (PK), efficacy, and safety of atezolizumab (anti-PD-L1) in high interest cancers in China, including esophageal cancer (EC), gastric cancer (GC), hepatocellular carcinoma (HCC), nasopharyngeal cancer (NPC), and non-small cell lung can-cer (NSCLC). METHODS: This phase I, open-label study was conducted at 6 Chinese sites from August 4, 2016 to April 15, 2019. The patients were ≥18 years old with a histologically documented incurable or metastatic solid tumor that was advanced or recurrent and had progressed since the last anti-tumor the-rapy. The PK phase characterized PK and safety of atezolizumab following multiple-dose administration when atezolizumab was administered as a single agent. The extension phase studied safety and efficacy of atezolizumab, as monotherapy (EC, GC, HCC, NPC) and with chemotherapy (NSCLC). RESULTS: This study enrolled 120 patients (PK phase: n=20; extension phase: n=20/cohort). Fourty-two patients (42.0%) were PD-L1 positive in atezolizumab monotherapy group (100 patients), of the 9 patients (9.0%) with microsatellite instability-high (MSI-H) tumors. Atezolizumab clearance was 0.219 L/d, and steady state was reached after 6 to 9 weeks (2-3 cycles) of repeated dosing. Objective response rates (ORRs) in EC, GC, HCC, NPC, and NSCLC were 10.0%, 15.0%, 10.0%, 5.0%, and 40.0%, respectively. In the patients with PD-L1 positive tumors, ORR was 11.9% with atezolizumab and 46.2% with atezolizumab plus gemcitabine and cisplatin. Two GC patients achieved durable response after pseudo-progression. The most common treatment-related adverse events in the atezolizumab monotherapy group were fatigue, anemia, fever, and decreased white blood cell count. The most common treatment-related adverse events in the combination group were anemia, decreased white blood cell count, and decreased appetite. No new safety signals were identified. CONCLUSION: Atezolizumab's PK, efficacy, and safety were similar in Chinese patients vs. global patients in previous studies.

Pembrolizumab versus chemotherapy for patients with esophageal squamous cell carcinoma enrolled in the randomized KEYNOTE-181 trial in Asia.

BACKGROUND: In the randomized phase III KEYNOTE-181 study, pembrolizumab prolonged overall survival (OS) compared with chemotherapy as second-line therapy in patients with advanced esophageal cancer and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥10. We report a post hoc subgroup analysis of patients with esophageal squamous cell carcinoma (ESCC) enrolled in KEYNOTE-181 in Asia, including patients from the KEYNOTE-181 China extension study. PATIENTS AND METHODS: Three hundred and forty Asian patients with advanced/metastatic ESCC were enrolled in KEYNOTE-181, including the China cohort. Patients were randomly assigned 1 : 1 to receive pembrolizumab 200 mg every 3 weeks for ≤2 years or investigator's choice of paclitaxel, docetaxel, or irinotecan. OS, progression-free survival, response, and safety were analyzed without formal comparisons. OS was evaluated based on PD-L1 CPS expression level. RESULTS: In Asian patients with ESCC, median OS was 10.0 months with pembrolizumab and 6.5 months with chemotherapy [hazard ratio (HR), 0.63; 95% CI 0.50-0.80; nominal P < 0.0001]. Median progression-free survival was 2.3 months with pembrolizumab and 3.1 months with chemotherapy (HR, 0.79; 95% CI 0.63-0.99; nominal P = 0.020). Objective response rate was 17.1% with pembrolizumab and 7.1% with chemotherapy; median duration of response was 10.5 months and 7.7 months, respectively. In patients with PD-L1 CPS <1 tumors (pembrolizumab versus chemotherapy), the HR was 0.99 (95% CI 0.56-1.72); the HR (95% CI) for death was better for patients with PD-L1 CPS cut-offs >1 [CPS ≥1, 0.57 (0.44-0.75); CPS ≥5, 0.56 (0.41-0.76); CPS ≥10, 0.53 (0.37-0.75)]. Treatment-related adverse events were reported in 71.8% of patients in the pembrolizumab group and 89.8% in the chemotherapy group; grade 3-5 events were reported in 20.0% and 44.6%, respectively. CONCLUSIONS: Pembrolizumab monotherapy demonstrated promising efficacy in Asian patients with ESCC, with fewer treatment-related adverse events than chemotherapy. PD-L1 CPS ≥1 is an appropriate cut-off and a predictive marker of pembrolizumab efficacy in Asian patients with ESCC.

Upregulation of lncRNA NCK1-AS1 predicts poor prognosis and contributes to non-small cell lung cancer proliferation by regulating CDK1.

