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Perioperative chemotherapy is the standard treatment for locally advanced gastric or gastro-esophageal junction cancer, and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. In this randomized, open-label, phase 2 study (NEOSUMMIT-01), patients with resectable gastric or gastro-esophageal junction cancer clinically staged as cT3-4aN + M0 were randomized (1:1) to receive either three preoperative and five postoperative 3-week cycles of SOX/XELOX (chemotherapy group, n = 54) or PD-1 inhibitor toripalimab plus SOX/XELOX, followed by toripalimab monotherapy for up to 6 months (toripalimab plus chemotherapy group, n = 54). The primary endpoint was pathological complete response or near-complete response rate (tumor regression grade (TRG) 0/1). The results showed that patients in the toripalimab plus chemotherapy group achieved a higher proportion of TRG 0/1 than those in the chemotherapy group (44.4% (24 of 54, 95% confidence interval (CI): 30.9%-58.6%) versus 20.4% (11 of 54, 95% CI: 10.6%-33.5%)), and the risk difference of TRG 0/1 between toripalimab plus chemotherapy group and chemotherapy group was 22.7% (95% CI: 5.8%-39.6%; P = 0.009), meeting a prespecified endpoint. In addition, a higher pathological complete response rate (ypT0N0) was observed in the toripalimab plus chemotherapy group (22.2% (12 of 54, 95% CI: 12.0%-35.6%) versus 7.4% (4 of 54, 95% CI: 2.1%-17.9%); P = 0.030), and surgical morbidity (11.8% in the toripalimab plus chemotherapy group versus 13.5% in the chemotherapy group) and mortality (1.9% versus 0%), and treatment-related grade 3-4 adverse events (35.2% versus 29.6%) were comparable between the treatment groups. In conclusion, the addition of toripalimab to chemotherapy significantly increased the proportion of patients achieving TRG 0/1 compared to chemotherapy alone and showed a manageable safety profile. ClinicalTrials.gov registration: NCT04250948 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: Hyperfibrinogenemia is associated with unfavorable prognosis and advanced tumor behavior in various malignancies, including esophageal squamous cell carcinoma (ESCC). However, its biological function in ESCC is unknown. The present study was designed to further validate the prognostic value of preoperative plasma hyperfibrinogenemia and evaluate the biological role of fibrinogen, as well as the underlying mechanism in ESCC., Methods: Data from 452 cases with newly diagnosed ESCC followed by curative surgery between 2006 and 2010 were retrospectively evaluated. The Clauss method was utilized to measure the preoperative plasma fibrinogen level. Correlations between the fibrinogen level and clinicopathologic characteristics and survival analysis were performed. The effects of fibrinogen on malignant behaviors, including tumor cell viability, colony formation, migration, and invasion, were also investigated., Results: The optimal cut-off value for plasma fibrinogen level was defined as 4.0 g/L according to recommendations. Thus, the proportion of hyperfibrinogenemia was 24.8% (112/452). Preoperative plasma hyperfibrinogenemia was significantly associated with advanced tumor length, deep tumor invasion, advanced tumor-node-metastasis stage, alcohol consumption, a higher white blood cell count, a higher platelet count, and high globulin levels. Univariate survival analysis revealed that compared to those with normal plasma fibrinogen levels, patients with hyperfibrinogenemia tended to have poorer disease-free survival (DFS) [hazard ratio (HR), 1.692; 95% confidence interval (CI), 1.304-2.196; P < 0.001] and overall survival (OS) (HR 1.864; 95% CI 1.424-2.440; P < 0.001). In the multivariate Cox regression models, these factors remained independent predictors for impaired DFS (HR 1.491; 95% CI 1.138-1.955; P = 0.004) and OS (HR 1.648; 95% CI 1.246-2.180; P < 0.001) after adjusting for other confounding variables. In addition, fibrinogen could significantly promote cell migration and invasion but not proliferation. Moreover, it could also induce epithelial-mesenchymal transition (EMT) and increase the levels of p-PTEN, p-AKT, and p-mTOR in ESCC cell lines., Conclusions: Preoperative plasma hyperfibrinogenemia might serve as an independent predictor of unfavorable survival in ESCC. Furthermore, fibrinogen may promote cell motility by inducing EMT via the p-AKT/p-mTOR pathway.

