Search

Abstract Long non-coding RNAs (lncRNAs), such as SNHG6, have been identified as crucial regulators in the progression of various cancers, including esophageal squamous cell carcinoma (ESCC). Although the role of SNHG6 in ESCC is not completely understood, our findings demonstrated that SNHG6 expression is upregulated in ESCC tissues compared to adjacent normal tissues. Furthermore, elevated levels of SNHG6 are significantly correlated with higher TNM stage and poorer clinical prognosis in ESCC patients. Functionally, both in vivo and in vitro experiments have shown that knocking down SNHG6 inhibits proliferation, invasion, and metastasis. Luciferase reporter assays and Ago2-RIP assay confirm that SNHG6 functions as a competing endogenous RNA (ceRNA) by sponging miR-26b-5p to modulate ITGB1 expression in ESCC. Given that ITGB1 is instrumental in EMT and metastasis, we assessed the expression of EMT-related proteins. The findings suggest that miR-26b-5p and reduced ITGB1 expression can reverse the EMT induced by lncRNA SHNG6, as demonstrated through rescue analysis. Overall, this study aims to elucidate the molecular mechanisms through which SNHG6 promotes EMT and metastasis in ESCC, providing a novel theoretical foundation for understanding ESCC progression and identifying new targets for improving outcomes in metastatic ESCC.

Abstract Background Neoadjuvant therapy followed by surgery has become the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC) and accurate pathological response assessment is critical to assess the therapeutic efficacy. However, it can be laborious and inconsistency between different observers may occur. Hence, we aim to develop an interpretable deep-learning model for efficient pathological response assessment following neoadjuvant therapy in ESCC. Methods This retrospective study analyzed 337 ESCC resection specimens from 2020–2021 at the Pudong-Branch (Cohort 1) and 114 from 2021–2022 at the Puxi-Branch (External Cohort 2) of Fudan University Shanghai Cancer Center. Whole slide images (WSIs) from these two cohorts were generated using different scanning machines to test the ability of the model in handling color variations. Four pathologists independently assessed the pathological response. The senior pathologists annotated tumor beds and residual tumor percentages on WSIs to determine consensus labels. Furthermore, 1850 image patches were randomly extracted from Cohort 1 WSIs and binarily classified for tumor viability. A deep-learning model employing knowledge distillation was developed to automatically classify positive patches for each WSI and estimate the viable residual tumor percentages. Spatial heatmaps were output for model explanations and visualizations. Results The approach achieved high concordance with pathologist consensus, with an R^2 of 0.8437, a RAcc_0.1 of 0.7586, a RAcc_0.3 of 0.9885, which were comparable to two senior pathologists (R^2 of 0.9202/0.9619, RAcc_0.1 of 8506/0.9425, RAcc_0.3 of 1.000/1.000) and surpassing two junior pathologists (R^2 of 0.5592/0.5474, RAcc_0.1 of 0.5287/0.5287, RAcc_0.3 of 0.9080/0.9310). Visualizations enabled the localization of residual viable tumor to augment microscopic assessment. Conclusion This work illustrates deep learning's potential for assisting pathological response assessment. Spatial heatmaps and patch examples provide intuitive explanations of model predictions, engendering clinical trust and adoption (Code and data will be available at https://github.com/WinnieLaugh/ESCC_Percentage once the paper has been conditionally accepted). Integrating interpretable computational pathology could help enhance the efficiency and consistency of tumor response assessment and empower precise oncology treatment decisions.

Background: Neoadjuvant therapy followed by surgery has become the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC) and accurate pathological response assessment is critical to assess the therapeutic efficacy. However, it can be laborious and inconsistency between different observers may occur. Hence, we aim to develop an interpretable deep-learning model for efficient pathological response assessment following neoadjuvant therapy in ESCC. Methods: This retrospective study analyzed 337 ESCC resection specimens from 2020–2021 at the Pudong-Branch (Cohort 1) and 114 from 2021–2022 at the Puxi-Branch (External Cohort 2) of Fudan University Shanghai Cancer Center. Whole slide images (WSIs) from these two cohorts were generated using different scanning machines to test the ability of the model in handling color variations. Four pathologists independently assessed the pathological response. The senior pathologists annotated tumor beds and residual tumor percentages on WSIs to determine consensus labels. Furthermore, 1850 image patches were randomly extracted from Cohort 1 WSIs and binarily classified for tumor viability. A deep-learning model employing knowledge distillation was developed to automatically classify positive patches for each WSI and estimate the viable residual tumor percentages. Spatial heatmaps were output for model explanations and visualizations. Results: The approach achieved high concordance with pathologist consensus, with an R^2 of 0.8437, a RAcc_0.1 of 0.7586, a RAcc_0.3 of 0.9885, which were comparable to two senior pathologists (R^2 of 0.9202/0.9619, RAcc_0.1 of 8506/0.9425, RAcc_0.3 of 1.000/1.000) and surpassing two junior pathologists (R^2 of 0.5592/0.5474, RAcc_0.1 of 0.5287/0.5287, RAcc_0.3 of 0.9080/0.9310). Visualizations enabled the localization of residual viable tumor to augment microscopic assessment. Conclusion: This work illustrates deep learning's potential for assisting pathological response assessment. Spatial heatmaps and patch examples provide intuitive explanations of model predictions, engendering clinical trust and adoption (Code and data will be available at https://github.com/WinnieLaugh/ESCC%5fPercentage once the paper has been conditionally accepted). Integrating interpretable computational pathology could help enhance the efficiency and consistency of tumor response assessment and empower precise oncology treatment decisions. [ABSTRACT FROM AUTHOR]

Abstract Background The combinations of PD-1 inhibitors with paclitaxel/cisplatinum (PD-1 + TP) and fluoropyrimidine/cisplatinum (PD-1 + FP) both have been shown to improve overall survival (OS) and progression-free survival (PFS) in patients with previously untreated, advanced esophageal squamous cell carcinoma (ESCC). However, there is no consensus on which chemotherapy regimen combined with PD-1 has better efficacy. To deal with this important issue in the first-line treatment of patients with ESCC, a network meta-analysis (NMA) was performed. Methods Data were collected from eligible studies searched in Medline, Web of Science, PubMed, the Cochrane Library and Embase. The pooled hazard ratio (HR) for the OS, and PFS, odds ratio (OR) for the objective response rate (ORR) and ≥ 3 grade treatment-related adverse events (≥ 3TRAEs) were estimated to evaluate the efficacy of PD-1 inhibitors combined with TP or FP. Results Five RCTs and one retrospective study involving 3685 patients and evaluating four treatments were included in this NMA. Compared to other treatments, PD-1 + TP was better. For the PFS, the HRs for PD-1 + TP compared to PD-1 + FP, TP and FP were 0.59 (0.44, 0.80), 0.56 (0.51, 0.61) and 0.45 (0.37, 0.56) respectively. For the OS, PD-1 + TP was also a better treatment compared to other treatments. The HRs were 0.74 (0.56, 0.96), 0.64 (0.57, 0.71), 0.53 (0.43, 0.67) respectively. For the ORR, there was no significant difference between PD-1 + TP and PD-1 + FP, and the ORs were 1.2 (0.69, 2.11). Compare with TP and FP, PD-1 + TP had an obvious advantage, ORs were 2.5 (2.04, 3.04) and 2.95 (1.91, 4.63). For ≥ 3TRAEs, PD-1 + TP compared to other treatments, ORs were 1.34 (0.74, 2.46) and 1.13 (0.92, 1.38) and 2.23 (1.35, 3.69). Conclusion PD-1 + TP significantly improved both PFS and OS compared to PD-1 + FP. Taking into account both efficacy and safety, PD-1 + TP may be a superior first-line treatment option for ESCC.