OBJECTIVE: To detect the expression of long non-coding ribonucleic acid (lncRNA) NCK1-AS1 in non-small cell lung cancer (NSCLC), analyze the association between its expression and the clinicopathological characteristics of NSCLC patients, and study the biological function of NCK1-AS1 in vitro. PATIENTS AND METHODS: The relative expression of NCK1-AS1 in NSCLC tissues and cells was detected via quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The association between the expression of NCK1-AS1 and the clinicopathological characteristics of NSCLC was statistically analyzed. The effects of interference in the expression of NCK1-AS1 on the biological behaviors of NSCLC cells were detected via in vitro experiments, including Cell Counting Kit-8 (CCK-8) assay, colony formation assay and flow cytometry. After interference in the expression of NCK1-AS1, the expression of cyclin-dependent kinase 1 (CDK1) was determined using Western blotting. RESULTS: The results of qRT-PCR showed that the expression of NCK1-AS1 was up-regulated in 50 out of 64 cases of NSCLC tissues. It was found via statistical analysis that highly expressed NCK1-AS1 was positively correlated with tumor size, TNM stage and lymph node metastasis. The results of qRT-PCR revealed that the expression of NCK1-AS1 was also up-regulated in NSCLC cells. After interference in the expression of NCK1-AS1, the proliferation of NSCLC cells was inhibited, and the cell cycle was arrested at G2/M phase. The results of Western blotting manifested that the expression of CDK1 was suppressed after interference in the expression of NCK1-AS1. CONCLUSIONS: The expression of NCK1-AS1 is up-regulated in NSCLC, which indicates a poor prognosis. Highly expressed NCK1-AS1 promotes the proliferation of NSCLC cells through activating CDK1.

[Thyroid disruptor p, p'-DDE inhibited the expression of LHX4 and DIS3L protein in Nthy-ori-3-1 cells].

Objective: To observe the changes of LHX4 and DIS3L mRNA and protein expression in Nthy-ori-3-1 cells after the treatment of thyroid disruptor p, p'-DDE. Methods: Nthy-ori-3-1 cells in logarithmic growth phase were treated with 0, 0.5, 1.0, 2.0 and 5.0 µg/ml p, p'-DDE solution. The growth state and morphology of the cells were observed by microscope. The mRNA levels of LHX4 and DIS3L were detected by real-time fluorescent quantitative PCR, and the protein expression levels of LHX4 and DIS3L were detected by Western blot. Results: when the concentrations of p, p'-DDE were 0, 0.5, 1.0 and 2.0 µg/ml, Nthy-ori-3-1 cells grew normally. There were 33 differential genes in 2.0 µg/ml group, among which 13 genes were down regulated and 20 genes were up-regulated. Compared with the control group, the protein expression levels of LHX4 and DIS3L in 1.0 and 2.0 µg/ml groups were significantly decreased (P<0.05) , and the relative expression levels of LHX4 and DIS3L protein mRNA in 1.0 µg/ml group were significantly decreased (P<0.05) . Conclusion: p, p'-DDE can affect the protein expression of LHX4 and dis3l in nthy-ori-3-1 cells.

Circ-ZNF609 promotes carcinogenesis of gastric cancer cells by inhibiting miRNA-145-5p expression.

OBJECTIVE: To elucidate the expression pattern and biological function of circular RNA ZNF609 (circ-ZNF609) in gastric cancer (GC). PATIENTS AND METHODS: Circ-ZNF609 expression in GC tissues and adjacent normal tissues (ANT) was determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The regulatory effect of circ-ZNF609 on growth and metastasis of GC cells was evaluated through the Cell Counting Kit-8 (CCK-8), colony formation and transwell invasion assay, respectively. GC cell apoptosis influenced by circ-ZNF609 was examined by flow cytometry. The binding between circ-ZNF609 and miRNA-145-5p was verified by the Dual-Luciferase reporter gene assay. Finally, a series of rescue experiments were conducted to explore the mechanism of the circ-ZNF609/miRNA-145-5p axis in regulating GC progression. RESULTS: QRT-PCR data revealed a higher level of circ-ZNF609 in GC tissues relative to ANT. Identically, circ-ZNF609 was highly expressed in GC cell lines relative to controls. The knockdown of circ-ZNF609 in BGC823 and MGC803 cells suppressed proliferative and invasive abilities. MiRNA-145-5p was predicted to be the target gene of circ-ZNF609 by bioinformatics, and further verified by the Dual-Luciferase reporter gene assay. Rescue experiments showed that miRNA-145-5p knockdown partially reversed the regulatory effect of circ-ZNF609 on growth and metastasis of GC cells. CONCLUSIONS: Circ-ZNF609 promotes proliferative and invasive abilities of gastric cancer cells by inhibiting miRNA-145-5p expression as a ceRNA, thus accelerating gastric cancer progression.