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Tertiary lymphoid structures (TLSs) were associated with survival in esophageal squamous cell carcinoma (ESCC) undergoing surgery alone (SA). However, their clinical relevance in neoadjuvant therapies remains less known. Here, we firstly investigated the presence, maturation and spatial distribution of TLSs in 359 ESCC patients receiving neoadjuvant chemotherapy (NCT), neoadjuvant immunotherapy (NCI), neoadjuvant chemoradiotherapy (NCRT) or SA. We found mature TLS (MTLS) was an independent prognostic factor in ESCC. NCI group had the lowest immature TLS cases. NCRT group had the lowest MTLSs. MTLSs mostly located in stromal and normal compartments; these MTLSs were positively correlated with neoadjuvant therapy outcomes. NCI group displayed the highest T cells within 150 μm proximity of TLSs among the four groups. Most T cells were dispersed up to more than 150 μm from TLSs, while B cells remained concentrated within TLSs. Innate lymphoid cells and follicular dendritic cells infiltrated and connected with survival differently in NCRT and NCI groups compared with SA group. The novel PD-L1 combined positive score, NCPS, was positively connected with MTLSs and neoadjuvant therapy efficacy. ScRNA-seq analysis revealed TLS+ tumors had increased plasma cells, B cells, Th17, Tfh and Th1, and elevated exhausted CD8 + T cells that highly expressed checkpoint molecules and granzymes. Conclusively, MTLSs favored treatment outcome in ESCC patients receiving multiple neoadjuvant therapies. The spatial distribution of MTLSs was associated with multiregional immune status modified by the neoadjuvant therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The average five-year survival rate for esophageal cancer, a common malignant tumor of the digestive system, is barely 20%. The majority of esophageal squamous cell carcinoma (ESCC) patients had already progressed to a locally advanced or even advanced stage at initial diagnosis, making routine surgery ineffective. Chemotherapy and immunotherapy are important neoadjuvant treatments for ESCC, however, it remains unknown how treatment will affect the immunological microenvironment, especially at the spatial level. Here, we presented the TME characters of ESCC from the temporal and spatial dimensions using scRNA-seq and ST, investigated the changes of immune cell clusters in the TME under neoadjuvant chemotherapy and preoperative immunotherapy, and explored the potential mechanisms. It was found that compared with chemotherapy, immunotherapy combined with chemotherapy increased the level of T cell proliferation, partially restored the function of exhausted T cells, induced the expansion of specific exhausted CD8 T cells, increased the production of dendritic cells (DCs), and supported the immune hot microenvironment of the tumor. We also found that CD52 and ID3 have potential as biomarkers of ESCC. Particularly, CD52 may be served as a predictor of the efficacy to screen the advantaged population of different regimens. Through multiple pathways, CAF2 and CAF5's antigen-presenting role affected the other fibroblast clusters, resulting in malignant transformation. We analyzed the immune microenvironment differences between the two regimens to provide a more thorough description of the ESCC microenvironment profile and serve as a foundation for customized neoadjuvant treatment of ESCC., (© 2024. The Author(s).)

To evaluate the efficacy and postoperative complications of endoscopic thoracoscopic and laparoscopic radical esophagectomy compared to open surgery in esophageal cancer treatment. This retrospective study included 103 esophageal cancer patients admitted from August 2018 to March 2022, divided into observation (endoscopic surgery) and control (open surgery) groups. We compared intraoperative parameters, postoperative outcomes, immune function, and one-year overall survival (OS). Intraoperative bleeding volume, the retention time of chest tube, postoperative fasting time, and hospital stay in the observation group were smaller than those in the control group (P < .05). The differences were not statistically significant (P > .05) when comparing operative time, the number of intraoperative blood transfusion cases, and the rate of operating room extubation in these 2 groups. The differences were not statistically significant when comparing the amount of resected lymph nodes and the positive rate of incisal edge in these 2 groups (P > .05). There was no statistically significant difference in the complication rates such as pneumonia, pleural effusion, pneumothorax, pulmonary embolism, anastomotic fistula, the leakage of thoracic duct, the injury of RLN and arrhythmia in these 2 groups (P > .05). At 7 days postoperatively, the CD4+ and CD4+/CD8+ in the observation group and the control group were smaller than the preoperative ones in their same groups, and they were larger in the observation group than those in the control group (P < .05); There was no statistically significant difference on the CD8+ in the observation group and the control group at 7 days postoperatively compared with the preoperative ones in their same groups (P > .05). The 1-year postoperative OS rate was 81.63% (40/49) in the observation group and 72.22% (39/54) in the control group, and the difference was not statistically significant when comparing the OS rates of these 2 groups (P = .238, HR = 0.622, 95% CI = 0.279-1.385). Endoscopic thoracoscopic and laparoscopic esophagectomy offers less invasive treatment with significant short-term benefits and better preservation of immune function in esophageal cancer patients, making it a safe and effective surgical option., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Ubiquitin-specific protease 4 (USP4) represents a potential oncogene involved in various human cancers. Nevertheless, the biological roles and precise mechanism of USP4 in esophageal squamous cell carcinoma (ESCC) progression are not understood. Here, USP4 expression was found to be markedly upregulated in ESCC tumor tissues and cells. Loss- and gain-of-function assays suggested that USP4 silencing inhibited ESCC cell proliferation, migration, and invasion, while USP4 overexpression promoted these behaviors. Consistently, USP4 silencing repressed tumor growth and metastasis in an ESCC nude mouse model in vivo. As a target molecule of USP4, transforming growth factor-β-activated kinase 1 (TAK1) also showed high expression in ESCC. Moreover, we observed that USP4 specifically interacted with TAK1 and stabilized TAK1 protein levels via deubiquitination in ESCC cells. Importantly, USP4 promotes ESCC proliferation, migration, and invasion via the MEK/ERK signaling pathway and can be inhibited by U0126. Neutral red (NR), an inhibitor of USP4 can suppress ESCC progression in vitro and in vivo. Overall, this study revealed that USP4/TAK1 plays crucial roles in ESCC progression by modulating proliferation, migration, and invasion, and USP4 might be a potential therapeutic target in ESCC., (© 2023. The Author(s).)

Background: The spatial distribution of tumor-infiltrating T cells and its dynamics during chemoradiotherapy combined with PD-1 blockade is little known in esophageal squamous cell carcinoma (ESCC)., Methods: We applied the multiplex immunofluorescence method to identify T cells (CD4 + , CD8 + T cells, and their PD-1 - or PD-1 + subsets) and myeloid-derived cells (CD11c + dendritic cells, CD68 + macrophages, and their PD-L1 + subpopulations) in paired tumor biopsies ( n = 36) collected at baseline and during combination (40 Gy of radiation) from a phase Ib trial (NCT03671265) of ESCC patients treated with first-line chemoradiotherapy plus anti-PD-1 antibody camrelizumab. We used the FoundationOne CDx assay to evaluate tumor mutational burden (TMB) in baseline tumor biopsies ( n = 14). We dynamically assessed the nearest distance and proximity of T-cell subsets to tumor cells under combination and estimated the association between T-cell spatial distribution and combination outcome, myeloid-derived subsets, TMB, and patient baseline characteristics., Findings: We found that the tumor compartment had lower T-cell subsets than the stromal compartment but maintained a comparable level under combination. Both before and under combination, PD-1 - T cells were located closer than PD-1 + T cells to tumor cells; T cells, dendritic cells, and macrophages showed the highest accumulation in the 5-10-μm distance. Higher CD4 + T cells in the tumor compartment and a shorter nearest distance of T-cell subsets at baseline predicted poor OS. Higher baseline CD4 + T cells, dendritic cells, and macrophages were associated with worse OS in less than 10-μm distance to tumor cells, but related with better OS in the farther distance. Higher on-treatment PD-1-positive-expressed CD4 + and CD8 + T cells within the 100-μm distance to tumor cells predicted longer OS. T cells, dendritic cells, and macrophages showed a positive spatial correlation. Both high TMB and smoking history were associated with a closer location of T cells to tumor cells at baseline., Conclusions: We firstly illustrated the T-cell spatial distribution in ESCC. Combining chemoradiotherapy with PD-1 blockade could improve the antitumor immune microenvironment, which benefits the treatment outcome. Further understanding the precision spatiality of tumor-infiltrating T cells would provide new evidence for the tumor immune microenvironment and for the combination treatment with immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yan, Huang, Zheng, Ma, Zhao, Zhang, Chen, Cao, Wei, Dong, Tang, Jiang, Wang, Wang, Pang and Zhang.)