Background: The combinations of PD-1 inhibitors with paclitaxel/cisplatinum (PD-1 + TP) and fluoropyrimidine/cisplatinum (PD-1 + FP) both have been shown to improve overall survival (OS) and progression-free survival (PFS) in patients with previously untreated, advanced esophageal squamous cell carcinoma (ESCC). However, there is no consensus on which chemotherapy regimen combined with PD-1 has better efficacy. To deal with this important issue in the first-line treatment of patients with ESCC, a network meta-analysis (NMA) was performed. Methods: Data were collected from eligible studies searched in Medline, Web of Science, PubMed, the Cochrane Library and Embase. The pooled hazard ratio (HR) for the OS, and PFS, odds ratio (OR) for the objective response rate (ORR) and ≥ 3 grade treatment-related adverse events (≥ 3TRAEs) were estimated to evaluate the efficacy of PD-1 inhibitors combined with TP or FP. Results: Five RCTs and one retrospective study involving 3685 patients and evaluating four treatments were included in this NMA. Compared to other treatments, PD-1 + TP was better. For the PFS, the HRs for PD-1 + TP compared to PD-1 + FP, TP and FP were 0.59 (0.44, 0.80), 0.56 (0.51, 0.61) and 0.45 (0.37, 0.56) respectively. For the OS, PD-1 + TP was also a better treatment compared to other treatments. The HRs were 0.74 (0.56, 0.96), 0.64 (0.57, 0.71), 0.53 (0.43, 0.67) respectively. For the ORR, there was no significant difference between PD-1 + TP and PD-1 + FP, and the ORs were 1.2 (0.69, 2.11). Compare with TP and FP, PD-1 + TP had an obvious advantage, ORs were 2.5 (2.04, 3.04) and 2.95 (1.91, 4.63). For ≥ 3TRAEs, PD-1 + TP compared to other treatments, ORs were 1.34 (0.74, 2.46) and 1.13 (0.92, 1.38) and 2.23 (1.35, 3.69). Conclusion: PD-1 + TP significantly improved both PFS and OS compared to PD-1 + FP. Taking into account both efficacy and safety, PD-1 + TP may be a superior first-line treatment option for ESCC. [ABSTRACT FROM AUTHOR]

Abstract Background Radical concurrent chemoradiotherapy (CCRT) is frequently used as the first-line treatment for patients with locally advanced esophageal cancer. Unfortunately, some patients respond poorly. To predict response to radical concurrent chemoradiotherapy in pre-treatment patients with esophageal squamous carcinoma (ESCC), and compare the predicting efficacies of radiomics features of primary tumor with or without regional lymph nodes, we developed a radiomics-clinical model based on the positioning CT images. Finally, SHapley Additive exPlanation (SHAP) was used to explain the models. Methods This retrospective study enrolled 105 patients with medically inoperable and/or unresectable ESCC who underwent radical concurrent chemoradiotherapy (CCRT) between October 2018 and May 2023. Patients were classified into responder and non-responder groups with RECIST standards. The 11 recently admitted patients were chosen as the validation set, previously admitted patients were randomly split into the training set (n = 70) and the testing set (n = 24). Primary tumor site (GTV), the primary tumor and the uninvolved lymph nodes at risk of microscopic disease (CTV) were identified as Regions of Interests (ROIs). 1762 radiomics features from GTV and CTV were respectively extracted and then filtered by statistical differential analysis and Least Absolute Shrinkage and Selection Operator (LASSO). The filtered radiomics features combined with 13 clinical features were further filtered with Mutual Information (MI) algorithm. Based on the filtered features, we developed five models (Clinical Model, GTV Model, GTV-Clinical Model, CTV Model, and CTV-Clinical Model) using the random forest algorithm and evaluated for their accuracy, precision, recall, F1-Score and AUC. Finally, SHAP algorithm was adopted for model interpretation to achieve transparency and utilizability. Results The GTV-Clinical model achieves an AUC of 0.82 with a 95% confidence interval (CI) of 0.76–0.99 on testing set and an AUC of 0.97 with a 95% confidence interval (CI) of 0.84–1.0 on validation set, which are significantly higher than those of other models in predicting ESCC response to CCRT. The SHAP force map provides an integrated view of the impact of each feature on individual patients, while the SHAP summary plots indicate that radiomics features have a greater influence on model prediction than clinical factors in our model. Conclusion GTV-Clinical model based on texture features and the maximum diameter of lesion (MDL) may assist clinicians in pre-treatment predicting ESCC response to CCRT.

Background: Esophageal squamous carcinoma (ESCC) is one of the most malignant cancers in the world due to nodal metastasis. Therefore, a reasonable nodal staging system is extremely important for further treatment strategies. Recently the positive lymph node ratio (PLNR) is an important prognostic factor in various solid tumors Method: In this study, we investigated the clinical significance of the PLNR in stage II∼III ESCC patients. We collected the pathological characteristics of 272 stage II∼III ESCC patients from the SEER database from 2004–2016. ROC curves were used to calculate the best cutoff value of the PLNR; Pearson's Chi-square (χ2) and Fisher's exact probability tests were used to compare the clinical baseline and characteristics of patients. For continuous variables, Student's t-test and ANOVA were performed to evaluate statistical significance. Clinical outcomes were estimated by using the Kaplan‒Meier method and log-rank test. Furthermore, univariate and multivariate Cox regression models were utilized to analyze independent prognostic factors of ESCC patients. Results: Consequently, advanced ESCC patients were effectively stratified into two groups by prognosis using a PLNR cutoff value of 0.15 (P value = 0.04). The median survival time of patients with PLNR 45 mm (HR 1.32, 95 % CI 1.02–1.70), N stage (HR 1.41, 95 % CI 0.98–2.01) and PLNR ≥0.15 (HR 1.35, 95 % CI 0.87–1.74) were independent risk factors for prognostic prediction in ESCC patients. Meanwhile, 117 II∼III ESCC patients from Shaanxi Provincial People's Hospital shown that the overall survival with a PLNR

Background: Radical concurrent chemoradiotherapy (CCRT) is frequently used as the first-line treatment for patients with locally advanced esophageal cancer. Unfortunately, some patients respond poorly. To predict response to radical concurrent chemoradiotherapy in pre-treatment patients with esophageal squamous carcinoma (ESCC), and compare the predicting efficacies of radiomics features of primary tumor with or without regional lymph nodes, we developed a radiomics-clinical model based on the positioning CT images. Finally, SHapley Additive exPlanation (SHAP) was used to explain the models. Methods: This retrospective study enrolled 105 patients with medically inoperable and/or unresectable ESCC who underwent radical concurrent chemoradiotherapy (CCRT) between October 2018 and May 2023. Patients were classified into responder and non-responder groups with RECIST standards. The 11 recently admitted patients were chosen as the validation set, previously admitted patients were randomly split into the training set (n = 70) and the testing set (n = 24). Primary tumor site (GTV), the primary tumor and the uninvolved lymph nodes at risk of microscopic disease (CTV) were identified as Regions of Interests (ROIs). 1762 radiomics features from GTV and CTV were respectively extracted and then filtered by statistical differential analysis and Least Absolute Shrinkage and Selection Operator (LASSO). The filtered radiomics features combined with 13 clinical features were further filtered with Mutual Information (MI) algorithm. Based on the filtered features, we developed five models (Clinical Model, GTV Model, GTV-Clinical Model, CTV Model, and CTV-Clinical Model) using the random forest algorithm and evaluated for their accuracy, precision, recall, F1-Score and AUC. Finally, SHAP algorithm was adopted for model interpretation to achieve transparency and utilizability. Results: The GTV-Clinical model achieves an AUC of 0.82 with a 95% confidence interval (CI) of 0.76–0.99 on testing set and an AUC of 0.97 with a 95% confidence interval (CI) of 0.84–1.0 on validation set, which are significantly higher than those of other models in predicting ESCC response to CCRT. The SHAP force map provides an integrated view of the impact of each feature on individual patients, while the SHAP summary plots indicate that radiomics features have a greater influence on model prediction than clinical factors in our model. Conclusion: GTV-Clinical model based on texture features and the maximum diameter of lesion (MDL) may assist clinicians in pre-treatment predicting ESCC response to CCRT. [ABSTRACT FROM AUTHOR]

Background and purpose: The standard treatment for patients with locally advanced esophageal cancer is neoadjuvant chemoradiotherapy (NCRT) plus radical resection. However, the technical aspects for implementing this comprehensive treatment strategy differ, especially in the controversial definition of the radiotherapy target area in NCRT. This study aimed to analyze the feasibility of involving field irradiation (IFI) in NCRT for locally advanced esophageal cancer. Methods: Retrospective analysis of locally advanced esophageal squamous cell carcinoma patients receiving NCRT in Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine from July 2016 to May 2017 showed that the radiotherapy target of all patients was our recommended IFI. The radiotherapy plan was redesigned for the enrolled patients according to the two traditional target delineation of elective node irradiation (ENI) and primary subclinical lesion irradiation (SLI). The dosimetric parameters of the three groups and the dose differences of organ at risk (OAR), such as lungs, heart and spinal cord, were compared, and the relationship between IFI Recurrence pattern and radiation target volumes was analyzed. Results: A total of 26 patients were enrolled. The average target volume of IFI was (277±77) cm3, which was significantly lower compared with ENI and SLI (P

Esophageal squamous carcinoma (ESCC) is a prevalent and highly lethal malignant tumor, with a five-year survival rate of approximately 20 %. Tumor-associated macrophages (TAMs) are the most prominent immune cells in the tumor microenvironment (TME), comprising over 50 % of the tumor volume. TAMs can be polarized into two distinct phenotypes, M1-type and M2-type, through interactions with cancer cells. M2-type TAMs are more abundant than M1-type TAMs in the TME, contributing to tumor progression, such as tumor cell survival and the construction of an immunosuppressive environment. This review focuses on the role of TAMs in ESCC, including their polarization, impact on tumor proliferation, angiogenesis, invasion, migration, therapy resistance, and immunosuppression. In addition, we discuss the potential of targeting TAMs for clinical therapy in ESCC. A thorough comprehension of the molecular biology about TAMs is essential for the development of innovative therapeutic strategies to treat ESCC.