Cisplatin and nedaplatin show significant antitumor activity and have been widely used for esophageal squamous cell carcinoma (ESCC). However, it is still unclear whether the efficacy and safety of nedaplatin-based regimens are comparable to those of cisplatin-based regimens in patients with metastatic/recurrent or advanced ESCC. Therefore, we conducted a systematic review and meta-analysis to compare the efficacy and safety of these two regimens for the treatment of metastatic/recurrent and advanced ESCC. We systematically searched Pubmed, Web of Science, and the Cochrane Database, as well as abstracts presented at conferences (all up to January 2015), for randomized-controlled and nonrandomized clinical trials that compared cisplatin-based and nedaplatin-based regimens in patients with metastatic/recurrent or advanced ESCC. Data were extracted from the original studies by two independent reviewers. This meta-analysis was performed using Review Manager (RevMan) Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) software. Ten eligible trials, including 598 patients diagnosed with metastatic/recurrent or advanced ESCC, were included in our analysis. Our results demonstrated that the nedaplatin-based regimens were comparable to the cisplatin-based regimens in terms of overall survival (OS) (hazard ratio, HR: 1.22, 95% confidence interval, CI: 0.86-1.74, p = 0.26) and overall response rate (ORR) (risk ratio, RR: 0.92, 95% CI: 0.77-1.10, p = 0.37) and generated fewer grade 3 and 4 side effects including nausea (RR: 3.41, 95% CI: 1.67-6.96, p < 0.001) and vomiting (RR: 3.62, 95% CI: 1.77-7.40, p < 0.001) and fewer grade 1 and 2 adverse events including nausea (RR: 1.54, 95% CI: 1.23-1.93, p < 0.001), vomiting (RR: 1.76, 95% CI: 1.76-2.30, p < 0.001), peripheral neuropathy (RR: 1.75, 95% CI: 1.08-2.84, p = 0.02) and renal dysfunction (creatinine) (RR: 3.28, 95% CI: 1.37-7.84, p = 0.008). This systematic review and meta-analysis indicated that the efficacy of nedaplatin-based regimens was comparable to that of cisplatin-based regimens for patients with metastatic/recurrent or advanced ESCC, and that nedaplatin-based regimens were associated with less toxicity and better tolerability. However, this study was a meta-analysis of previously released data; therefore, there is a potential publication bias and heterogeneity among the included trials. Future, well-designed RCTs with large cohorts are warranted., (© 2016 International Society for Diseases of the Esophagus.)

This study retrospectively investigated the prognostic significance of the preoperative albumin-globulin score (AGS) and albumin/globulin ratio (AGR) in esophageal squamous cell carcinoma (ESCC). A cohort of 458 newly diagnosed ESCC patients who underwent radical esophagectomy in Sun Yat-sen University Cancer Center (Guangzhou, China) between January 2006 and December 2010 were selected into this study. The optimal cut-off value was identified to be 45.6 g/L, 26.9 g/L and 1.30 for albumin (ALB), globulin (GLB) and AGR in terms of survival, respectively. Patients with low ALB levels (< 45.6 g/L) and high GLB levels (≥ 26.9 g/L) were assigned an AGS of 2, those with only one of the two abnormalities were assigned an AGS of 1, and those with neither of the two abnormalities were assigned an AGS of 0. Univariate survival analysis showed that low AGS (0) was significantly associated with favorable disease free survival (DFS) [hazard ratio (HR), 0.635; 95% confidence interval (CI), 0.441-0.914; P = 0.015] and overall survival (OS) (HR, 0.578; 95% CI, 0.387-0.862; P = 0.007), and it remained an independent predictor for OS (HR, 0.630; 95% CI, 0.418-0.952; P = 0.028), but not for DFS (HR, 0.697; 95% CI, 0.479-1.061; P = 0.060) in multivariate models. High AGR (≥ 1.30) was also correlated with favorable DFS (HR, 0.626; 95% CI, 0.430-0.910; P = 0.014) and OS (HR, 0.622; 95% CI, 0.422-0.916; P = 0.016) in univariate analysis, but it failed to be an independent prognostic indicator for DFS (HR, 0.730; 95% CI, 0.494-1.078; P = 0.114) or OS (HR, 0.759; 95% CI, 0.507-1.137; P = 0.181) by multivariate analysis. Low preoperative AGS could serve as a valuable and convenient biochemical marker to predict favorable long-term survival in ESCC patients., Competing Interests: The authors declared that they have no potential conflicts of interest.