Background: PTPRF interacting protein alpha 1 (PPFIA1) is reportedly related to the occurrence and progression of several kinds of malignancies. However, its role in esophageal squamous cell carcinoma (ESCC) is unclear. This current study investigated the prognostic significance and biological functions of PPFIA1 in ESCC., Methods: Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), and Gene Expression Omnibus (GEO) were used to investigate PPFIA1 expression in esophageal cancer. The relationship between PPFIA1 expression and clinicopathological characteristics and patient survival was evaluated in GSE53625 dataset, and verified in the cDNA array based on qRT-PCR and tissue microarray (TMA) dataset based on immunohistochemistry. The impact of PPFIA1 on the migration and invasion of cancer cells were investigated by wound-healing and transwell assays, respectively., Results: The expression of PPFIA1 was obviously increased in ESCC tissues versus adjacent esophageal tissues according to online database analyses (all P < 0.05). High PPFIA1 expression was closely related to several clinicopathological characteristics, including tumor location, histological grade, tumor invasion depth, lymph node metastasis, and tumor-node-metastasis (TNM) stage. High PPFIA1 expression was related to worse outcomes and was identified as an independent prognostic factor of overall survival in ESCC patients (GSE53625 dataset, P = 0.019; cDNA array dataset, P < 0.001; TMA dataset, P = 0.039). Downregulation of PPFIA1 expression can significantly reduce the migration and invasion ability of ESCC cells., Conclusion: PPFIA1 is related to the migration and invasion of ESCC cells, and can be used as a potential biomarker to evaluate the prognosis of ESCC patients., (© 2023. The Author(s).)

Background: Esophageal squamous cell carcinoma (ESCC) has a dismal prognosis, and hypoxia plays a key role in metastasis and proliferation of ESCC. Thus, we aimed to develop a hypoxia-based gene signature to assist in the treatment decisions and prognosis., Methods: We performed consensus clustering analysis on samples from GSE53625 dataset from the Gene Expression Omnibus (GEO) database and used weighted gene co-expression network analysis to filter out candidate modules, which were then intersected with differentially expressed genes from clustered subgroups to obtain hypoxia-related genes (HRGs). After that, the aforementioned genes were used to construct risk score models and validated in The Cancer Genome Atlas (TCGA) database and Cox regression analysis were used to construct a nomogram. Immunohistochemical was used to detect protein expression levels of relevant genes. Moreover, the relationship between risk scores and tumor microenvironment was explored., Results: A hypoxia risk model containing six genes (PNPLA1, CARD18, IL-18, SLC37A2, ADAMTS18, and FAM83C) was constructed by screening key HRGs. Poorer prognosis in the high-risk group than in the low-risk group. And Cox regression analysis showed that risk score was an independent prognostic factor. The nomogram based on risk scores could well predict 1-, 3-, and 5-year survival. P53, Wnt, and hypoxia signaling pathways may be some regulatory mechanisms of hypoxia associated with the tumor microenvironment. In addition, we confirmed the high expression of BGN and low expression of IL-18 in ESCC tissues., Conclusions: Our study determined the prognostic value of a 6-hypoxia gene signature and a prognostic model, providing potential prognostic predictors and therapeutic targets for ESCC., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Patients with esophageal squamous cell carcinoma (ESCC) with lymph node metastasis may be misclassified as pN0 due to an insufficient number of lymph nodes examined (LNE). The purpose of this study was to confirm that patients with ESCC are indeed pN0 and to propose an adequate number for the correct nodal stage using the nodal staging score (NSS) developed by the beta-binomial model., Methods: A total of 1249 patients from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2017, and 1404 patients diagnosed with ESCC in our database between 2005 and 2018 were included. The NSS was developed to assess the probability of pN0 status based on both databases. The effectiveness of NSS was verified using survival analysis, including Kaplan-Meier curves and Cox models., Results: Many patients were misclassified as pN0 based on our algorithm due to insufficient LNE. As the number of LNE increased, false-negative findings dropped; accordingly, the NSS increased. In addition, NSS was an independent prognostic indicator for pN0 in patients with ESCC in the SEER database (hazard ratio [HR] 0.182, 95% confidence interval [CI] 0.046-0.730, p = 0.016) and our database (HR 0.215, 95% CI 0.055-0.842, p = 0.027). A certain number of nodes must be examined to achieve 90% of the NSS., Conclusions: NSS could determine the probability of true pN0 status for patients, and it was sufficient in predicting survival and obtaining adequate numbers for lymphadenectomy., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Synchronous multiple primary esophageal squamous cell carcinoma (S-MPESCC) refers to more than one primary esophageal carcinoma detected in a solitary patient at the time of initial presentation. The purpose of this study was to evaluate the clinicopathological features, appropriate surgical approaches and long-term survival in patients with S-MPESCC by comparing with those with solitary esophageal squamous cell carcinoma (SESCC)., Methods: In total, 567 patients with esophageal squamous cell carcinoma surgically resected in Tianjin Medical University Cancer Institute and Hospital from January 2012 to December 2018 were screened for retrospective analysis (50 in the S-MPESCC group and 516 in the SESCC group)., Results: No significant difference was observed in terms of other characteristics except total alcohol consumption (P = 0.029). S-MPESCC had higher lymph node rate than SESCC (62.0% and 44.1%, respectively; P = 0.015) especially in upper mediastinal (32.0% and 18.6%, respectively; P = 0.023) and abdominal (38.0% and 22.8%, respectively; P = 0.017) regions. The survival was not different between the two groups, and the 5-year survival rates of S-MPESCC and SESCC were 46.2% and 50.8%, respectively (P = 0.507). But for patients with pT3-4 cancers, the survival in S-MPESCC was worse than that in SESCC (P = 0.033). In the multivariate analysis, pT stage of primary cancer was an important independent predictor of prognosis in patients with S-MPESCC (hazard ratio [HR], 3.968; 95% confidence interval [CI], 1.031 to 15.268; P = 0.045)., Conclusions: S-MPESCC was significantly different from SESCC in terms of clinicopathological characteristics include alcohol intake and pattern of lymphatic metastasis. Furthermore, S-MPESCC showed worse long-term survival than SESCC with increasing depth of primary cancer infiltration., (© 2022. The Author(s).)