Background: The tricarboxylic acid cycle (TCA cycle) is an important metabolic pathway and closely related to tumor development. However, its role in the development of esophageal squamous cell carcinoma (ESCC) has not been fully investigated. Methods: The RNA expression profiles of ESCC samples were retrieved from the TCGA database, and the GSE53624 dataset was additionally downloaded from the GEO database as the validation cohort. Furthermore, the single cell sequencing dataset GSE160269 was downloaded. TCA cycle-related genes were obtained from the MSigDB database. A risk score model for ESCC based on the key genes of the TCA cycle was built, and its predictive performance was evaluated. The association of the model with immune infiltration and chemoresistance were analyzed using the TIMER database, the R package "oncoPredict" score, TIDE score and so on. Finally, the role of the key gene CTTN was validated through gene knockdown and functional assays. Results: A total of 38 clusters of 8 cell types were identified using the single-cell sequencing data. The cells were divided into two groups according to the TCA cycle score, and 617 genes were identified that were most likely to influence the TCA cycle. By intersecting 976 key genes of the TCA cycle with the results of WGCNA, 57 genes significantly associated with the TCA cycle were further identified, of which 8 were screened through Cox regression and Lasso regression to construct the risk score model. The risk score was a good predictor of prognosis across subgroups of age, N, M classification and TNM stage. Furthermore, BI-2536, camptothecin and NU7441 were identified as possible drug candidates in the high-risk group. The high-risk score was associated with decreased immune infiltration in ESCC, and the low-risk group had better immunogenicity. In addition, we also evaluated the relationship between risk scores and immunotherapy response rates. Functional assays showed that CTTN may affect the proliferation and invasion of ESCC cells through the EMT pathway. Conclusion: We constructed a predictive model for ESCC based on TCA cycleassociated genes, which achieved good prognostic stratification. The model are likely associated with the regulation of tumor immunity in ESCC. [ABSTRACT FROM AUTHOR]

Lymph node metastasis, the leading cause of mortality in esophageal squamous carcinoma (ESCC) with a highly complex tumor microenvironment, remains underexplored. Here, the transcriptomes of85 263 single cells are analyzed from four ESCC patients with lymph node metastases. Strikingly, it is observed that the metastatic microenvironment undergoes the emergence or expansion of interferon induced IFIT3+ T, B cells, and immunosuppressive cells such as APOC1+APOE+ macrophages and myofibroblasts with highly expression of immunoglobulin genes (IGKC) and extracellular matrix component and matrix metallopeptidase genes. A poor-prognostic epithelial-immune dual expression program regulating immune effector processes, whose activity is significantly enhanced in metastatic malignant epithelial cells and enriched in CD74+CXCR4+ and major histocompatibility complex (MHC) class II genes upregulated malignant epithelia cells is discovered. Comparing with primary tumor, differential intercellular communications of metastatic ESCC microenvironment are revealed and furtherly validated via multiplexed immunofluorescence and immunohistochemistry staining, which mainly rely on the crosstalk of APOC1+APOE+ macrophages with tumor and stromal cell. The data highlight potential molecular mechanisms that shape the lymph-node metastatic microenvironment and may inform drug discovery and the development of new strategies to target these prometastatic nontumor components for inhibiting tumor growth and overcoming metastasis to improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Background and purpose: The standard treatment for patients with locally advanced esophageal cancer is neoadjuvant chemoradiotherapy (NCRT) plus radical resection. However, the technical aspects for implementing this comprehensive treatment strategy differ, especially in the controversial definition of the radiotherapy target area in NCRT. This study aimed to analyze the feasibility of involving field irradiation (IFI) in NCRT for locally advanced esophageal cancer. Methods: Retrospective analysis of locally advanced esophageal squamous cell carcinoma patients receiving NCRT in Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine from July 2016 to May 2017 showed that the radiotherapy target of all patients was our recommended IFI. The radiotherapy plan was redesigned for the enrolled patients according to the two traditional target delineation of elective node irradiation (ENI) and primary subclinical lesion irradiation (SLI). The dosimetric parameters of the three groups and the dose differences of organ at risk (OAR), such as lungs, heart and spinal cord, were compared, and the relationship between IFI Recurrence pattern and radiation target volumes was analyzed. Results: A total of 26 patients were enrolled. The average target volume of IFI was (277±77) cm³, which was significantly lower compared with ENI and SLI (P＜0.05). IFI could significantly reduce relative volume fraction of lungs irradiated more than 5 and 20 Gy (V5 and V20), lungs average dose (Dmean), heart V30, heart Dmean and spinal cord maximum dose (Dmax) (P＜0.05), compared with ENI. Lungs V20, lungs Dmean, heart Dmean and spinal cord Dmax decreased by 27.1%, 22.5%, 27.4% and 6.4% compared with ENI, and 24.1%, 22.0%, 24.8% and 5.7% compared with SLI, respectively. After 28 to 69 months of follow-up, 13 patients had recurrence and metastasis, of whom 7 patients had distant metastasis, 4 patients had recurrence in the irradiation field, and 1 patient had local recurrence in the irradiation field. The 3-year overall survival (OS) rate and disease-free survival (DFS) rate were 50.0% and 42.3%, respectively. Conclusion: IFI recommended by our institution is feasible to ensure clinical efficacy while significantly reducing the radiation dose of lungs, heart and spinal cord. [ABSTRACT FROM AUTHOR]

Background: N6-methyladenosine (m6A) RNA methylation plays a crucial role in important genomic processes in a variety of malignancies. However, the characterization of m6A with infiltrating immune cells in the tumor microenvironment (TME) in esophageal squamous carcinoma (ESCC) remains unknown. Methods: The single-cell transcriptome data from five ESCC patients in our hospital were analyzed, and TME clusters associated with prognosis and immune checkpoint genes were investigated. Cell isolation and qPCR were conducted to validate the gene characterization in different cells. Results: According to distinct biological processes and marker genes, macrophages, T cells, and B cells clustered into three to four different subgroups. In addition, we demonstrated that m6A RNA methylation regulators were strongly related to the clinical and biological features of ESCC. Analysis of transcriptome data revealed that m6A-mediated TME cell subsets had high predictive value and showed a close relationship with immune checkpoint genes. The validation results from qPCR demonstrated the characteristics of essential genes. CellChat analysis revealed that RNA from TME cells m6A methylation-associated cell subtypes had substantial and diversified interactions with cancer cells. Further investigation revealed that MIF- (CD74+CXCR4) and MIF- (CD74+CD44) ligand-receptor pairings facilitated communication between m6A-associated subtypes of TME cells and cancer cells. Conclusion: Overall, our study demonstrated for the first time the function of m6A methylation-mediated intercellular communication in the microenvironment of tumors in controlling tumor development and anti-tumor immune regulation in ESCC.

Objective: To compare the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for preventive or delayed treatment in neutropenia, completion rate of concurrent chemoradiotherapy and hospitalization rate in patients with esophageal squamous carcinoma during definitive concurrent chemoradiotherapy. Methods: A total of 70 patients with esophageal squamous carcinoma in Peking University Cancer Hospital from January 2019 to December 2020, who received PEG-rhG-CSF during concurrent chemoradiotherapy, were enrolled in this retrospective analysis. There were 32 patients in the preventive group, and 38 patients in the delayed group. The incidence of neutropenia, completion rate of concurrent chemoradiotherapy and neutropenia-related hospitalization rate were compared between PEG-rhG-CSF preventive group and delayed group. Results: The incidence of severe neutropenia (Grades 3–4) in all patients was 31.4%. Comparison between preventive group and delayed group showed that the incidence of severe neutropenia was 6.3% and 39.4% (χ2 ​= ​10.428, P ​= ​0.001), respectively. In preventive group, the incidence of severe neutropenia was 3.7% and 20.0%, respectively, for primary prevention and secondary prevention of PEG-rhG-CSF (χ2 ​= ​12.321, P ​= ​0.001). The completion rate of concurrent chemoradiotherapy was 93.8% in the preventive group and 63.2% in the delayed group (χ2 ​= ​9.220, P ​= ​0.002). The incidence of treatment interruption was 25.7% in the whole group, 12.5% in the preventive group and 36.8% in the delayed group (χ2 ​= ​5.389, P ​= ​0.020). Seven patients (7/70, 10.0%) were hospitalized and treated with intravenous antibiotics for neutropenia, including 1 in the preventive group and 6 in the delayed group (P ​= ​0.078). Conclusions: Prophylactic use of PEG-rhG-CSF during concurrent chemoradiotherapy for patients with esophageal squamous carcinoma can effectively reduce the incidence of neutropenia, ensure the safety of treatment, and improve the completion rate of concurrent chemoradiotherapy.

