Comparative efficacy and safety of PD-1/PD-L1 Inhibitors versus platinum-based chemotherapy for the first-line treatment of advanced non-small cell lung cancer: a meta analysis of randomized controlled trials.

OBJECTIVE: The main aim of this study was to systematically evaluate the efficacy and safety of inhibitors of programmed cell death receptor 1 (PD-1) and its ligand, programmed cell death ligand-1 (PD-L1), in the treatment of advanced non-small cell lung cancer (NSCLC). METHODS: Randomized controlled trials assessing the efficacy of PD-1/PD-L1 inhibitors relative to platinum-based chemotherapy for advanced NSCLC in PubMed, EMBASE, and Cochrane libraries from 2015 to 2020 were searched, along with review of studies at American Society of Clinical Oncology (ASCO) and European society for Medical Oncology (ESMO). Pooled hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS) and odds ratios (OR) for adverse events (AE) were calculated using STATA and Revman software. RESULTS: PD-1/PD-L1 inhibitors alone or combined with chemotherapy significantly improved OS (HR = 0.82, 95% CI:0.74-0.91, P = 0.01 or HR = 0.74, 95% CI:0.67-0.82, P = 0.001). PD-1/PD-L1 inhibitors alone did not benefit PFS (HR = 0.99, 95% CI: 0.89-1.10, P = 0.892), while combination therapy led to prolonged PFS (HR = 0.61, 95% CI: 0.56-0.67, P < 0.001). Subgroup analysis showed that in NSCLC with PD-L1 ≥ 50%, treatment with PD-1/PD-L1 inhibitors alone significantly improved both PFS and OS. In patients subjected to the combined treatment regimen, we observed significant differences in PFS among groups stratified by PD-L1 expression (p < 0.001), immune drug type (p = 0.029), gender (p = 0.014) and liver metastasis (p = 0.035) and OS among groups stratified by immune drug type (p < 0.001), gender (P = 0.001) and smoking status (P = 0.041). Safety analysis showed that combination therapy increased chemotherapy-induced adverse events (AE), while PD-1/PD-L1 inhibitors alone were associated with a lower incidence of any grade of treatment-related AEs (TRAE). A higher incidence of Grade 3-5 TRAEs and hypothyroidism was observed with PD-1 inhibitors than PD-L1 inhibitors. CONCLUSIONS: First-line treatment of advanced NSCLC with immune monotherapy or immunochemotherapy confers a greater survival benefit than chemotherapy alone. Combination of chemotherapy with PD-1/PD-L1 inhibitors leads to an increase in adverse events, and PD-1 inhibitors offer enhanced survival benefits and fewer adverse events than PD-L1 inhibitors. Remarkably, female patients undergoing combination therapy had longer overall survival than male patients.

Effects of pamidronate disodium on the loss of osteoarthritic subchondral bone and the expression of cartilaginous and subchondral osteoprotegerin and RANKL in rabbits.

BACKGROUND: Osteoarthritis (OA) is a major health problem in the increasingly elderly population. Therefore, it is crucial to prevent and treat OA at an early stage. The present study investigated whether pamidronate disodium (PAM), a bone-loss inhibitor, can significantly prevent or reverse the progression of early anterior cruciate ligament transection (ACLT)-induced OA. Whether therapeutic intervention is associated with regulation of the expression of osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL), metalloproteinase-9 (MMP-9) or Toll-like receptor-4 (TLR-4) in cartilage and/or subchondral bone was also investigated. METHODS: 60 New Zealand rabbits were randomized into four groups: Sham-operated (n = 20); ACLT (n = 20); short-term treatment with PAM (PAM-S, n = 10) and long-term treatment with PAM (PAM-L, n = 10). For cartilage and subchondral bone testing, rabbits from Sham and ACLT groups were harvested at 2, 4, 6, and 14 weeks. Rabbits were given PAM from the 4th week after ACLT operation in PAM-S and PAM-L group, and were harvested at 6 and 14 weeks, respectively. Trabecular characteristics and cartilage changes were detected using Micro-CT, safranin O and rapid green staining, respectively. Immunohistochemical staining for OPG and RANKL were also performed. OPG, RANKL, MMP-9 and TLR-4 expression was evaluated by western blot analysis. RESULTS: Micro-CT and histology analyses indicated that PAM treatment for 2 or 10 weeks could completely prevent or reverse osteoarthritic subchondral bone loss and cartilage surface erosion. Immunohistochemistry and western blot analysis indicated that expression of OPG and RANKL increased, although RANKL expression increased more significantly than that of OPG. Therefore the ratio of OPG to RANKL was lower in the ACLT group. However, the ratio of OPG to RANKL in the PAM group was significantly higher than that in the ACLT group. Additionally, expression of MMP-9 and TLR-4 were upregulated in the ACLT group and downregulated in the PAM treated groups. CONCLUSIONS: PAM can significantly inhibit and even reverse early osteoarthritic subchondral bone loss, thus alleviating the process of cartilaginous degeneration. The mechanisms involved may be associated with the upregulation of OPG expression, and downregulation of RANKL, MMP-9 and TLR-4 expression.