Background and Purpose: More than 40% of patients with esophageal squamous cell carcinoma (ESCC) exhibit pathological complete responses (pCR) after neoadjuvant chemoradiotherapy (nCRT), and theoretically, these patients may be cured by CRT and omit surgery. This prospectively randomized pilot study compared definitive chemoradiotherapy (dCRT) with nCRT in patients with locally advanced ESCC who achieved clinical complete responses (cCRs) to nCRT., Materials and Methods: Single center, randomized, open phase 2 study of 256 patients with locally advanced ESCC enrolled between April 2016 and November 2018. Immediately when nCRT finished, patients enrolled underwent response evaluations within 1 week. Patients with cCR were randomly allocated to undergo surgery (arm A) or complete CRT up to the definitive radiation dose (arm B). The primary end point was 3-year disease-free survival (DFS)., Results: Finally, 71 patients were randomly assigned to the nCRT (n = 36) and dCRT (n = 35) arms. The median observation time was 35.7 months. The 3-year DFS rate was 56.43 % in arm A versus 54.73 % in arm B (hazard ratio [HR] = 0.862, 95 % confidence interval [CI] = 0.452 to 1.645, P = 0.652). The 3-year overall survival (OS) rates in arms A and B were 69.5 % and 62.3 % (HR = 0.824, 95 % CI = 403-1.688, P = 0.597), respectively., Conclusions: According to our treatment response evaluation criteria, survival of the patients with cCR after nCRT was not significant different between nCRT group and dCRT group. An optimized response evaluation strategy soon after nCRT may guide next therapy decisions for patients with locally advanced ESCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Background: The outcome of patients with T4 esophageal squamous cell carcinoma (ESCC) is extremely poor. Two distinct therapeutic options are currently available for T4 esophageal cancers: neochemoradiotherapy followed by surgery (CRT-S) and definitive chemoradiotherapy (D-CRT). This study aimed to investigate the clinicopathologic characteristics of T4 ESCC in Chinese patients and compare the survival between the two therapeutic options., Methods: We retrospectively analyzed 125 patients with clinically unresectable T4 ESCC in Tianjin Medical University Cancer Institute and Hospital from January 2010 to December 2020. Overall survival (OS), progression-free survival (PFS) and associated factors were analyzed., Results: A total of 106 of 125 T4 ESCC patients were downstaged of the tumor by neoadjuvant CRT. Among 106 patients, 32 patients underwent CRT-S, and 74 patients underwent D-CRT. Patients in the CRT-S group had a higher OS (20.4 months vs. un-reached median OS, p = 0.037) and PFS (8.6 months vs. 21.0 months, p = 0.008) than those in the D-CRT group. In multivariate analysis, treatment was an independent predictor of PFS. After propensity score matching (PSM), 50 patients (CRT-S = 25; D-CRT = 25) were matched. Among these 50 patients, patients in the CRT-S group had a higher OS (15.6 months vs. un-reached median OS, p = 0.025) and PFS (7.2 months vs. 18.8 months, p = 0.026) than those in the D-CRT group. In multivariate analysis, treatment was an independent predictor for PFS., Conclusion: We demonstrated that CRT-S was superior to D-CRT for T4 ESCC patients who were downstaged by neo-CRT with respect to longer OS and PFS. Randomized controlled trials involving large population samples are needed to define the standard treatment for T4 ESCC., (© 2022. The Author(s).)

Platinum-based chemotherapy is the standard first-line treatment for advanced esophageal squamous cell carcinoma (ESCC). In this phase 3 study (ClinicalTrial.gov: NCT03829969), 514 patients with treatment-naïve advanced ESCC were randomized (1:1) to receive toripalimab or placebo in combination with paclitaxel plus cisplatin (TP) every 3 weeks for up to 6 cycles, followed by toripalimab or placebo maintenance. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS is observed for the toripalimab arm over the placebo arm (hazard ratio [HR] = 0.58; 95% CI, 0.46-0.74; p < 0.0001). The prespecified interim analysis of overall survival (OS) also reveals a significant OS improvement for patients treated with toripalimab plus TP over placebo plus TP (HR = 0.58; 95% CI, 0.43-0.78; p = 0.0004). The incidences of grade ≥3 treatment-emergent adverse events are similar between the two arms. Toripalimab plus TP significantly improves PFS and OS in patients with treatment-naïve, advanced ESCC, with a manageable safety profile., Competing Interests: Declaration of interests X.L. is employed by Shanghai Junshi Biosciences. X.T., H.F., and S. Yao are employed by Shanghai Junshi Biosciences and TopAlliance Biosciences. R.M. and P.K. are employed by TopAlliance Biosciences. R.-H.X. has served as a consulting or advisory role for Bristol-Myers Squibb, Merck Serono, Roche, Astellas, and AstraZeneca. All other authors have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