Abstract Lymph node metastasis, the leading cause of mortality in esophageal squamous carcinoma (ESCC) with a highly complex tumor microenvironment, remains underexplored. Here, the transcriptomes of 85 263 single cells are analyzed from four ESCC patients with lymph node metastases. Strikingly, it is observed that the metastatic microenvironment undergoes the emergence or expansion of interferon induced IFIT3+ T, B cells, and immunosuppressive cells such as APOC1+APOE+ macrophages and myofibroblasts with highly expression of immunoglobulin genes (IGKC) and extracellular matrix component and matrix metallopeptidase genes. A poor‐prognostic epithelial‐immune dual expression program regulating immune effector processes, whose activity is significantly enhanced in metastatic malignant epithelial cells and enriched in CD74+CXCR4+ and major histocompatibility complex (MHC) class II genes upregulated malignant epithelia cells is discovered. Comparing with primary tumor, differential intercellular communications of metastatic ESCC microenvironment are revealed and furtherly validated via multiplexed immunofluorescence and immunohistochemistry staining, which mainly rely on the crosstalk of APOC1+APOE+ macrophages with tumor and stromal cell. The data highlight potential molecular mechanisms that shape the lymph‐node metastatic microenvironment and may inform drug discovery and the development of new strategies to target these prometastatic nontumor components for inhibiting tumor growth and overcoming metastasis to improve clinical outcomes.

Multiple primary malignancies in general and synchronous cancers, in particular, are relatively rare but have increased in recent decades. We report a case of a 62-year-old Vietnamese male who visited our hospital with the chief symptom was mild dysphagia. An irregular lesion causing the total luminal obstruction was detected at the low third part of the esophagus via endoscopy and two suspicious nodules in the segment V of the liver were incidentally encountered through the Computed tomography (CT). Multiple biopsies from the lesions were then performed. Histopathology and immunohistochemistry results demonstrated Squamous cell carcinoma of the esophagus and Hepatocellular carcinoma of the liver, which verified the existence of synchronous cancers in the patient.

• The comparison between nCRT and nCT in locally advanced ESCC remains inconclusive. • A pooled analysis of IPD from 6 RCTs revealed significant OS and PFS benefits for nCRT compared to doublet chemotherapy. • These findings continue to support the clinical practice of nCRT as one of the standard treatment strategies in resectable ESCC. The comparison of neoadjuvant chemoradiotherapy (nCRT) versus neoadjuvant chemotherapy (nCT) for locally advanced esophageal squamous cell carcinoma (ESCC) remains inconclusive, and the optimal regimen is still under investigation. Prospective randomized clinical trials were systematically searched in electronic databases from inception to Oct 2023. A graphical reconstructive algorithm was employed to extract time-to-event outcomes from Kaplan-Meier curves presented in the original studies. Using reconstructed individual patient data, summary overall survival (OS) and disease progression-free survival (DFS) for nCRT versus nCT, primarily doublet chemotherapy were recalculated. Hazard Ratios (HRs) of OS and DFS reported were also pooled by the fixed-effects model. A total of 6 randomized clinical trials comprising 1162 patients were included in our analysis. In the individual patient data (IPD) pooled analysis, a significant OS benefit was found for nCRT in ESCC (HR=0.81, 95 %CI:0.67–0.98, p=0.029), compared with the treatment of nCT. The median overall survival time were 53 months (95 %CI:41.9–67.7 m) and 66 months(95 %CI:57.2-NA) respectively in the nCT and nCRT groups. Additionally, a significant improvement in PFS for nCRT compared to nCT in the IPD pooled analysis (HR=0.79,95 %CI:0.64–0.98; p=0.027). Consistent with above results, the pooled HRs of OS and DFS for nCRT versus nCT were 0.78 (95 % CI 0.65–0.92, p=0.004) and 0.79 (95 % CI: 0.65–0.97, p=0.02), respectively. Notably, no substantial heterogeneity across studies was observed. Our findings indicate that nCRT offers better survival outcomes for ESCC, at least when compared to neoadjuvant doublet chemotherapy.This evidence continues to support the clinical practice of employing nCRT in locally advanced resectable ESCC. [ABSTRACT FROM AUTHOR]

Background: Studies suggested that circadian clock genes (CCGs) in human esophageal squamous carcinoma (ESCC) samples are dysregulated. However, the relevance of CCGs to lymph node metastasis (LNM) and prognosis of ESCC remains unclear. Methods: The differentially expressed genes (DEGs) between normal and ESCC samples in The Cancer Genome Atlas database (TCGA) database were intersected with the genes associated with LNM (LNMGs) in ESCC samples and 300 CCGs to obtain the differentially expressed LNM-associated CCGs (DE-LNM-CCGs). The risk model was constructed by Cox regression analysis in the TCGA-ESCC training set, and the accuracy of the risk model was verified by risk profile and overall survival profile. Furthermore, differences of 23 immune cells, 13 immune functions, and immune checkpoint molecules between the high- and low-risk groups were assessed using the single-sample gene set enrichment analysis (ssGSEA) algorithm. Gene set enrichment analysis (GSEA) was conducted to investigate the functional differences between low- and high-risk groups. Finally, we validated the mRNA expression levels of prognostic model genes by quantitative real-time polymerase chain reaction (qRT-PCR). Results: A total of six DE-LNM-CCGs were identified in TCGA-ESCC. TP53 and NAGLU were selected by Cox regression analysis to construct the risk model. Risk profile plots, overall survival plots, and validation results of the risk model in the validation set indicated that the constructed risk model was reliable. The result of ssGSEA showed that the percentages of activated B cells, activated dendritic cells, effector memory CD8 T cells, immune function in neutrophils, plasmacytoid dendritic cells, T cell co-inhibition, and Type 17 T helper cells were different between the high- and low-risk groups. In addition, the expression of CD274, PDCD1, TNFRSF18, and TNFRSF9 was dysregulated between the high- and low-risk groups. GSEA revealed that the high-risk group was associated with cell differentiation, oxidative phosphorylation, and steroid biosynthesis pathways, while the low-risk group was associated with chromosome, ECM–receptor interaction, and other pathways. Finally, qRT-PCR results showed that the mRNA expression levels of two prognostic genes were consistent with TCGA. Conclusion: In conclusion, the risk model constructed based on TP53 and NAGLU could accurately predict the prognosis. [ABSTRACT FROM AUTHOR]

Purpose: Discovery of noninvasive urinary biomarkers for the early diagnosis of esophageal squamous carcinoma (ESCC). Methods: We conducted proteomic analyses of 499 human urine samples obtained from healthy individuals (n = 321) and ESCC (n = 83), bladder cancer (n = 17), breast cancer (n = 12), colorectal cancer (n = 16), lung cancer (n = 33) and thyroid cancer (n = 17) patients from multiple medical centers. Those samples were divided into a discovery set (n = 247) and an independent validation set (n = 157). Results: Among urinary proteins identified in the comprehensive quantitative proteomics analysis, we selected a panel of three urinary biomarkers (ANXA1, S100A8, TMEM256), and established a logistic regression model in the discovery set that can correctly classify the majority of ESCC cases in the validation sets with the area under the curve (AUC) values of 0.825. This urinary biomarker panel not only discriminates ESCC patients from healthy individuals but also differentiates ESCC from other common tumors. Notably, the panel distinguishes stage I ESCC patients from healthy individuals with AUC values of 0.886. On the analysis of stage-specific biomarkers, another combination panel of protein (ANXA1, S100A8, SOD3, TMEM256) demonstrated a good AUC value of 0.792 for stage I ESCC. Conclusions: Urinary biomarker panel represents a promising auxiliary diagnostic tool for ESCC, including early-stage ESCC. [ABSTRACT FROM AUTHOR]

Background/Aim: To clarify the clinical significance of measuring the mean corpuscular volume (MCV) of red blood cells before applying neoadjuvant chemotherapy (NAC) in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who will receive NAC followed by curative resection. Patients and Methods: We retrospectively investigated 169 eligible patients at the Kanagawa Cancer Center between 2011-2018. The patients were divided into high and low-MCV groups. The cutoff value of the MCV was determined by the maximum χ2 statistic value on the log-rank test and was set at 92.8 fl. Clinicopathological features and outcomes were compared between the two groups. Results: There was no significant association between the MCV and clinicopathological features. Both five-year recurrence-free survival (RFS) and overall survival (OS) in the high-MCV group were significantly poorer than those in the low-MCV group (RFS, p=0.026; OS, p=0.006). On multivariate analysis, a high-MCV was an independent predictive survival factor for RFS [hazard ratio (HR)=1.728; 95% confidence interval (CI)=1.033-2.891; p=0.037] and OS (HR=1.836; 95%CI=1.002-3.365; p=0.049). Conclusion: Measurement of the MCV before NAC may be a useful prognostic biomarker in patients with locally advanced ESCC who will receive NAC followed by curative resection. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs), such as SNHG6, have been identified as crucial regulators in the progression of various cancers, including esophageal squamous cell carcinoma (ESCC). Although the role of SNHG6 in ESCC is not completely understood, our findings demonstrated that SNHG6 expression is upregulated in ESCC tissues compared to adjacent normal tissues. Furthermore, elevated levels of SNHG6 are significantly correlated with higher TNM stage and poorer clinical prognosis in ESCC patients. Functionally, both in vivo and in vitro experiments have shown that knocking down SNHG6 inhibits proliferation, invasion, and metastasis. Luciferase reporter assays and Ago2-RIP assay confirm that SNHG6 functions as a competing endogenous RNA (ceRNA) by sponging miR-26b-5p to modulate ITGB1 expression in ESCC. Given that ITGB1 is instrumental in EMT and metastasis, we assessed the expression of EMT-related proteins. The findings suggest that miR-26b-5p and reduced ITGB1 expression can reverse the EMT induced by lncRNA SHNG6, as demonstrated through rescue analysis. Overall, this study aims to elucidate the molecular mechanisms through which SNHG6 promotes EMT and metastasis in ESCC, providing a novel theoretical foundation for understanding ESCC progression and identifying new targets for improving outcomes in metastatic ESCC., (© 2024. The Author(s).)