The elevation of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) has been demonstrated to predict worse prognosis in various malignancies; however, their prognostic value in esophageal squamous cell carcinoma has not been well studied. We conducted a retrospective study of 906 patients with esophageal squamous cell carcinoma to explore their prognostic value for overall survival. The optimal cutoff points for ALP and LDH were determined. We analyzed the association between the levels of ALP and LDH and clinicopathological characteristics. Their prognostic value for overall survival was explored by univariate and multivariate analysis. We also proposed the ALP and LDH classification and examined its prognostic value in the general population and subgroups. The optimal cutoff points of ALP and LDH to predict overall survival were 90.7 and 361.5 U/L respectively. Higher levels of ALP and LDH were both associated with more advanced TNM stage (P = 0.003 and 0.002, respectively) and more distant metastasis (P = 0.001 and P < 0.001, respectively). Both ALP (≤90.7/>90.7 U/L) and LDH (≤361.5/>361.5 U/L) were independent prognostic factors for overall survival in esophageal squamous cell carcinoma (P = 0.004 and P < 0.001 by multivariate analysis). The ALP and LDH classification categorized patients into three subgroups with distinct prognosis (P < 0.001 by multivariate analysis) and identified a small group of patients who had extremely poor overall survival with a median of 4.2 months. In conclusion, ALP and LDH were both independent prognostic factors for overall survival. A combination of the two indexes might contribute to further identification of survival differences in esophageal squamous cell carcinoma.

Background: Plenty of studies have demonstrated the prognostic value of various inflammation-based indexes in cancer. This study was designed to investigate the prognostic value of the C-reactive protein/albumin (CRP/Alb) ratio in esophageal squamous cell carcinoma., Methods: A retrospective study of 423 cases with newly diagnosed esophageal squamous cell carcinoma was conducted. We analyzed the association of the CRP/Alb ratio with clinicopathologic characteristics. The prognostic value was explored by univariate and multivariate survival analysis. In addition, we compared the discriminatory ability of the CRP/Alb ratio with other inflammation-based prognostic scores by evaluating the area under the receiver operating characteristics curves (AUC), including the modified Glasgow Prognostic Score (mGPS), neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR)., Results: The optimal cut-off value was identified to be 0.095 for the CRP/Alb ratio. A higher level of the CRP/Alb ratio was associated with larger tumor size (P < 0.001), poorer differentiation (P = 0.019), deeper tumor invasion (P = 0.003), more lymph node metastasis (P = 0.015), more distant metastasis (P <  .001) and later TNM stage (P < 0.001). The CRP/Alb ratio was identified to be the only inflammation-based prognostic score with independent association with overall survival by multivariate analysis (P = 0.031). The AUC value of the CRP/Alb ratio was higher compared with the NLR and PLR, but not mGPS at 6, 12 and 24 months of follow-up. In addition, the CRP/Alb ratio could identify a group of patients with mGPS score of 0 who had comparable overall survival with those with mGPS score of 1., Conclusions: The CRP/Alb ratio is a novel but promising inflammation-based prognostic score in esophageal squamous cell carcinoma. It is a valuable coadjutant for the mGPS to further identify patients' survival differences.