C-X-C motif chemokine receptor 4 (CXCR4) belongs to the CXC chemokine receptor family, which mediates the metastasis of tumor cells and promotes the malignant development of cancers. However, its biological role and regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we found that CXCR4 expression was associated with lymph node metastasis and a poor prognosis. In vitro and in vivo studies demonstrated that CXCR4 overexpression promoted ESCC cell proliferation, migration, invasion, and survival, whereas silencing CXCR4 induced the opposite effects. Mechanically, HIF-1α transcriptionally regulates CXCR4 expression by binding to a hypoxia response element in its promoter. HIF-1α-induced ESCC cell migration and invasion were reversed by CXCR4 knockdown or treatment with MSX-122, a CXCR4 antagonist. Collectively, these data revealed that the HIF-1α/CXCR4 axis plays key roles in ESCC growth and metastasis and indicated CXCR4 as a potential target for ESCC treatment., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Patients with locally advanced esophageal squamous cell carcinoma (ESCC) show poor survival after concurrent chemoradiotherapy. This study investigated the safety and feasibility of combining concurrent chemoradiotherapy with the anti-PD-1 antibody camrelizumab as first-line treatment for these patients. In this phase 1b study (ClinicalTrials.gov NCT03671265), patients received concurrent chemotherapy (cisplatin [25 mg/m 2 ] plus docetaxel [25 mg/m 2 ] for 4 weeks) and radiotherapy (2.0 Gy/fraction, total 60 Gy) with camrelizumab (200 mg every 2 weeks for 32 weeks). Primary endpoints were safety and tolerability, and health-related quality of life. Secondary endpoints were radiological and pathological response rates, overall survival (OS), and progression-free survival (PFS). Candidate biomarkers in tumor and peripheral blood were monitored at baseline and after 40 Gy radiation. Twenty patients were enrolled. The most common treatment-related grade 3 adverse events included radiation esophagitis (20%) and esophageal fistula (10%). Serious treatment-related adverse events occurred in eight (40%) patients. No treatment-related deaths were reported. Health-related quality of life did not deteriorate. Thirteen (65%) patients had an objective response after 40 Gy radiation. At a median follow-up of 23.7 months (95% CI 21.9-24.5), OS and PFS time ranged from 8.2-28.5 and 4.0-28.5 months, respectively. The 12-month and 24-month OS rate was 85.0% and 69.6%; PFS rate was 80.0% and 65.0%. Tumor PD-L1 expression and CD11c + dendritic cells and peripheral-blood IL-27, IL-15, Eotaxin-3, and IL-22 were associated with OS. First-line concurrent chemoradiotherapy plus camrelizumab had a manageable safety profile and promising antitumour efficacy for ESCC, and deserves further study., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: To investigate the expression of high-mobility group AT-hook 2 (HMGA2) and miR-204-5p in oesophageal squamous cell carcinoma (ESCC) and their biological roles in ESCC development and progression., Methods: HMGA2 and miR-204-5p expression levels in ESCC tissues and cell lines were detected by qRT-PCR, Western blotting and immunohistochemical staining. ESCC cell lines were transfected with a small interfering RNA for HMGA2 and miR-204-5p mimic to downregulate and upregulate the expression levels of HMGA2 and miR-204-5p, respectively. The growth, migration and invasion abilities of ESCC cells were assessed by MTT, colony formation, wound-healing and Transwell assays, respectively. A luciferase reporter gene assay was used to determine whether the 3'-untranslated coding regions of HMGA2 could be directly bound by miR-204-5p., Results: HMGA2 expression was markedly upregulated (P < .001), while miR-204-5p expression was markedly downregulated (P = .003) in ESCC tissues compared with adjacent normal tissues. HMGA2 expression was correlated with tumour size, invasion depth, lymph node metastasis and tumour-node-metastasis stage (all P < .05) and was identified as an independent prognostic factor for ESCC patients. The expression levels of HMGA2 and miR-204-5p were negatively correlated (r 2  = 0.609, P < .001). HMGA2 knockdown or miR-204-5p overexpression markedly inhibited ESCC cell growth, migration and invasion (P < .05). In addition, restoration of HMGA2 expression partly reversed the inhibitory effects of miR-204-5p overexpression on migration and invasion (P < .05). The luciferase reporter gene assay suggested that HMGA2 is a direct downstream target of miR-204-5p., Conclusion: HMGA2 functions as an oncogene in the growth and metastasis of ESCC and is negatively regulated by miR-204-5p., (© 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: The aim of this study was to explore whether the ratio between negative and positive lymph nodes (R NP ) could predict the overall survival (OS) of esophageal cancer (EC) patients with lymph node metastasis following esophagectomy., Methods: We utilized the Surveillance, Epidemiology and End Results (SEER) database to include the records of 2374 patients with lymph node metastases post-surgery. All patients were randomly assigned into the training cohort (n = 1424) and validation cohort (n = 950). Multivariate Cox regression analyses were performed to identify independent prognostic factors. A novel R NP -based TR NP M staging system was proposed. The prognostic value of N, R NP , TNM and TR NP M staging system was evaluated using the linear trend χ 2 test, likelihood ratio χ 2 test, and Akaike information criterion (AIC) to determine the potential superiorities. We constructed nomograms to predict survival in both cohorts, and the calibration curves confirmed the predictive ability., Results: Univariate analyses showed that N and R NP stage significantly influenced the OS of patients. Multivariate analyses revealed that R NP was an independent prognostic predictor in both the training and validation cohorts. For the stratification analysis in the two cohorts, we found significant differences in the prognosis of patients in different R NP groups on the basis of the different N stages and the number of dissected lymph nodes. In addition, the lower AIC value of R NP stage and TR NP M staging system represented superior predictive accuracy for OS than the N stage and TNM staging system, respectively. Furthermore, the calibration curves for the probability of three- and five-year survival showed good consistency between nomogram predictive abilities and actual observation., Conclusions: We demonstrated that compared to the classical pathological lymph nodal staging system, the R NP stage showed superior predictive accuracy for OS and can serve as a more effective prognostic guidance for lymph node positive EC patients., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Lessons Learned: Patient compliance with the oral dosage treatment was good, with no need for hospitalization. Patients with tracheal and esophageal fistulas can take crushed apatinib by nutrient tube, with the same bioavailability and efficacy. Apatinib may be an effective and safe second- or further-line treatment for advanced esophageal cancer., Background: Apatinib is an inhibitor of vascular endothelial growth factor receptor-2 (VEGFR2), which is thought to play a role in esophageal cancer progression. Our goal was to evaluate the efficacy and safety of apatinib in patients with unresectable esophageal cancer and to examine whether VEGFR2 expression influenced the clinical response., Methods: This single-arm, open-label, investigator-initiated phase II study enrolled patients with advanced squamous cell carcinoma (SCC) or adenocarcinoma of the esophagus or esophagogastric junction who were admitted to Tianjin Medical University Cancer Institute and Hospital between August 2017 and January 2019. Apatinib monotherapy (500 mg/day) was given orally or via an enteral tube until disease progression, unacceptable toxicity, withdrawal, or death. Patients were followed until treatment was discontinued or death. The main endpoints were tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs)., Results: Among 32 patients screened for inclusion, 30 were included in the safety and survival analyses (i.e., received apatinib), and 26 were included in the efficacy analysis (at least one imaging follow-up). Median follow-up time and exposure to apatinib were 5.34 months and 72 days, respectively. Among 26 patients included in the efficacy analysis, 2 had a partial response (PR; 7.7%) and 14 had stable disease (SD; 53.8%). The overall response rate (ORR) was 7.7%, and the disease control rate (DCR) was 61.5%. Median PFS and OS were 4.63 months (95% confidence interval, 2.11-7.16 months) and 6.57 months (4.90 months to not estimable), respectively. Fifteen patients (50.0%) experienced treatment-related AEs, most commonly hypertension (26.7%), diarrhea (20.0%), and hand-foot-skin reaction (10.0%). No patients had grade ≥4 treatment-related AEs., Conclusion: Apatinib was effective as second- or further-line treatment for advanced esophageal cancer., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Background: The present study was to investigate the influence of induction therapy on robot-assisted McKeown esophagectomy (RAME) with radical superior mediastinal lymph node dissection for esophageal squamous cell carcinoma in a high-volume cancer center., Methods: A consecutive patient cohort who underwent RAME from January 2017 to May 2019 were reviewed. The perioperative outcomes of patients with induction therapy were compared with those who had surgery alone., Results: In total, 118 patients underwent RAME during the study period. The average age was 59.1 ± 7.5 years, including 100 male and 18 female patients. Thirty patients (25.4%) had induction therapy, and 88 patients did not receive induction therapy. The average age of the patients treated with induction therapy was younger than those received surgery alone (56.8 ± 6.1 vs. 59.5 ± 7.6 years, p = 0.039). There were no statistically significant differences in the mean operative time and estimated blood loss between both groups. Complications occurred in 46 (39.0%) patients. There were no statistically significant differences in the rates of any complications between both groups (p = 0.951). There were no deaths in either group. The hospital stay was prolonged in patients with induction therapy than those in the surgery-alone group (20.8 ± 8.9 vs. 16.8 ± 6.0, p = 0.048). There was no statistically significant difference in the average number of dissected lymph nodes in total and both recurrent laryngeal nerve stations between both groups., Conclusion: For patients with esophageal squamous cell carcinoma, induction therapy has no influence on RAME with radical superior mediastinal lymph node dissection., (© 2020 S. Karger AG, Basel.)

Growing evidence indicates that systemic inflammation response and malnutrition status are correlated with survival in certain types of solid tumors. The aim of this study is to evaluate the association between the systemic immune-inflammation index (SII) and prognostic nutritional index (PNI) and overall survival (OS) in patients with esophageal squamous cell carcinoma (ESCC) after esophagectomy. A consecutive series of 655 patients with resected ESCC who underwent esophagectomy were enrolled in the retrospective study. The preoperative SII was defined as platelet × neutrophil/lymphocyte counts. The PNI was calculated as albumin concentration (g/L) + 5 × total lymphocyte count (10 9 /L). The optimal cut-off values of SII, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and PNI were determined by receiver operating characteristic analysis. Survival analysis was performed using the Kaplan-Meier method with a log-rank test, followed by a multivariate Cox proportional hazards model. A high SII was significantly related to tumor size, histological type, invasion depth, and TNM stage (p < 0.05). A low PNI was significantly associated with age, tumor size, invasion depth, lymph node metastasis, and TNM stage (p < 0.05). Univariate analysis revealed that age, smoking history, tumor size, invasion depth, lymph node metastasis, SII, NLR, PLR, and PNI were predictors of OS (p < 0.05). Multivariate analysis identified age (p = 0.041), tumor size (p = 0.016), invasion depth (p < 0.001), lymph node metastasis (p < 0.001), SII (p = 0.033), and PNI (p = 0.022) as independent prognostic factors correlated with OS. There was a significant inverse relationship between the SII and PNI (r = 0.309; p < 0.001). The predictive value increased when the SII and PNI were considered in combination. Our results demonstrate that the preoperative high SII and low PNI are powerful indicators of aggressive biology and poor prognosis for patients with ESCC. The combination of SII and PNI can enhance the accuracy of prognosis., (© 2018 Wiley Periodicals, Inc.)