Increasing evidence has indicated that long non-coding RNAs (LncRNAs) play multiple functions in the development of cancer and function as indicators of diagnosis and prognosis. This aim of this study was to investigate the roles LncRNA C9orF139 had in the progression of esophageal squamous carcinoma (ESCC). We found C9orf139 was highly expressed in ESCC and knock down the expression of C9orf139 significantly suppressed cell proliferation, promoted apoptosis, and inhibited migration and invasion. C9orf139 was able to negatively regulate miR-661 expression. At the same time, HDAC11 expression was negatively regulated by miR-661. The C9orf139/miR-661/HDAC11 axis was further involved in regulating the expression of the NF-κB signaling pathway. The association between the C9orf139 knockdown and the reduced tumor growth and size was observed during in vivo study. C9orf139 is highly expressed in ESCC, and is thus qualified to be used as a potential diagnostic and prognostic marker for ESCC. Its promotion of ESCC progression is achieved by mediating the miR-661/HDAC11 axis.

Background: To evaluate and compare the potential performance of various diffusion parameters obtained from mono-exponential model (MEM)-, bi-exponential model (BEM)-, and stretched exponential model (SEM)-based diffusion-weighted imaging (DWI) in grading of esophageal squamous carcinoma (ESC). Methods: Eighty-two patients with pathologically confirmed ESC without treatment underwent multi-b-value DWI scan with 13 b values (0~12,00 s/mm2). The apparent diffusion coefficient (ADC) deriving from the MEM; the pure molecular diffusion (ADCslow), pseudo-diffusion coefficient (ADCfast), perfusion, and fraction (f) deriving from the BEM; and the distributed diffusion coefficient (DDC) and water molecular diffusion heterogeneity index (a) deriving from the SEM were calculated and compared between poorly differentiated and well/moderately differentiated ESC, respectively. The prediction parameters and diagnostic efficiency were compared by drawing receiver operating characteristic (ROC) curves. Results: The ADC, ADCslow, ADCfast, and DDC in poorly ESC were significantly lower than those in well/moderately differentiated ones. By using only one parameter, ADCslow, DDC had the moderate diagnostic efficiency and the areas under the curve (AUC) were 0.758 and 0.813 in differentiating ESC. The DDC had the maximum AUC with sensitivity (88.00%) and specificity (68.42%). Combining ADC with ADCfast, ADCslow, and DDC and combining ADCslow with ADCfast can provide a higher diagnostic accuracy with AUC ranging from 0.756, 0.771, 0.816, and 0.793, respectively. Conclusion: Various parameters derived from different DWI models including MEM, BEM, and SEM were potentially helpful in grading ESC. DDC obtained from SEM was the most promising diffusion parameter for predicting the grade of ESC. [ABSTRACT FROM AUTHOR]

Esophageal cancer is a complex gastrointestinal malignancy with an extremely poor outcome. Approximately 80% of cases of this malignancy in Asian countries including India are of squamous cell origin, termed Esophageal Squamous Cell Carcinoma (ESCC).The five-year survival rate in ESCC patients is less than 20%. Neo-adjuvant chemo-radiotherapy (NACRT) followed by surgical resection remains the major therapeutic strategy for patients with operable ESCC. However, resistance to NACRT and local recurrence after initial treatment are the leading cause of dismal outcomes in these patients. Therefore, an alternative strategy to promote response to the therapy and reduce the post-operative disease recurrence is highly needed. At the molecular level, wide variations have been observed in tumor characteristics among different populations, nevertheless, several common molecular features have been identified which orchestrate disease progression and clinical outcome in the malignancy. Therefore, determination of candidate molecular pathways for targeted therapy remains the mainstream idea of focus in ESCC research. In this review, we have discussed the key signaling pathways associated with ESCC, i.e., Notch, Wnt, and Nrf2 pathways, and their crosstalk during disease progression. We further discuss the recent developments of novel agents to target these pathways in the context of targeted cancer therapy. In-depth research of the signaling pathways, gene signatures, and a combinatorial approach may help in discovering targeted therapy for ESCC. [ABSTRACT FROM AUTHOR]

Beina Hui,1 Shupei Pan,2 Shaomin Che,1 Yuchen Sun,1 Yanli Yan,1 Jia Guo,1 Tuotuo Gong,1 Juan Ren,1 Xiaozhi Zhang1 1Department of Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, People’s Republic of China; 2Department of Radiation Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710004, People’s Republic of ChinaCorrespondence: Juan Ren; Xiaozhi Zhang Tel +86 2985324029; +86 2985324621Email 869491533@qq.com; zhangxiaozhi@xjtu.edu.cnPurpose: Resistance to radiotherapy results in a high treatment failure rate for locally advanced esophageal squamous cell carcinoma (ESCC). Ubiquitin-like with plant homeodomain and ring-finger domains 1 (UHRF1), is associated with poor prognosis in ESCC. The present study aims to characterize the effect of UHRF1 silencing on the radiosensitivity of ESCC and its potential mechanism.Methods: Both in vitro and in vivo experiments were conducted to observe the effects of UHRF1 silencing on the radiosensitivity of ESCC. The effects of UHRF1 silencing on the apoptosis of ESCC cells were assessed by flow cytometry. The expression of apoptosis-related factors (caspase-3 and Bcl-2), PI3K/Akt/mTOR signaling pathway-related factors (PTEN, p-Akt and Akt, p-mTOR and mTOR), and DNMT1 were measured via Western blot, and the status of PTEN methylation was detected by methylation-specific PCR. Immunohistochemistry was used to detect the expressions of PTEN, p-AKT, and p-mTOR in xenograft tumor tissues.Results: In vitro and in vivo experiments showed that UHRF1 knock-down inhibited ESCC cell growth and enhanced their radiosensitivity. shUHRF1 combined with radiation significantly increased ESCC cell apoptosis. Meanwhile, it activated the expression of caspase-3 and inhibited the expression of Bcl-2. shUHRF1 inhibited the expression of DNMT1 and reduced the methylation of PTEN, and then upregulated the expression of PTEN to inhibit the PI3K/Akt/mTOR signaling pathway. On the contrary, the PI3K/Akt/mTOR signaling pathway can be activated by upregulation of UHRF1.Conclusion: Our findings provide a theoretical basis for UHRF1 as a target to improve the radiosensitivity of ESCC.Keywords: radiosensitivity, UHRF1, esophageal squamous carcinoma, shRNA, PI3K/Akt/mTOR

To figure out the molecular mechanism in the esophageal squamous carcinoma (ESCC) with the discrepancy in the tissue-resident microbiota, we selected clinical features, RNA sequences, and transcriptomes of ESCC patients from The Cancer Genome Atlas (TCGA) website and detailed tissue-resident microbiota information from The Cancer Microbiome Atlas (n = 60) and explored the infiltration condition of particular microbiota in each sample. We classified the tissue-resident micro-environment of ESCC into two clusters (A and B) and built a predictive classifier model. Cluster A has a higher proportion of certain tissue-resident microbiota with comparatively better survival, while Cluster B has a lower proportion of certain tissue-resident microbiota with comparatively worse survival. We showed traits of gene and clinicopathology in the esophageal tissue-resident micro-environment (ETM) phenotypes. By comparing the two clusters’ molecular signatures, we find that the two clusters have obvious differences in gene expression and mutation, which lead to pathway expression discrepancy. Several pathways are closely related to tumorigenesis. Our results may demonstrate a synthesis of the infiltration pattern of the esophageal tissue-resident micro-environment in ESCC. We reveal the mechanism of esophageal tissue-resident microbiota discrepancy in ESCC, which may contribute to therapy progress for patients with ESCC.

