First-line or second-line PD-1 inhibition in advanced oesophageal squamous cell carcinoma: A prospective, multicentre, registry study.

WHAT IS KNOWN AND OBJECTIVE: First-line and second-line immunotherapy with programmed death-1 (PD-1) inhibitors both improve overall survival in patients with advanced oesophageal squamous cell cancer (ESCC). This study explored survival differences between first-line and second-line PD-1 inhibition in advanced ESCC. METHODS: This registry study included 167 patients with advanced ESCC who were exposed to PD-1 inhibitors in either a first-line or a second-line setting between 15 January 2019 and 31 October 2020. The primary endpoint was overall survival, and secondary endpoints included overall tumour response, progression-free survival (PFS) and PFS2. A propensity score-matching (PSM) analysis was performed using the nearest-neighbour method. RESULTS AND DISCUSSION: Sixty-one patients started first-line treatment with chemotherapy and a PD-1 inhibitor (Group 1), while 106 started chemotherapy as the first-line choice and received a PD-1 inhibitor as the second-line choice (Group 2). The median PFS was 7.1 months in Group 1 and 4.1 months in Group 2 (log-rank p = 0.001). The median PFS2 was 7.1 months in Group 1 and 7.4 months in Group 2 (log-rank p = 0.4). Before PSM, the median overall survival was 13.5 months in Group 1 and 14.1 months in Group 2 (log-rank p = 0.9), and the sensitivity analysis showed consistent results (14.0 vs. 14.1 months). After PSM, the median overall survival rates for Group 1 (n = 61) and Group 2 (n = 61) were 13.5 and 13.1 months (log-rank p = 0.7) respectively. WHAT IS NEW AND CONCLUSION: In this study, patients with advanced ESCC who received first-line or second-line PD-1 inhibitors seemed to have comparable overall survival.

The prognostic value of preoperative serum lactate dehydrogenase levels in patients underwent curative-intent hepatectomy for colorectal liver metastases: A two-center cohort study.

BACKGROUND: The prognostic value of lactate dehydrogenase (LDH) in colorectal cancer patients has remained inconsistent between nonmetastatic and metastatic settings. So far, very few studies have included LDH in the prognostic analysis of curative-intent surgery for colorectal liver metastases (CRLM). PATIENTS AND METHODS: Five hundred and eighty consecutive metastatic colorectal cancer patients who underwent curative-intent CRLM resection from Sun Yat-sen University Cancer Center (434 patients) and Sun Yat-sen University Sixth Affiliated Hospital (146 patients) in 2000-2019 were retrospectively collected. Overall survival (OS) was the primary end point. Cox regression model was performed to identify the prognostic values of preoperative serum LDH levels and other clinicopathology variables. A modification of the established Fong CRS scoring system comprising LDH was developed within this Chinese population. RESULTS: At the median follow-up time of 60.5 months, median OS was 59.5 months in the pooled cohort. In the multivariate analysis, preoperative LDH >upper limit of normal (250 U/L) was the strongest independent prognostic factor for OS (HR 1.73, 95% confidence interval [CI], 1.22-2.44; p < 0.001). Patients with elevated LDH levels showed impaired OS than patients with normal LDH levels (27.6 months vs. 68.8 months). Five-year survival rates were 53.7% and 22.5% in the LDH-normal group and LDH-high group, respectively. Similar results were also confirmed in each cohort. In the subgroup analysis, LDH could distinguish the survival regardless of most established prognostic factors (number and size of CRLM, surgical margin, extrahepatic metastases, CEA, and CA19-9 levels, etc.). Integrating LDH into the Fong score contributed to an improvement in the predictive value. CONCLUSION: Our study implicates serum LDH as a reliable and independent laboratory biomarker to predict the clinical outcome of curative-intent surgery for CRLM. Composite of LDH and Fong score is a potential stratification tool for CRLM resection. Prospective, international studies are needed to validate these results across diverse populations.

[Study of sequence-dependent in vitro effects of zoledronic acid and paclitaxel upon human nasopharyngeal carcinoma cell line HNE1].

OBJECTIVE: To explore the in vitro effects of anti-proliferation and apoptosis-inducing with different sequence regimens of zoledronic acid plus paclitaxel in human nasopharyngeal carcinoma cell line HNE1 so as to explore the optimal sequence regimen of these two drugs and related mechanism. METHODS: The cytotoxic effects of different sequence schemes of zoledronic acid plus paclitaxel on HNE1 cells were detected by methyl-thiazol-tetrazolium (MTT) assay. Annexin V-FITC/PI double staining flow cytometry (FCM) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay were used to measure the effects of zoledronic acid plus paclitaxel upon apoptosis. The expressions of mRNA of Bcl-2, Bax, Caspase3 and Caspase9 gene were detected by real-time quantitative-polymerase chain reaction (PCR) and protein was detected by Western blot. RESULTS: All experiment groups enhanced the effect of anti-proliferation by MTT assay (P < 0.05); the treatment of zoledronic acid followed by paclitaxel was superior to the other two regimens (P < 0.05). As detected by FCM, the early apoptotic rate of control group was 2.59% ± 0.28% and the experiment groups were 13.89% ± 0.69%, 11.73% ± 0.54%, 23.97% ± 0.68%, 10.45% ± 0.16% and 8.59% ± 0.74% respectively (P < 0.05). TUNEL assay detected the late apoptosis of HNE1 cells and the experiment groups enhanced the effect of apoptosis-inducing (P < 0.05). The treatment of zoledronic acid followed by paclitaxel was superior to the other regimens (P < 0.05). Such an effect was due to the down-regulation of anti-apoptotic protein Bcl-2 and up-regulations of pro-apoptotic proteins Bax, Caspase3 and Caspase9 at the expression levels of mRNA and protein. There was a greater regulation in the group of zoledronic acid followed by paclitaxel. CONCLUSION: Zoledronic acid can enhance the in vitro effects of anti-proliferation and apoptosis-inducing for paclitaxel on HNE1 cell. The treatment of zoledronic acid followed by paclitaxel may be the optimal regimen. Synergistic induction of apoptosis is via the effects of Bcl-2 family and through the mitochondrial pathway.