Background: To compare the lymph node dissection with the right transthoracic Ivor-Lewis (IL) procedure to that with the left transthoracic (LT) approach for Siewert type II adenocarcinoma of the esophagogastric (AEG) junction., Methods: In this study, 136 patients with Siewert type II AEG who met the inclusion criteria underwent surgical resection were divided into the IL (47 cases) and LT (89 cases) groups. The number and frequency of the dissected lymph nodes in each station were compared between the two groups., Results: The IL group had a longer proximal surgical margin (P = 0.000) and more total (P = 0.000), thoracic (P = 0.000), and abdominal lymph nodes (P = 0.000) dissected than the LT group. In general, the IL group had a higher dissection rate in each thoracic lymph node station (P < 0.05) than the LT group. The dissection rates of the hepatic artery, splenic artery and celiac trunk lymph nodes were higher in the IL group than in the LT group (P < 0.05). The lymph node metastasis rate was 78.7% in the IL group, higher than the 61.8% in the LT group (P = 0.045)., Conclusions: The right transthoracic IL procedure was demonstrated to be a better application than the LT approach for Siewert type II AEG in terms of the number and frequency of lymph node resections., (© 2017 Royal Australasian College of Surgeons.)

Objective: To evaluate the prevalence, pattern and risk factors of lymph node metastasis (LNM) for pathological T1 (pT1) esophageal cancer (EC)., Methods: The clinical data of 143 cases of pT1 patients who underwent esophagectomy and lymph node dissection during January 2011 and July 2016 were reviewed, including 120 male patients and 23 female patients with a median age of 60 years. The pattern of LNM was analyzed and the risk factors related to LNM were assessed by logistic regression analysis. The nomogram model was used to estimate the individual risk of lymph node metastasis., Results: Of 143 patients with T1 tumors, 25 patients had LNM, and the LNM rate was 17.5%. The LNM rate was 8.0% for T1a tumors, and 22.5% for T1b tumors. The logistic regression analysis showed that the depth of tumor infiltration (P < 0.05), tumor size (P < 0.01), tumor location (P < 0.05), and tumor differentiation (P < 0.01) were independent risk factors related to LNM for T1 EC. These four parameters allowed the compilation of a nomogram to estimate the individual risk of LNM. Tumor differentiation (P < 0.05) was an independent risk factor related to LNM for T1a tumors, and tumor size (P < 0.05) and tumor location (P < 0.05) were independent risk factors related to LNM for T1b tumors. Of 25 patients with LNM, one patient had cervical LNM, 15 patients with thoracic LNM, and 17 patients with abdominal LNM. The relatively highest LNM sites were laryngeal recurrent nerve (n = 8), the left gastric artery (n = 8), right and left cardiac (n = 6) and thoracic paraesophageal (n = 5)., Conclusions: T1 EC has a relatively high LNM rate, and the depth of tumor infiltration, tumor size, tumor location and tumor differentiation are correlated with LNM. The LNM risk and extent must be considered comprehensively in decision-making of a better surgical treatment and lymph node dissection strategy., (Copyright © 2017. Published by Elsevier Ltd.)

Introduction: The aim of this study is to investigate the number of negative lymph nodes (NLNs) as a prognostic factor for survival in patients with resected esophageal squamous cell carcinoma., Methods: A total of 381 esophageal squamous cell carcinoma patients who had underwent surgical resection as the primary treatment was enrolled into this retrospective study. The impact of number of NLNs on patient's overall survival was assessed and compared with the factors among the current tumor-nodes-metastasis (TNM) staging system., Results: The number of NLNs was closely related to the overall survival, and the 5-year survival rate was 45.4% for number of NLNs of >20 (142 cases) and 26.4% for NLNs ≤ 20 (239 cases) (P = 0.001). In multivariate survival analysis, the number of NLNs remained an independent prognostic factor (P = 0.002) as did the other current TNM factors. For subgroup analysis, the predictive value of number of NLNs was significant in patients with T3 or T4 disease (P = 0.001) and patients with N1 and N2-3 disease (P = 0.025, 0.043), but not in patients with T1 or T2 disease or patients with N0 disease., Conclusions: The number of NLNs, which represents the extent of lymphadenectomy for esophageal squamous cell carcinoma, could impact the overall survival of patients with resected esophageal squamous cell carcinoma, especially among those with nodal-positive disease and advanced T-stage tumor., (© 2016 John Wiley & Sons Australia, Ltd.)

The present study was aimed to investigate the application of right thansthoracic Ivor-Lewis (IL), left transthoracic (LTT), and left thoracoabdominal (LTA) approach in Siewert type II adenocarcinoma of esophagogastric junction (AEG).The data of 196 patients with Siewert type II AEG received surgical resection in our cancer center between January 2014 and April 2016 was retrospectively analyzed. Finally, 136 patients met the inclusion criteria were enrolled in the study and divided into the IL (47 cases), LTT (51 cases), and LTA group (38 cases). Clinical and short-term treatment effects were compared among the 3 groups.The patients with weight loss, diabetes, and heart disease increased in the LTT group (P = 0.054, P = 0.075, and P = 0.063, respectively). Operation time was significantly longest in the IL group (P < 0.001), but the amount of bleeding and tumor size did not significantly differ among the 3 groups (P = 0.176 and P = 0.228, respectively). The IL group had the significantly longest proximal surgical margin (P < 0.001) and most number of total (P < 0.001) and thoracic lymph nodes (P < 0.001) dissected. Both the IL and LTA groups had more abdominal lymph nodes dissected than the LTT group (P < 0.001). In general, the IL and LTT groups had the highest dissection rates of every station of thoracic (P < 0.05) and lower mediastinal lymph nodes (P < 0.05), respectively. The dissection rate of the paracardial, left gastric artery, and gastric lesser curvature lymph nodes did not differ significantly among the 3 groups (P > 0.05), but the dissection rate of the hepatic artery, splenic artery, and celiac trunk lymph nodes was significantly highest in the IL group (P < 0.05). Postoperative hospital stay, perioperative complications, and mortality did not differ significantly among the 3 groups (P > 0.05).Compared with the traditional left transthoracic approach, the Ivor-Lewis approach did not increase the perioperative mortality and complication rates in Siewert type II AEG, but obtained satisfactory length of the proximal surgical margin, and was better than the left transthoracic approach in thoracic and abdominal lymph node dissection. However, the advantages of Ivor-Lewis procedure requires further follow-up and validation through prospective randomized controlled trials.

Aims: To investigate the prognostic significance of body mass index (BMI) on the survival of patients with esophageal squamous cell carcinoma (ESCC) after esophagectomy., Methods: Between 2005 and 2008, 291 patients with ESCC who met the inclusion criteria were included in the study. The BMI cut-off values were as follows: 18.5-23 kg/m2 for normal weight; 23-27.5 kg/m2 for overweight; and ≥27.5 kg/m2 for those with obesity. Univariate and multivariate analyses were performed to identify prognostic factors for long-term survival., Results: Patients were divided into 3 groups: normal weight (n = 138), overweight (n = 103), and obese (n = 50). The median survival time was 56 months. The 5-year overall survival (OS) rates were 40.8, 44.7, and 20.8% for normal weight, overweight, and obese patients respectively (p < 0.05). Multivariate analysis identified BMI as an independent prognostic factor for OS (p < 0.05). For 179 patients without lymph node metastasis, the 5-year OS rates were 46.5, 50.7, and 27.0% for normal weight, overweight, and obese patients respectively (p < 0.05)., Conclusions: A BMI ≥27.5 kg/m2 has a distinctly adverse impact on the long-term survival of ESCC patients after esophagectomy. High BMI is a potential predictor of worse prognosis in ESCC patients, particularly in patients without lymph node metastasis., (© 2017 S. Karger AG, Basel.)