Background and Purpose: This study aimed to evaluate the geometrical differences in and metabolic parameters of 18F-fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDG PET-CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) performed before and during radiotherapy (RT) for patients with esophageal cancer based on the three-dimensional CT (3DCT) medium and explore whether the high signal area derived from DW-MRI can be used as a tool for an individualized definition of the volume in need of dose escalation for esophageal squamous cancer. Materials and Methods: Thirty-two patients with esophageal squamous cancer sequentially underwent repeated 3DCT, 18F-FDG PET-CT, and enhanced MRI before the initiation of RT and after the 15th fraction. All images were fused with 3DCT images through deformable registration. The gross tumor volume (GTV) was delineated based on PET Edge on the first and second PET-CT images and defined as GTVPETpre and GTVPETdur, respectively. GTVDWIpre and GTVDWIdur were delineated on the first and second DWI and corresponding T2-weighted MRI (T2W-MRI)-fused images. The maximum, mean, and peak standardized uptake values (SUVs; SUVmax, SUVmean, and SUVpeak, respectively); metabolic tumor volume (MTV); and total lesion glycolysis(TLG) and its relative changes were calculated automatically on PET. Similarly, the minimum and mean apparent diffusion coefficient (ADC; ADCmin and ADCmean) and its relative changes were measured manually using ADC maps. Results: The volume of GTVCT exhibited a significant positive correlation with that of GTVPET and GTVDWI (both p < 0.001). Significant differences were observed in both ADCs and 18F-FDG PET metabolic parameters before and during RT (both p < 0.001). No significant correlation was observed between SUVs and ADCs before and during RT (p = 0.072–0.944) and between ∆ADCs and ∆SUVs (p = 0.238–0.854). The conformity index and degree of inclusion of GTVPETpre to GTVDWIpre were significantly higher than those of GTVPETdur to GTVDWIdur (both p < 0.001). The maximum diameter shrinkage rate (∆LDDWI) (24%) and the tumor volume shrinkage rate (VRRDWI) (60%) based on DW-MRI during RT were significantly greater than the corresponding PET-based ∆LDPET (14%) and VRRPET (41%) rates (p = 0.017 and 0.000, respectively). Conclusion: Based on the medium of CT images, there are significant differences in spatial position, biometabolic characteristics, and the tumor shrinkage rate for GTVs derived from 18F-FDG PET-CT and DW-MRI before and during RT for esophageal squamous cancer. Further studies are needed to determine if DW-MRI will be used as tool for an individualized definition of the volume in need of dose escalation. [ABSTRACT FROM AUTHOR]

Background and PurposeThis study aimed to evaluate the geometrical differences in and metabolic parameters of 18F-fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDG PET-CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) performed before and during radiotherapy (RT) for patients with esophageal cancer based on the three-dimensional CT (3DCT) medium and explore whether the high signal area derived from DW-MRI can be used as a tool for an individualized definition of the volume in need of dose escalation for esophageal squamous cancer.Materials and MethodsThirty-two patients with esophageal squamous cancer sequentially underwent repeated 3DCT, 18F-FDG PET-CT, and enhanced MRI before the initiation of RT and after the 15th fraction. All images were fused with 3DCT images through deformable registration. The gross tumor volume (GTV) was delineated based on PET Edge on the first and second PET-CT images and defined as GTVPETpre and GTVPETdur, respectively. GTVDWIpre and GTVDWIdur were delineated on the first and second DWI and corresponding T2-weighted MRI (T2W-MRI)-fused images. The maximum, mean, and peak standardized uptake values (SUVs; SUVmax, SUVmean, and SUVpeak, respectively); metabolic tumor volume (MTV); and total lesion glycolysis(TLG) and its relative changes were calculated automatically on PET. Similarly, the minimum and mean apparent diffusion coefficient (ADC; ADCmin and ADCmean) and its relative changes were measured manually using ADC maps.ResultsThe volume of GTVCT exhibited a significant positive correlation with that of GTVPET and GTVDWI (both p < 0.001). Significant differences were observed in both ADCs and 18F-FDG PET metabolic parameters before and during RT (both p < 0.001). No significant correlation was observed between SUVs and ADCs before and during RT (p = 0.072–0.944) and between ∆ADCs and ∆SUVs (p = 0.238–0.854). The conformity index and degree of inclusion of GTVPETpre to GTVDWIpre were significantly higher than those of GTVPETdur to GTVDWIdur (both p < 0.001). The maximum diameter shrinkage rate (∆LDDWI) (24%) and the tumor volume shrinkage rate (VRRDWI) (60%) based on DW-MRI during RT were significantly greater than the corresponding PET-based ∆LDPET (14%) and VRRPET (41%) rates (p = 0.017 and 0.000, respectively).ConclusionBased on the medium of CT images, there are significant differences in spatial position, biometabolic characteristics, and the tumor shrinkage rate for GTVs derived from 18F-FDG PET-CT and DW-MRI before and during RT for esophageal squamous cancer. Further studies are needed to determine if DW-MRI will be used as tool for an individualized definition of the volume in need of dose escalation.

Background: The prognostic value and clinical relevance of tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) in esophageal squamous cell carcinoma (ESCC) remain unclear., Aims: To investigate the prognostic value and functional involvement of TILs in ESCC., Methods: We included 40 patients across different stages of ESCC from Xinjiang. Multiplex fluorescent immunohistochemistry characterized TILs and TAMs. TILs in different tumor regions were quantified and correlated with overall survival (OS) using log-rank test and Cox regression analyses., Results: Invasive ESCC exhibited increased CD4 T cells and Tregs compared to carcinoma in situ, with a higher Tregs/CD4 T cells ratio (p < 0.05). TAMs, primarily in stromal regions, were significantly associated with Foxp3+ cells (p < 0.05). Higher infiltration of stromal TAMs and a higher CD4/CD8 T cells ratio correlated with poorer OS, while a higher CD8 T/Foxp3+ cells ratio indicated better survival. Multivariate Cox analysis revealed TNM stage, tumor length, and stromal CD4/CD8 T cells ratio as independent prognostic factors (p < 0.05). An immune prognostic risk score-based nomogram was constructed to predict patient outcomes., Conclusions: The spatial distribution and abundance of TILs significantly correlated with prognosis, providing a useful immune classification for ESCC., Competing Interests: Conflicts of interest The authors declare that there are no conflict of interests, we do not have any possible conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Background and Objective: The intercourse between Esophageal squamous cell carcinoma etc. (ESC) and Celiac disease (CD) is still a complicated subject. The purpose of this research was to define the relationship between CD and ESC, and the factors associated with CD in patients with ESC. Methods: This research was conducted by Van University Medical Center in Turkey from 2012 to 2016. CD was identified by analyzing duodenal biopsy materials from 63 ESC patients via histopathologic examinations. Serum samples from the patients were also serologically tested to identify CD. A control group was selected from among subjects who underwent gastroduodenoscopy due to dyspepsia. Distinctions between case characteristics were evaluated with chi-square tests and t-tests for categorical and continuous factors, respectively. Results: Of the 63 study cases, 6 (9.5%) were both histological and serological positive for CD. Of the 290 control group, 8 (2.8%) had histopathological CD and tested positive for celiac antibodies. The patients with ESC had a significantly higher prevalence of CD compared to the dyspeptic patients (p<0.001). In addition, the mean creatinine levels of ESC patients with histopathological-proven CD were higher than those without CD (p=0.026). Furthermore, ESC patients who tested positive for tTg IgA had significantly higher levels of glucose and AST than those who were negative for tTg IgA (p=0.032) and (p=0.008), respectively. Conclusion: The present study demonstrated a statistically significant positive correlation between ESC and CD. Most remarkably, higher creatinine, glucose, and AST levels may predict CD in patients with ESC. These evidences may lead novel approaches for preventing ESC in patients with CD. [ABSTRACT FROM AUTHOR]

Background: Studies suggested that circadian clock genes (CCGs) in human esophageal squamous carcinoma (ESCC) samples are dysregulated. However, the relevance of CCGs to lymph node metastasis (LNM) and prognosis of ESCC remains unclear. Methods: The differentially expressed genes (DEGs) between normal and ESCC samples in The Cancer Genome Atlas database (TCGA) database were intersected with the genes associated with LNM (LNMGs) in ESCC samples and 300 CCGs to obtain the differentially expressed LNM-associated CCGs (DE-LNM-CCGs). The risk model was constructed by Cox regression analysis in the TCGA-ESCC training set, and the accuracy of the risk model was verified by risk profile and overall survival profile. Furthermore, differences of 23 immune cells, 13 immune functions, and immune checkpoint molecules between the high- and low-risk groups were assessed using the single-sample gene set enrichment analysis (ssGSEA) algorithm. Gene set enrichment analysis (GSEA) was conducted to investigate the functional differences between low- and high-risk groups. Finally, we validated the mRNA expression levels of prognostic model genes by quantitative real-time polymerase chain reaction (qRT-PCR). Results: A total of six DE-LNM-CCGs were identified in TCGA-ESCC. TP53 and NAGLU were selected by Cox regression analysis to construct the risk model. Risk profile plots, overall survival plots, and validation results of the risk model in the validation set indicated that the constructed risk model was reliable. The result of ssGSEA showed that the percentages of activated B cells, activated dendritic cells, effector memory CD8 T cells, immune function in neutrophils, plasmacytoid dendritic cells, T cell co-inhibition, and Type 17 T helper cells were different between the high- and low-risk groups. In addition, the expression of CD274, PDCD1, TNFRSF18, and TNFRSF9 was dysregulated between the high- and low-risk groups. GSEA revealed that the high-risk group was associated with cell differentiation, oxidative phosphorylation, and steroid biosynthesis pathways, while the low-risk group was associated with chromosome, ECM–receptor interaction, and other pathways. Finally, qRT-PCR results showed that the mRNA expression levels of two prognostic genes were consistent with TCGA. Conclusion: In conclusion, the risk model constructed based on TP53 and NAGLU could accurately predict the prognosis.