Background: Primary small cell carcinoma of the esophagus (SCCE) is characterized as highly aggressive with a poor prognosis. To identify potential prognostic factors and to assess the role of surgical procedures, chemotherapy, and radiotherapy for SCCE, we retrospectively analyzed patients with SCCE from three large institutions in China., Methods: All of the SCCE patients between 1998 and 2012 were identified from three clinical databases of the Sun Yat-Sen University Cancer Center, Peking Union Cancer Hospital and Shantou Cancer Hospital. Potential prognostic factors were analyzed with univariate analysis and a Cox regression model. Subgroup analysis based on the 2002 American Joint Committee on Cancer staging system for esophageal cancer was applied to examine the effect of treatment on survival., Results: In patients with stage I/II SCCE, 85% underwent operations and showed improved survival (median survival time [MST] 29 vs 17.4 months, p = 0.082). However, chemotherapy did not further improve survival. In patients with stage IIB/III SCCE, chemotherapy, instead of operation, improved survival (MST 13.0 vs 6.1 months, p = 0.003), and radiotherapy resulted in improved survival. In stage IV patients, chemotherapy improved survival (MST 12.5 vs 4.0 months, p < 0.001), and chemotherapy combined with radiotherapy was superior to chemotherapy alone (MST 13.2 vs 8.9 months, p = 0.014)., Conclusions: Surgical procedures alone can be recommended for stage I/IIA patients. In patients with stage IIB disease or above, chemotherapy should be the main treatment approach, and chemotherapy combined with radiotherapy tended to improve survival., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Primary small cell carcinoma of the esophagus (SCCE) is a highly aggressive disease characterized by early dissemination and poor prognosis. Because of the rarity of this disease, few previous studies have investigated the biomarkers associated with its prognosis. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) is a stem cell marker and a member of the canonical Wnt-signaling cascade. However, the clinical role of Lgr5 in SCCE remains unknown., Methods: Tissue sections were obtained from 44 patients diagnosed with SCCE and expression of Lgr5 was examined by immunohistochemistry. The correlations between Lgr5 expression, and clinical parameters and prognostic significance were evaluated., Results: Lgr5 was expressed in SCCE cancer tissues. High Lgr5 expression was significantly correlated with lymph node metastasis (p = 0.003), late stage (p = 0.003) and unfavorable response to chemotherapy (p = 0.013) according to RECIST 1.0 criteria. Patients with higher Lgr5 expression levels had shorter overall survival times than those with lower expression levels., Conclusions: These results demonstrated that overexpression of Lgr5 was significantly correlated with lymph node metastasis, tumor stage, and response to chemotherapy. Furthermore, high levels of Lgr5 expression appeared to be associated with poorer survival in patients with SCCE.

Background and Objective: Various factors affect the radioresistance of tumor cells, with unknown molecular mechanism(s). Many genes have been found to associate with the radioresistance of tumor cells, however, the precise mechanism of these genes have not been elucidated. This paper was to analyze the differential expressions of DNA repair genes in esophageal carcinoma cells at different time after X-ray irradiation, and to investigate the role of these DNA repair genes in radiation resistance., Methods: Esophageal cancer parental cells Seg-1 were treated with continuous 2 Gy of fractionated irradiation until the total dose reached 60 Gy to establish the radioresistant cell line Seg-1R. Total RNA was extracted from each cell line at 0, 8, and 24 h after irradiation. Illumine Human-6 V3 microarray was used to identify differentially expressed genes between parental and radioresistant cells. Ten genes involved in DNA repair were obtained and their expressions at different time points after irradiation were analyzed by Gene Ontology analysis., Results: Ten DNA repair associated genes were found to be differentially expressed. Three of these genes, SLK, HMGB1, and PMS1, were not only differentially expressed between parental and radioresistant cell lines, but also expressed differently at different time points after irradiation in the same cell line., Conclusions: PMS1 may be an important factor involved in the mechanism of radioresistance of esophageal carcinoma cells.