ABSTRACT
Background: The KEYNOTE-048 and KEYNOTE-040 study have demonstrated the efficacy of pembrolizumab in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC), we conducted this real-world study to investigate the efficacy of pembrolizumab in patients with R/M HNSCC. Methods: This is a single-center retrospective study conducted in the Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Shanghai, China). Between December 2020 and December 2022, a total of 77 patients with R/M HNSCC were included into analysis. The primary endpoint of the study was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), overall response rate (ORR)and toxicity.Efficacy was assessed according to RECIST version 1.1.SPSS 27.0 and GraphPad Prism 8.0 software were utilized to perform the statistical analysis. Results: By the cut-off date (February 28, 2023), the median OS,PFS and ORR were 15.97 months,8.53 months and 48.9% in patients treated with the pembrolizumab regimen in the first line therapy. Among these patients, 17 patients received pembrolizumab with cetuximab,and 18 received pembrolizumab with chemotherapy.We observed no significant differences between two groups neither in median OS (13.9 vs 19.4 months, P=0.3582) nor PFS (unreached vs 8.233 months, P= 0.2807). In the ≥2nd line therapy (n=30), the median OS, PFS and ORR were 5.7 months, 2.58 months and 20% respectively. Combined positive score (CPS) was eligible from 54 patients. For first line therapy, the median OS and PFS were 14.6 and 8.53 months in patients with CPS ≥1, and median OS and PFS were 14.6 and 12.33 months in patients with CPS ≥20. The immune-related adverse events (irAEs) were occurred in the 31 patients (31/77, 40.26%), and the most common potential irAEs were hypothyroidism (25.97%), and pneumonitis (7.79%). Conclusion: Our real-world results indicated that pembrolizumab regimen is a promising treatment in patients with R/M HNSCC.
ABSTRACT
Hepatocellular carcinoma (HCC) is highly metastatic and invasive. CircRNA participates in gene regulation of multiple tumor metastases, but little is known whether it is a bystander or an actual player in HCC metastasis. We aim to explore the molecular mechanisms of novel circRNAs in HCC metastasis. RT-qPCR was used to detect the expression of 13 circRNAs derived by the ERBB3 gene. The function of circ_0098823 and DNM1L in HCC cells were estimated by CCK-8, transwell assays, flow cytometry, electron microscope, and in vivo experiments. RNA binding protein of circ_0098823 was confirmed by RNA pull-down, mass spectrometry, and RNA immunoprecipitation. The expression of DNM1L after IGF2BP3 knockdown was detected by RT-qPCR and western blot. Circ_0098823 was significantly up-regulated both in HCC tissues and HGF induced cell lines. Circ_0098823 overexpression significantly enhanced proliferation, migration, and invasion but decreased apoptosis of HCC cells, particularly promoted mitochondrial fission. Compared with the control group, the tumors in the circ_0098823 knockdown mice were significantly smaller and lighter. Circ_0098823 silencing suppressed DNM1L expression, a key molecule for fission, which enhanced proliferation, migration and invasion, and inhibited apoptosis of HCC cell. IGF2BP3 was a binding protein of circ_0098823. The expression and mRNA stability of DNM1L were down-regulated by IGF2BP3 knockdown. IGF2BP3 knockdown significantly alleviated the excessive migration, invasion and apoptosis of HCC cells caused by circ_0098823 overexpression. This study uncovered a novel circ_0098823 with tumor-promoting effect, and the mechanism by which circ_0098823 participates in HCC progression through IGF2BP3-guided DNM1L. Our study broadens molecular understanding of HCC progression.
Subject(s)
Apoptosis , Carcinoma, Hepatocellular , Cell Proliferation , Dynamins , Gene Expression Regulation, Neoplastic , Liver Neoplasms , Mitochondrial Dynamics , RNA, Circular , RNA-Binding Proteins , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Humans , RNA, Circular/genetics , RNA, Circular/metabolism , Mitochondrial Dynamics/genetics , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Dynamins/genetics , Dynamins/metabolism , Animals , Mice , Cell Line, Tumor , Apoptosis/genetics , Cell Proliferation/genetics , Cell Movement/genetics , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Male , Neoplasm Metastasis , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , GTP Phosphohydrolases/genetics , GTP Phosphohydrolases/metabolism , Mice, Nude , Mice, Inbred BALB CABSTRACT
Purpose: The prognosis of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) that are refractory to programmed cell death protein 1 (PD-1) immunotherapy is relatively poor. The salvage therapy was rarely investigated and urgently needed. Methods: We conducted a single center retrospective real-world study to explore the efficacy of cetuximab plus PD-1 inhibitors as salvage therapy in patients progressed from first-line immunotherapy. Results: In the present study, 28 eligible patients were included between October 2020 and May 2023. By the cut-off date (Sep 24th, 2023), the objective response rate (ORR) was 46.4% (95% CI, 29.5%-64.2%). Kaplan-Meier survival analysis revealed the median progression free survival (mPFS) in the study was 6.87 months (95% CI, 4.77-8.97 months), and median overall survival (mOS) was 9.67 months (95% CI, 4.79-14.55 months). Multivariate Cox regression analysis indicated that ECOG performance status and best response to salvage therapy was found to be the prognosis factor of salvage therapy. For the safety, the most common treatment related adverse events (TRAEs) were rash (72.1%), anemia (64.3%) and fatigue (46.5%) during the salvage therapy. The most common potential irAEs were hypothyroidism (25%), and pneumonitis (14.3%). Only 3 patients (10.7%) experienced grade 3 TRAEs, and no treatment-related deaths occurred. Conclusions: Our study showed the combination of cetuximab with PD-1 inhibitors might be a potential efficacy and safety choice in PD-1 refractory patients with R/M HNSCC which need further investigation.
ABSTRACT
Pembrolizumab with cisplatin and 5-fluorouracil showed survival benefit but relatively high occurrence of treatment-related adverse events (TRAEs) for recurrent/metastatic oral squamous cell carcinoma (R/M OSCC). A more tolerable regime is needed. This trial enrolled 20 R/M OSCC patients with previously untreated and PD-L1 positive. Patients were administered camrelizumab with docetaxel and cisplatin every 3 weeks for six cycles, followed by camrelizumab monotherapy every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was occurrence of grade ≥ 3 TRAEs, secondary endpoints included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). 45% patients experienced grade ≥ 3 TRAEs, which the most common were anemia (15%), stomatitis (15%), and neutropenia (10%). The most common potential immune-related adverse events were reactive cutaneous capillary endothelial proliferation (RCCEP; 60%), hypothyroidism (35%), and pneumonitis (15%). No treatment-related deaths occurred. The median OS, PFS, and ORR was 14.4 months, 5.35 months, and 40.0% respectively. The study also found RCCEP occurrence, lower FOXP3+ cells, and higher density of intratumor tertiary lymphoid structure were associated with improved efficacy. Our data suggest that camrelizumab with docetaxel/cisplatin as first-line therapy was well tolerable and had potentially favorite efficacy in PD-L1-positive patients with R/M OSCC.