Zoledronic acid inhibits human nasopharyngeal carcinoma cell proliferation by activating mitochondrial apoptotic pathway.

We investigated the apoptosis-inducing effect of zoledronic acid in human nasopharyngeal carcinoma cell HNE-1 and explore the potential mechanism. Human nasopharyngeal carcinoma cell HNE-1 was exposed to various concentrations (0-40 µmol/L) of zoledronic acid. Cell proliferation was studied by an MTT assay. Cell apoptosis was analyzed by flow cytometry and TdT-mediated dUTP nick-end labeling (TUNEL) assay. Cell cycle was analyzed by flow cytometry. Gene expressions were investigated by quantitative real-time PCR, and protein expressions were investigated by Western blot. The results showed zoledronic acid decreased cell proliferation not in a time- or dose-dependent fashion. TUNEL assay, together with Annexin V/propidium iodide FACS analysis, confirmed the increase in apoptotic HNE-1 cells treated with zoledronic acid. Cell cycle analysis showed a larger number of treated cells occupied the S-phase. Quantitative RT-PCR and Western blot revealed that the pro-apoptotic genes, Bad, Bax, and Caspase-9, were upregulated in treated HNE-1 cells, whereas the anti-apoptotic gene, Bcl-2, was downregulated in both mRNA and protein levels. In conclusion, zoledronic inhibits human nasopharyngeal carcinoma cell proliferation by inducing apoptosis via the mitochondrial apoptotic pathway.

Zoledronic acid inhibits proliferation and impairs migration and invasion through downregulating VEGF and MMPs expression in human nasopharyngeal carcinoma cells.

To demonstrate the effect of zoledronic acid in proliferation, invasion, and migration of human nasopharyngeal carcinoma cell HNE-1 and explore the potential role of VEGF, MMP-2, and MMP-9 proteins in vitro. Human nasopharyngeal carcinoma cell HNE-1 was exposed to various concentrations (0-40 µmol/l) of zoledronic acid. Zoledronic acid inhibited proliferation of HNE-1 cells though not in a dose-dependent manner. Zoledronic acid had exerted a dose-dependent effect on the migration and invasion of HNE-1 cells. Both expressions of mRNA and protein of MMP2, MMP9, and VEGF were reduced, respectively, detected by RT-PCR and Western blot assays. These data suggested that zoledronic acid not only inhibited growth but also invasion and migration of HNE-1 cells in vitro. The anti-cancer action of zoledronic acid was partially associated with the suppression of VEGF expression and secretion and downregulating the expression of MMP2 and MMP9.

[Inhibitory effects of zoledronic acid on cell proliferation and invasion in human nasopharyngeal carcinoma cell line HNE1].

OBJECTIVE: To explore the in vitro anti-tumor effects of zoledronic acid on cell proliferation and invasion in human nasopharyngeal carcinoma cell line HNE1. METHODS: The cytotoxic effects of zoledronic acid on HNE1 cells were detected by MTT assay, invasion of HNE1 cells by Transwell assay, secretion of (vascular endothelial growth factor)VEGF by (enzyme-linked immunosorbent assay) ELISA and the activities of MMP (matrix metalloproteinase) 2 and MMP9 by gelatine zymography. And the expressions of mRNA and proteins of MMP2, MMP9 and VEGF were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot respectively. RESULTS: After a treatment of zoledronic acid at 2.5, 5, 10, 20 and 40 mol/L for 48 h or 72 h, the highest inhibition rate of proliferation at approximately 50% was observed in the 40 mol/L group after 72 h. The inhibitory effect was not in a dose/time-dependent manner. After a 24-hour treatment of zoledronic acid at different concentrations (0, 10, 20 and 40 mol/L), the numbers of membrane-invading cells were 75.8 ± 2.6, 54.8 ± 5.4, 44.6 ± 6.4 and 38.6 ± 8.2 respectively (all P < 0.01). Gelatinase zymography demonstrated that the activities of MMP2 and MMP9 were inhibited significantly only in cells treated at 0 µmol/L. After a 24-hour exposure to zoledronic acid at 0, 10, 20 and 40 µmol/L, the concentrations of VEGF in supernatant were (5264 ± 89), (4626 ± 30), (4155 ± 40) and (1908 ± 171) g/L respectively (all P < 0.01). The expressions of mRNA and protein of MMP2, MMP9 and VEGF were down-regulated. CONCLUSION: Zoledronic acid can inhibit the in vitro proliferation and invasion of HNE1 cell through suppressing the secretion of VEGF, the activities of MMP2 and MMP9 and the expressions of VEGF, MMP2 and MMP9.