This study aimed to evaluate the prognostic significance of lymph node ratio (LNR) by establishing a hypothetical tumor-ratio-metastasis (TRM) staging system in patients with esophageal squamous cell carcinoma (ESCC). The records of 387 ESCC patients receiving curative esophagectomy were retrospectively investigated. The optimal cut-point for LNR was assessed via the best cut-off approach. Potential prognostic parameters were identified through univariate and multivariate analyses. A novel LNR-based TRM stage was proposed. The prognostic discriminatory ability and prediction accuracy of each system were determined using hazard ratio (HR), Akaike information criterion (AIC), concordance index (C-index), and area under the receiver operating characteristic curve (AUC). The optimal cut-points of LNR were set at 0, 0~0.2, 0.2~0.4, and 0.4~1.0. Multivariate Cox analysis indicated that the LNR category was an independent risk factor of overall survival (P < 0.001). The calibration curves for the probability of 3- and 5-year survival showed good consistency between nomogram prediction and actual observation. The LNR category and TRM stage yielded a larger HR, a smaller AIC, a larger C-index, and a larger AUC than the N category and TNM stage did. In summary, the proposed LNR category was superior to the conventional N category in predicting the prognosis of ESCC patients.

This study aimed to assess the prognostic value of the hypothetical tumor-N-ratio (rN)-metastasis (TrNM) staging system in adenocarcinoma of the esophagogastric junction (AEG). The clinical data of 387 AEG patients who received surgical resection were retrospectively reviewed. The optimal cut-off point of rN was calculated by the best cut-off approach using log-rank test. Kaplan-Meier plots and Cox regressions model were applied for univariate and multivariate survival analyses. A TrNM staging system based on rN was proposed. The discriminating ability of each staging was evaluated by using an adjusted hazard ratio (HR) and a -2log likelihood. The prediction accuracy of the model was assessed by using the area under the curve (AUC) and the Harrell's C-index. The number of examined lymph nodes (LNs) was correlated with metastatic LNs (r = 0.322, P < 0.001) but not with rN (r = 0.098, P > 0.05). The optimal cut-points of rN were calculated as 0, 0~0.3, 0.3~0.6, and 0.6~1.0. Univariate analysis revealed that pN and rN classifications significantly influenced patients' RFS and OS (P < 0.001). Multivariate analysis adjusted for significant factors revealed that rN was recognized as an independent risk factor. A larger HR, a smaller -2log likelihood and a larger prediction accuracy were obtained for rN and the modified TrNM staging system. Taken together, our study demonstrates that the proposed N-ratio-based TrNM staging system is more reliable than the TNM staging system in evaluating prognosis of AEG patients after curative resection.

This study aimed to investigate whether the inclusion of tumor size could improve the prognostic accuracy in patients with esophageal squamous cell cancer (ESCC). A total of 387 patients with ESCC who underwent curative resection were enrolled in this analysis. The patients were categorized into small-sized tumors (SSTs) and large-sized tumors (LSTs) using an appropriate cut-off point for tumor size. Kaplan-Meier survival curve and log-rank test were used to evaluate the prognostic value of tumor size. A Cox regression model was adopted for multivariate analysis. Their accuracy was compared based on the presence or absence of tumor size. Using 3.5 cm as the optimal cut-off point, 228 and 159 patients presented with LSTs (≥ 3.5 cm) and SSTs (< 3.5 cm), respectively. The patients with LSTs had significantly worse prognoses than patients with SSTs (23.9% vs. 43.2%, P < 0.001). Multivariate analysis revealed that tumor size, histological type, invasion depth, and lymph node metastasis were independent predictors of overall survival. The addition of tumor size to the AJCC TNM staging improved the predictive accuracy of the 5-year survival rate by 3.9%. Further study showed that tumor size and T stage were independent predictors of the prognosis of node-negative patients, and the combination of tumor size and T stage improved the predictive accuracy by 3.7%. In conclusion, tumor size is indeed a simple and practical prognostic factor in patients with ESCC. It can be used to improve the prognostic accuracy of the current TNM staging, especially for patients with node-negative disease.

Objective: To study the impact of preoperative fasting plasma glucose(FPG) on postoperative morbidity and outcome following surgical resection of esophageal squamous cell carcinoma (ESCC), and to analyze the risk factor of postoperative complication in ESCC., Methods: Clinicopathological data of 314 ESCC patients undergoing esophagectomy in our center between January 2011 and December 2012 were retrospectively collected. Patients were divided into two groups according to their preoperative FBG: normal FPG group (FPG<6.1 mmol/L, 252 cases) and high FBG group (FPG≥6.1 mmol/L, 62 cases, including 14 diabetes cases). Clinicopathological data and postoperative morbidity were analyzed and compared between two groups. Multivariate logistic regression analysis was used to evaluate risk factors for postoperative complications., Results: There were 278 male and 36 female patients with a median age of 59 years (range 42-83 years). As compared to normal FPG group, high FBG group had higher ratio of female [22.6%(14/62) vs. 8.7%(22/252), P=0.000], older median age (66 years vs. 59 years, P=0.010), lower ratio of smoking and alcohol drinking [48.4%(30/62) vs. 73.8%(186/252), 38.7%(24/62) vs. 69.0%(174/252), both P=0.000], higher ratio of comorbid diabetes and hypertension [51.6%(32/62) vs. 15.1%(38/252), 16.1%(10/62) vs. 1.6%(4/252), both P=0.000]. Pathology results showed 206 patients in normal FPG group (81.7%, 206/252) were moderate-poor differentiation, which was obviously lower than 93.5%(58/62) in high FPG group(P=0.023). Patients of two groups completed their operations successfully. Perioperative overall complication morbidity was 24.2%(76/314), and the most common was lung lesions (24 cases of pneumonia, 10 cases of respiratory failure), then was anastomotic leakage (28 cases) and incision infection (18 cases). Differences in overall and other complication morbidity were not significant between two groups (all P>0.05). Multivariate logistic regression analysis revealed that operation time was an independent risk factor of postoperative complications (P=0.047), anastomosis site was an independent risk factor of anastomotic leakage (P=0.036), and FPG was not a risk factor of postoperative complications(respectively, P=0.683, P=0.836, P=0.784, P=0.637)., Conclusions: Preoperative control of FBG does not increase the postoperative complication morbidity. Shortening operation time and choosing appropriate surgical procedure are important to decrease postoperative complications.

Objective: To compare the perioperative complications and the stress response between thoracoscopic esophagectomy and open esophagectomy in patients with esophageal cancer., Methods: Clinicopathologic data of 154 patients with esophageal cancer undergoing thoracoscopic esophagectomy (thoracoscope group) and 113 undergoing open procedure(open group) in the Tianjin Medical University Cancer Institute and Hospital from October 2012 to September 2014 were analyzed retrospectively. The incidence of perioperative complications and the change of stress response index in patients without complications were compared between two groups., Results: The total complication rate in thoracoscope and open group was 33.8% and 38.1%(P = 0.470) respectively. Compared with open group, incidence of ligation of thoracic duct(2.6% vs. 14.2%), recurrent laryngeal nerve paralysis (16.9% vs. 28.3%), chylothorax (0 vs. 4.4%), atelectasis (1.3% vs. 7.1%), pleural effusion (0.6% vs. 6.2%) and acute respiratory distress(0.6% vs. 6.2%) were obviously decreased in thoracoscope group(all P<0.05). No significant differences were observed in other complications (all P>0.05). Thirty-two cases and 24 cases without complication and with complete test data in thoracoscope and open group were selected for the detection of stress response index. There were no significant differences in white blood cell count, and the levels of cortisol, thyroxine (FT3 and FT4) and C-reactive protein between two groups at the same time points (before operation, 1, 3 and 6 days after operation) (all P>0.05)., Conclusion: Thoracoscopic esophagectomy has some obvious advantages associated with less pulmonary complications, lower morbidity of injury in thoracic duct and recurrent laryngeal nerve, while no significant difference of stress response is found in patients without complication between thoracoscope group and open group.