Purpose/objectives: Primary small cell esophageal carcinoma (SCEC) is a rare malignancy without an established treatment strategy. This study investigated the gene expression profile of SCEC and compared it with the expression profiles of small cell lung cancer (SCLC) and esophageal adeno/squamous carcinoma (EAC/ESCC).Materials/methods: All patients with SCEC, SCLC, and EAC/ESCC in the Surveillance, Epidemiology, and End Results (SEER) database 1973–2014 were included. Overall survival (OS) and prognostic analysis were conducted. De novo expression array analysis was performed on three pairs of frozen primary SCEC tissues and the corresponding normal samples from the institutional tissue bank using the Affymetrix HG U133 plus 2.0 Array. These data were complemented with public domain expression data sets from the Gene Expression Omnibus (GEO) repository using the same working platforms, which included primary SCLC, EAC/ESCC, and normal lung/esophagus specimens (series GSE30219 and GSE26886). After individual normalization, the primary tumors were submitted to statistical analysis (GeneSpring GX 13.0) to identify the differentially expressed genes (DEGs) relative to their paired normal tissues. Enrichments of genes categorized by function and gene interactions were analyzed by DAVID 6.8 and STRING 11.0, respectively.Results: The clinical outcomes of the patients with SCEC were significantly more worse than those with EAC/ESCC and SCLC in the SEER database. SCEC had more DEGs in common with SCLC than EAC/ESCC [829 vs. 450; false discovery rate (FDR) < 0.01; and fold change ≥2], leading to a stronger correlation between SCEC and SCLC (Pearson's correlation coefficient was 0.60 for SCEC vs. SCLC, 0.51 or 0.45 for SCEC vs. ESCC or EAC, and the coefficient was 0.73 for ESCC vs. EAC). Similar findings were obtained by principal component analysis (PCA) using all DEGs retrieved from these four groups. Functional annotation showed that a higher proportion of pathways and biological processes were common between SCEC and SCLC and were associated with the cell cycle (mitosis), DNA replication, telomere maintenance, DNA repair, and P53 and RB pathways (Benjamini p < 0.05). Compared with EAC/ESCC, SCEC shared more co-upregulated DEGs coding for the aforementioned common pathways with SCLC (584 vs. 155). In addition, SCEC and SCLC were found to have possessed overlapping gene-interactive networks, with centromere protein F (CENPF), never in mitosis gene A-related kinase 2 (NEK2), kinesin family member 11 (KIF11), thymopoietin (TMPO), and forkhead box protein M1 (FOXM1) as common skeletons centered by gene regulatory network (NUF2).Conclusions: This study is the first attempt to examine the genomic signatures of SCEC at the transcriptomic level and compare the expression profiles between SCEC, SCLC, and EAC/ESCC. Our preliminary data indicate that SCEC and SCLC display notably similar patterns of gene expression for mitosis and DNA repair. Further validation studies are warranted.

Objective To investigate CircHIPK3 expression in esophageal squamous cell carcinoma (ESCC) tissues, so as to find a new way of diagnosis and targeted therapy. Methods qRT-PCR, CCK-8, Transwell and flow cytometry were performed to detect the difference of CircHIPK3 expression in tumor tissues and adjacent normal tissues, and its effect on cell proliferation, invasion, migration and apoptosis, respectively. Bioinformatics analysis was used to determine the possible pathway of CircHIPK3, and Western blot was used to verify its pathway-related functional proteins. Results qRT-PCR results showed the abnormal expression of CircHIPK3 in 11 cases of cancer tissues and 7 cases of paracancerous tissues (P=0.027). The high expression of CircHIPK3 increased cell proliferation (P < 0.001), migration (P < 0.001) and invasion (P < 0.001) abilities. CircHIPK3 overexpression inhibited the apoptosis of EC9706 cells and tumor suppressor gene p53, activated intracellular Akt-Mdm2 signaling pathway, and increased the expression of p53-Akt-Mdm2 pathway protein accordingly. Ultimately, cancer cell proliferation, migration, invasion and cancer protein expression were enhanced. Conclusion CircHIPK3 promotes the proliferation, migration and invasion of human esophageal cancer cells, and inhibits the apoptosis by regulating the p53-Akt-Mdm2 signaling pathway. CircHIPK3 may be a potential target for the diagnosis and treatment of esophageal cancer.

Objective To explore the effect and mechanism of metformin(Metf) on side population(SP) cells of human esophageal squamous cell carcinoma. Methods We detected SP ratio of different esophageal squamous cell lines and sorted of SP cells by flow cytometry. The effects of metformin on the proliferation of SP cells in vitro were detected by CCK-8 method, plate cloning and sphere assay. The effect of Metf on the expression of SP cell-associated gene protein was detected by Western blot. Results The SP ratio of the nine esophageal squamous carcinoma cell lines in this experiment was 0.2%-2%. Metf could reduce the SP ratio of KYSE 150, significantly inhibiting the cell proliferation, the number of clones and the number of spheres of SP cells. The degree of inhibition was positively correlated with Metf concentration and administration time. The difference is statistically significant (P < 0.01). In addition, Metf reduced the expression of the relevant stem genes SOX2 and OCT4 in SP cells to varying degrees. Conclusion Metf could reduce the ratio of SP cells in esophageal squamous cell carcinoma, which may provide a new approach for the treatment and prevention of esophageal cancer.

Immune checkpoint inhibitors have demonstrated promising efficacy and tolerable safety for advanced malignancies. However, a proportion of patients who had received immunotherapy may experience hyperprogressive disease and a resultant poor prognosis. Here, we report a patient with advanced esophageal squamous carcinoma who developed hyperprogressive disease shortly after immunotherapy. This patient received nivolumab after multiple lines of treatment, including chemotherapy, radiotherapy, and antiangiogenic therapy. Through the comprehensive analysis of NGS results, we concluded that the PI3K/AKT signaling pathway might be associated with hyperprogressive disease after immunotherapy. Additionally, potential mechanisms underlying hyperprogressive disease after immunotherapy reported in other malignant tumors were also summarized. [ABSTRACT FROM AUTHOR]

Background : Death domain-associated protein (DAXX), originally identified as a pro-apoptotic protein, is now understood to be either a pro-apoptotic or an anti-apoptotic factor with a chromatin remodeler, depending on the cell type and context. This study evaluated DAXX expression and its clinical implications in squamous cell carcinoma of the esophagus. Methods : Paraffin-embedded tissues from 60 cases of esophageal squamous carcinoma were analyzed immunohistochemically. An immune reaction with more than 10% of tumor cells was interpreted as positive. Positive reactions were sorted into 2 groups: reactions in 11%-50% of tumor cells and reactions in more than 51% of tumor cells, and the correlations between expression and survival and clinical prognosticators were analyzed. Results : Forty-three of the 60 cases (71.7%) showed strong nuclear DAXX expression, among which 19 cases showed a positive reaction (31.7%) in 11%-50% of tumor cells, and 24 cases (40.0%) showed a positive reaction in more than 51% of tumor cells. A negative reaction was found in 17 cases (28.3%). These patterns of immunostaining were significantly associated with the N stage (p=0.005) and American Joint Committee on Cancer stage (p=0.001), but overall survival showed no significant difference. There were no correlations of DAXX expression with age, gender, or T stage. However, in stage IIB (p=0.046) and stage IV (p=0.014) disease, DAXX expression was significantly correlated with survival. Conclusion : This investigation found upregulation of DAXX in esophageal cancer, with a 71.7% expression rate. DAXX immunostaining could be used in clinical practice to predict aggressive tumors with lymph node metastasis in advanced-stage disease, especially in stages IIB and IV.