Effect of CD44st and HER2 expression on the postoperative prognosis of breast cancer patients.

OBJECTIVE: CD44st is a member of the CD44 family; abnormal expression of some CD44 isoforms are closely associated with axillary lymph node metastasis, cancer progression, and patients' prognosis. The objective of this study is to investigate the correlation between the expression of CD44st and HER2 in breast cancer and the effect on patients' prognosis. METHODS: Primers were designed to target the CD44st mRNA (Gene Bank No FJ216964) which has been newly identified in a drug-resistant breast cancer cell line. The expression of CD44st and HER2 mRNA and proteins in cancerous and paracancerous tissue of postoperative breast cancer patients was detected and compared. Tissue samples were obtained from 102 cases of invasive ductal carcinoma, 19 cases of intraductal carcinoma, and 11 cases of medullary carcinoma. The correlation between CD44st and HER2 expression and clinical pathological features was examined. RESULTS: The expression rate of CD44st mRNA and protein in breast cancer tissue was 64.4% (85/132), while HER2 mRNA and protein was expressed in 22.0% (29/106) of the samples. The expression of CD44st and HER2 were low in paracancerous tissue. In breast cancer tissue, the expression rate of HER2 mRNA and protein in the CD44st-positive group was 28.2% (24/85), and 10.6% (5/47) in the CD44st-negative group. This difference was statistically significant (P=0.015). Sequencing analysis showed that the amplified CD44st gene in this study was the same as that which was previously discovered in the drug-resistant breast cancer cell line. A linear correlation was found between the expression of CD44st and HER2 (r=0.972, r2=0.945, F=2,213.51, P<0.001). The expression of CD44st and HER2 was also closely associated with luminal cancer subtypes, lymph node metastasis, and TNM stage (P<0.05), but not associated with age, pathological type, or tumor size (P>0.05). The median overall survival in the CD44st high-expression group was 51.85 months (95% CI: 48.48-55.22), which was significantly shorter than that in the CD44st low-expression group (57.61 months; 95% CI: 55.54-59.68, P=0.032). CONCLUSION: CD44st is closely related to the expression of HER2. The expression of CD44st affects patient prognosis and is associated with lymph node metastasis, TNM staging, and molecular subtyping.

Expression of Novel CD44st and MMP2 in NSCLC Tissues and Their Clinical Significance.

BACKGROUND: Abnormal expression of some CD44 molecules in tumor tissues can induce the degradation of the extracellular matrix, and is closely associated with axillary lymph node metastasis, angiogenesis, cancer progression, and drug resistance. PATIENTS AND METHODS: We measured and confirmed the expression of CD44st and MMP2 mRNAs and proteins in the cancer tissues and adjacent normal tissues of postoperative non-small cell lung cancer (NSCLC) patients with either adenocarcinoma (n = 72) or squamous cell carcinoma (n = 53) using quantitative reverse transcription polymerase chain reaction, gene sequencing, and immunohistochemical analysis. RESULTS: CD44st and MMP2 expression were closely associated with the histopathological classification, lymph node metastasis, and TNM stage of the tumors, and the difference was statistically significant (p < 0.05). The median overall survival (OS) for the high CD44st expression group was 30.52 months (95% confidence interval (CI) 24.02-36.15); for the low expression group it was 43.23 months (95% CI 31.81-52.02) (p = 0.020). The median OS for the high MMP-2 expression group was 30.53 months (95% CI 26.69-33.31); for the low expression group it was 40.06 months (95% CI 33.55-46.45) (p = 0.022). CONCLUSION: The rates of CD44st and MMP2 expression were higher in squamous cell carcinomas than in adenocarcinomas, were closely associated with lymph node metastasis and TNM stage, and affected patients' prognoses.