Objective: In esophageal cancer, depth of wall penetration, reflected by T classification, represents the most important prognostic variable. Our study aimed to investigate the impact of tumor length, measured as the longitudinal length, on the outcome of esophageal squamous cell carcinoma (ESCC) patients., Methods: The survival data of 362 ESCC patients who underwent surgical resection as the primary treatment between 1999 and 2007 were collected retrospectively. Receiver-operator characteristic analysis was applied to identify the optimal cut-off values., Results: 4.0 cm was identified as the optimal cut-off value within the whole group. Tumor length greater than 4.0 cm was associated with increasing T stage (P=0.001), N stage (P=0.046), and tumor differentiation (P=0.033). Univariate analysis and multivariate analysis both found that tumor length greater than 4.0 cm was associated with worse overall survival compared with shorter tumors (P<0.001). It appeared to have a greater impact on N0-N1 (P<0.001, P=0.026, respectively) than N2-N3 and appeared to have a higher impact on the lower-stage patients than the higher-stage patients., Conclusions: Tumor length proved to be an independent prognostic parameter for ESCC patients, especially for node-negative and lower-stage patients. More attention should be paid to its role in the management of ESCC.

Objective: To preliminarily investigate the expression and clinical significance of leptin and adiponectin in esophageal squamous cell carcinoma (ESCC)., Methods: The expression of leptin and adiponectin in ESCC and normal esophageal mucosal tissue was detected by immunohistochemical staining with tissue microarray. The correlation between leptin, adiponectin and clinicalpathological features was statistically analyzed., Results: The expression of leptin was significantly upregulated in the ESCC than in the normal esophageal mucosa tissue [65.6% (80/122) versus 27.5% (11/40), P < 0.001]. Expression of leptin was significantly correlated with lymph node involvement and advanced tumor stage (P = 0.009 and P = 0.043, respectively). Expression of adiponectin was significantly down-regulated in ESCC compared with that in normal esophageal mucosal tissue [22.1% (27/122) versus 47.5% (19/40), P = 0.002]. Expression of adiponectin was significantly correlated with lymph node involvement (P = 0.020). Correlation analysis showed a positive correlation between the expression of leptin and lymph node metastasis and TNM stage (r = 0.235 and r = 0.183, respectively), and a negative correlation between the expression of adiponectin and lymph node metastasis (r = -0.229). There was no significant correlation between the expressions of leptin and adiponectin (P > 0.05), and between the body mass index and the expression of leptin and adiponectin, and lymph node metastasis (P > 0.05 for all)., Conclusions: An imbalanced expression of adipocytokines exits in ESCC. The expression of leptin and adiponectin is correlated with lymph node metastasis and/or tumor stage. Therefore, imbalanced expression of leptin and adiponectin may have a potential role in the carcinogenesis and disease progression of ESCC.

Objective: To investigate the association of Kruppel-like factor 4 (KLF4) expressions with the prognosis of esophageal squamous cell carcinoma (SCC) patients., Methods: Ninety-eight cases of esophageal carcinoma patients were enrolled. The expression of KLF4 in the esophageal SCC and normal esophageal mucosa tissues were examined by immunohistochemistry. The correlations between the expression of KLF4 protein and patients' clinical characteristics and prognosis were analyzed., Results: We observed higher expressed KLF4 in normal esophageal mucosa tissues than esophageal SCC tissues, with positive rate of 82.7% (81/98) and 43.8% (43/98) respectively. In patients with lymphatic metastasis, the positive rate of KLF4 was 24.4% (10/41), whereas it was 57.9% (33/57) in patients without lymphatic metastasis, and the difference was significant (x(2) = 10.871, P = 0.001). The positive rates of KLF4 were 62.5% (5/8), 53.1% (26/49) and 29.3% (12/41) in stage I, II and III patients, respectively. There were no correlations between the expression of KLF4 and gender, age, tumor size, location, differentiation grade and infiltration depth. The 5-year survival rates and median survival times were 48.8% and 25.5%, and 55 and 26 months for the patients with KLF4 positive and negative expression, respectively. There were significant differences between the patients with KLF4 positive expression and negative expression in the 5-year survival rates and median survival times (x(2) = 5.747 and 4.493, P = 0.017 and 0.034)., Conclusion: KLF4 might act as a tumor suppressor in esophageal SCC and the expression status of KLF4 could be considered as a prognosis predictor for esophageal SCC patients.

Objective: To investigate the pattern of early lymph node metastasis of thoracic esophageal squamous cell carcinoma and its prognostic value., Methods: Clinical and follow-up data of 126 patients with pathological stage pN1 of esophageal squamous cell carcinoma undergoing radical esophagectomy in our department from January 2005 to December 2008 were analyzed retrospectively. Impact of lymph node metastasis pattern on prognosis was investigated., Results: The relatively common sites of lymph node metastasis were upper mediastinum(53.8%), middle and lower thoracic paraesophageal(38.3%), right and left cardiac(34.4%) and the left gastric artery(36.8%). Univariate analysis showed that the lymph node metastasis of subcarinal, middle and lower thoracic paraesophageal and the left gastric artery was associated with 5-year survival rate. Multivariate analysis revealed that the presence of subcarinal and middle and lower thoracic paraesophagea lymph node metastasis was an independent risk factor of survival., Conclusions: Upper mediastinal, middle and lower thoracic paraesophageal, right and left cardiac and the left gastric artery are the earliest lymph node metastasis sites of esophageal squamous cell carcinoma. The presence of subcarinal and middle and lower thoracic paraesophagea lymph node metastasis is an independent risk factor of survival. Patient prognosis should be analyzed with lymph node metastasis pattern based on the 7th edition UICC-AJCC TNM classification system.

Objective: To investigate the risk factors for early recurrence of gastroesophageal junction adenocarcinoma (Siewert type II/III) after curative resection and the prognosis of these patients., Methods: Retrospective analysis was performed for the 170 patients with recurrent AEG after curative resection in our hospital.Univariate and multivariate analysis were applied to investigate risk factors for early recurrence ( < 24 month), the prognosis of these patients were also analyzed., Results: The rate of early recurrence of AEG after curative resection was 75.3%. Univariate analysis showed that tumor Borrmann type, invasive depth, lymph node metastasis, metastasis lymph node ratio (LNR) and TNM stage were significant factors associated with early recurrence after curative resection (P < 0.05). Multivariate analysis identified that only LNR and tumor invasive depth were independent risk factors for early recurrence (P < 0.05). The median disease free survival time (9, 20 months, P < 0.01), 5-year survival rate (2.4%, 12.6%, P < 0.01) and the median survival time after recurrence(5, 8 months, P = 0.004) between patients with high-LNR group and low-LNR group were significantly difference., Conclusions: LNR and tumor invasive depth were determined to be independent risk factors associate with early recurrence after curative resection for AEG. The patients with high-LNR have a poorer survival compared with those with low-LNR; For the patients with serosa invaded and high LNR should be closely followed up to detect recurrence and take effective treatment timely to improve patients outcomes.

Background and Objectives: The purpose of this study is to estimate the effect of extranodal metastasis (EM) on recurrence and survival in patients with adenocarcinoma of the esophagogastric junction (AEG) after curative resection., Methods: Clinical data from 284 node-positive AEG patients who underwent curative resection were reviewed. Univariate and multivariate analyses were conducted to elucidate the effect of EM on recurrence-free survival (RFS) and overall survival (OS)., Results: EM was detected in 70 (24.6%) of the 284 cases. It had a significant correlation with tumor size, Lauren type, histopathological grading, depth of tumor invasion, number of metastatic nodes, lymph node ratio, and TNM stage. The 5-year RFS and OS rates were 22.2% and 24.3%, respectively. Patients with EM had a significantly decreased RFS (16 vs. 36 months, P < 0.001) and OS (23 vs. 41 months, P < 0.001) compared with those without EM. Multivariate analyses identified EM as an independent prognostic factor (P = 0.003 and 0.001, respectively)., Conclusion: The presence of EM increases recurrence probability and reduces OS probability of AEG patients with lymph node metastasis. EM is a powerful prognostic factor reflecting a particularly aggressive biological behavior. Better understanding of EM status can help clinicians with regard to treatment decision and prognosis evaluation., (© 2013 Wiley Periodicals, Inc.)

Objective: To explore the level of serum high-mobility group box 1 (HMGB1) in patients with esophageal squamous cell carcinoma (ESCC) and the feasibility of HMGB1 as a tumor marker., Methods: Serum HMGB1, carcinoembryonic antigen (CEA), cytokeratin 19 fragment antigen (Cyfra21-1) and squamous cell carcinoma antigen (SCC) were measured by enzyme-linked immunosorbent assay (ELISA), electrochemiluminescence immunoassay (ECLIA) and microparticle enzyme immunoassay (MEIA) respectively in 78 patients with ESCC preoperatively as well as a month after esophagectomy. At the same time, serum HMGB1, CEA, Cyfra21-1 and SCC of 60 healthy adult volunteers were detected with the same method. The unilateral P95 value of serum HMGB1 (>96 μg/L) was defined as positive. According to the Roche kit diagnostic criteria, CEA>5.0 μg/L, Cyfra21-1>3.3 μg/L and SCC>1.5 μg/L were defined as positive., Results: The preoperative positive ratio of serum HMGB1 in 78 patients with ESCC was 84.6%, and the level of serum HMGB1 was associated with the tumor size, infiltration depth, lymph node metastasis and tumor stage (P<0.01 or P<0.05). One month after esophagectomy, the level of serum HMGB1 in ESCC declined significantly compared with the preoperative level (P<0.01), and the level of serum HMGB1 in T4, N1, stage III was higher compared to corresponding T, N and tumor stage (P<0.01 or P<0.05). The positive ratio of CEA, Cyfra21-1 and SCC was 10.3%, 25.6% and 42.3% respectively in 78 ESCC patients preoperatively, so the sensitivity of these tumor markers was lower. One month after esophagectomy, serum Cyfra21-1 and serum SCC were significantly decreased compared to the preoperative level (P<0.01). However, there was no significant difference of preoperative serum CEA compared to a month after esophagectomy in ESCC (P>0.05). The specificity of HMGB1, CEA, Cyfra21-1 and SCC were 93.3%, 88.3%, 90.0% and 93.3% respectively., Conclusion: Compared to CEA, Cyfra21-1 and SCC, serum HMGB1 in ESCC patients is easier for detection and its sensitivity and specificity are higher, which may be used as a marker in diagnosis, prediction of prognosis and monitor of postoperative recurrence of ESCC.

Objective: To explore the effect of HMGB1 on the VEGF-C expression and proliferation of esophageal squamous cancer cells as well as its possible mechanism., Methods: A cassette encoding siRNA targeting HMGB1 mediated by rAAV was constructed, the rAAV-siHMGB1-hrGFP, and a vector encoding siRNA mismatching HMGB1 was constructed, the rAAV-miHMGB1-hrGFP. This experiment in vitro included three groups, namely, the blank control group (group A) of KYSE150 cells transfected by rAAV-hrGFP, negative mismatch control group (group B) of KYSE150 cells transfected with rAAV-miHMGB1-hrGFP, and RNA interference group (group C) of KYSE150 cells transfected with rAAV-siHMGB1-hrGFP. We examined the expression of HMGB1 mRNA and protein in the three group cells by real-time PCR and Western blot after 24 h and 48 h, respectively. Then, VEGF-C expression and cell proliferation in the three group cells with or without sRAGE, as an inhibitor of RAGE signal pathway, were assayed by ELISA and MTT after 24 h., Results: The expression of HMGB1 mRNA and protein in KYSE150 cells in vitro in the group C transfected with rAAV-siHMGB1-hrGFP at the final concentration of 2×10(6) v.g/cell was significantly lower than that of the group A or B after 24 h and 48 h (P < 0.01). The VEGF-C expression of KYSE150 cells was (502.43 ± 13.10) pg/ml in the group C, significantly reduced in comparison with that of the group A (686.40 ± 10.94) pg/ml or group B (682.31 ± 9.61) pg/ml after 24 h (P < 0.05). At the same time, the proliferation of KYSE150 cells in the group C was significantly inhibited compared with that of groups A and B after 24 h (P < 0.01). Moreover, sRAGE at the final concentration of 0.2 µg/ml inhibited the VEGF-C expression and proliferation of KYSE150 cells compared with the corresponding group without sRAGE after 24 h (P < 0.01 or P < 0.05). However, there was no significant difference of the VEGF-C expression and proliferation of KYSE150 cells with sRAGE in the group C compared with that of cells with sRAGE of the group A or group B after 24 h (P > 0.05)., Conclusions: In esophageal squamous cell carcinoma, HMGB1 can promote the VEGF-C expression and proliferation of the cancer cells through RAGE signal pathway, and HMGB1-RAGE may become a potential target for cell proliferation and lymph node metastasis of this cancer.

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive carcinomas of the gastrointestinal tract. We assessed the relevance of Slug in measuring the invasive potential of ESCC cells in vitro and in vivo in immunodeficient mice., Methods: We utilized RNA interference to knockdown Slug gene expression, and effects on survival and invasive carcinoma were evaluated using a Boyden chamber transwell assay in vitro. We evaluated the effect of Slug siRNA-transfection and Slug cDNA-transfection on E-cadherin and Bcl-2 expression in ESCC cells. A pseudometastatic model of ESCC in immunodeficient mice was used to assess the effects of Slug siRNA transfection on tumor metastasis development., Results: The EC109 cell line was transfected with Slug-siRNA to knockdown Slug expression. The TE13 cell line was transfected with Slug-cDNA to increase Slug expression. EC109 and TE13 cell lines were tested for the expression of apoptosis-related genes bcl-2 and metastasis-related gene E-cadherin identified previously as Slug targets. Bcl-2 expression was increased and E-cadherin was decreased in Slug siRNA-transfected EC109 cells. Bcl-2 expression was increased and E-cadherin was decreased in Slug cDNA-transfected TE13 cells. Invasion of Slug siRNA-transfected EC109 cells was reduced and apoptosis was increased whereas invasion was greater in Slug cDNA-transfected cells. Animals injected with Slug siRNA-transfected EC109 cells exhibited fewer seeded nodes and demonstrated more apoptosis., Conclusions: Slug down-regulation promotes cell apoptosis and decreases invasion capability in vitro and in vivo. Slug inhibition may represent a novel strategy for treatment of metastatic ESCC.