Background: There is increased interest in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for predicting the outcomes of patients with advanced esophageal cancer.Purpose: To explore whether DCE-MRI histogram parameters can predict 12-month progression-free survival (PFS) in patients with advanced esophageal squamous carcinoma receiving concurrent chemoradiation therapy (CRT).Material and Methods: This retrospective study enrolled 134 patients with advanced esophageal squamous carcinoma who were receiving CRT. The pre-CRT DCE-MRI histogram parameters (median, mean, SD, skewness, kurtosis, and 10th and 90th percentiles) of Ktrans, Kep, and Ve were collected. PFS analyses were performed using the Kaplan-Meier method and log-rank tests to compute the survival curves. The significant prognostic predictors among the data characteristics and DCE-MRI parameters were determined using multivariate Cox proportional hazards regression analyses.Results: There were 65 good responders (PFS ≥ 12 months) and 69 poor responders (PFS < 12 months). The median and mean values of Ktrans were higher, and the kurtosis value of Ktrans was lower in good responders. The median, mean, and 10th and 90th percentile values of Ktrans were higher, and the kurtosis values of Ktrans and Ve were lower in good responders. The PFS of patients aged ≥60 years, a CR effect, or a 10th percentile value of Ktrans ≥0.13 was increased (P < 0.001, <0.001, and 0.014, respectively).Conclusion: DCE-MRI histogram parameters can be used to evaluate the response to CRT in patients with advanced esophageal squamous carcinoma. The 10th percentile value of Ktrans has significant prognostic value for 12-month PFS. [ABSTRACT FROM AUTHOR]

Objective Our study aims to investigate the radiation associated H3 modification in regulating OIP5-AS1 to lay foundation for developing therapeutic targets on reversing radiation resistance of esophageal squamous carcinoma. Methods We recruited 137 ESCC patients from The First Affiliated Hospital of Xi􀆳an Medical College. qRT-PCR and Western blotting were used for detecting the expressions of target genes. Wound healing assay and CCK8 assay were used to detect the migration and proliferation abilities. ChIP assay was used to detect the interaction between OIP5-AS1 and H3K27ac. Results OIP5-AS1 was highly expressed in ESCC radiation resistant patients and promoted the migration and proliferation abilities of ESCC radiation resistant cells. H3K27ac was activated in ESCC radiation resistant cells and was enriched in the promoter region of OIP5-AS1. CBP was upregulated in ESCC radiation resistant cells; its inhibitor, C646, could suppress the enrichment of H3K27ac in the promoter region of OIP5-AS1. Conclusion OIP5-AS1 regulated radioresistance in ESCC. CBP promoted the interaction between H3K27ac and OIP5-AS1, thereby activating the expression of OIP5-AS1 and resulting in radioresistance. [ABSTRACT FROM AUTHOR]

Abstract Background Hereditary diffuse gastric carcinoma (HDGC) accounts for 1–3% of all gastric carcinomas. Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal (GI) tract but they comprise fewer than 1% of all GI malignancies. Small-cell carcinoma (SmCC) is a rare histological type of esophageal carcinoma, accounting for 0.4% to 2.8% of all esophageal tumors. Co-occurrence of SmCC with esophageal tumors caused by squamous carcinoma is also very uncommon. Although multiple primary malignancies are no longer rare in clinical practice, the simultaneous appearance of HDGC, GIST, esophageal small cell and squamous carcinoma in situ is extremely rare and very few cases have been reported. Case presentation We present a case of a 53 year-old woman with synchronous occurrence of four malignancies including HDGC, GIST, esophageal small cell- and local squamous carcinoma in situ. A total gastrectomy with D2 lymph node dissection and postoperative adjuvant chemotherapy with oxaliplatin and paclitaxel liposome were performed. After a 1-year follow-up, this patient was still in good condition with no evidence of recurrence. Conclusion This is the unique case that describes the co-existence of the aforementioned four types of neoplasm. This case demonstrates that a diagnosis of gastric cancer does not preclude the presence of other malignancies and every case should be thoroughly analyzed to avoid missing other problems, which may worsen the prognosis.

Guanine nucleotide exchange factor T (GEFT), a member of the Rho guanine nucleotide exchange factor family, is expressed in a variety of tumors. In the present study, the expression and clinical significance of GEFT in malignant digestive tract tumors was assessed. Tumor and adjacent control samples from 180 patients were tested. Positive GEFT expression rates were 80, 83.33 and 86.67% in esophageal squamous carcinoma (ESCC), gastric carcinoma (GC) and colorectal cancer (CRC), respectively. GEFT expression was associated with diffuse type carcinoma according to the Lauren classification (χ2=12.525, P=0.002) and tumor-node-metastasis (TNM) stages III/IV (χ2=4.033, P=0.045) in GC, and with vessel carcinoma embolus (χ2=7.890, P=0.005) and lymph node metastasis (χ2=5.455, P=0.020) in CRC, but was not associated with other clinicopathological parameters. Patients with high levels of GEFT protein expression had a less favorable outcome compared with patients with low levels of GEFT expression in patients with CRC (χ2=3.876, P=0.049). However, a significant association was not found between GEFT expression and overall survival in patients with ESCC (χ2=0.040, P=0.842) or GC (χ2=0.501, P=0.479). The rate of human epidermal growth factor receptor 2 upregulation in patients with GC was 13.33% and it was associated with nerve invasion (χ2=4.005, P=0.045) and TNM stages III/IV (χ2=5.600, P=0.018). Mismatch repair protein (MMRP) defect was observed in six cases, and the KRAS mutation rate was 26.67% in patients with CRC. GEFT expression was significantly correlated with MMRP (r=−0.285, P=0.027) and KRAS mutation in patients with CRC (r=0.697, P<0.001). These findings revealed frequent GEFT upregulation in malignant digestive tract tumors, which may have promoted tumor development. GEFT expression in CRC may be associated with microsatellite instability and KRAS mutation status, suggesting that GEFT may be a potential therapeutic target for patients with CRC. [ABSTRACT FROM AUTHOR]

Abundant evidence indicates that long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) serve important roles in tumorigenesis and tumour progression. However, their diagnostic and treatment value for esophageal squamous carcinoma (ESCC) remains unknown. A microarray (SBC human ceRNA array V1.0) was performed to assess the expression profiles and biological functions of lncRNAs, circRNAs and mRNAs in ESCC and para-cancerous tissues from three patients. Microarray data were validated by reverse transcription-quantitative polymerase chain reaction for a group of genes. A number of lncRNA-microRNAs (miRNA) and circRNA-miRNA-mRNA networks were constructed. Bioinformatics tools, including gene ontology and Kyoto Encyclopedia of Genes and Genomes biological pathway analyses, were used to predict the functions of differentially expressed lncRNAs, circRNAs and potentially co-expressed target genes. The results revealed that compared with the expression levels of para-cancerous tissues, 1,384 lncRNAs, 2,046 circRNAs and 936 mRNAs were frequently altered in ESCC tissues. Co-expression networks of lncRNAs-miRNAs-circRNAs-mRNAs were constructed based on the correlation analyses among the differentially expressed RNAs. Furthermore, using bioinformatics methods, correlation expression networks were constructed that included cis- and trans-regulatory elements. Therefore, these results suggest that lncRNAs and circRNAs may be involved in the pathogenesis and development of ESCC. These findings provide a novel and systematic perspective on the potential function of noncoding RNAs in ESCC. [ABSTRACT FROM AUTHOR]

Esophageal squamous carcinoma (ESCC) is a prevalent and highly lethal malignant tumor, with a five-year survival rate of approximately 20 %. Tumor-associated macrophages (TAMs) are the most prominent immune cells in the tumor microenvironment (TME), comprising over 50 % of the tumor volume. TAMs can be polarized into two distinct phenotypes, M1-type and M2-type, through interactions with cancer cells. M2-type TAMs are more abundant than M1-type TAMs in the TME, contributing to tumor progression, such as tumor cell survival and the construction of an immunosuppressive environment. This review focuses on the role of TAMs in ESCC, including their polarization, impact on tumor proliferation, angiogenesis, invasion, migration, therapy resistance, and immunosuppression. In addition, we discuss the potential of targeting TAMs for clinical therapy in ESCC. A thorough comprehension of the molecular biology about TAMs is essential for the development of innovative therapeutic strategies to treat ESCC. [Display omitted] • Summary of TAMs polarization in the tumor microenvironment. • A review on the role of TAMs in the progression and metastasis in ESCC. • Contribution of TAMs to treatment resistance and immunosuppressive microenvironment formation in ESCC. • Proposal of the possibility of targeting TAMs for the ESCC therapy. [ABSTRACT FROM AUTHOR]

Background: Esophageal squamous carcinoma (ESCC) is one of the most malignant cancers in the world due to nodal metastasis. Therefore, a reasonable nodal staging system is extremely important for further treatment strategies. Recently the positive lymph node ratio (PLNR) is an important prognostic factor in various solid tumors., Method: In this study, we investigated the clinical significance of the PLNR in stage II∼III ESCC patients. We collected the pathological characteristics of 272 stage II∼III ESCC patients from the SEER database from 2004-2016. ROC curves were used to calculate the best cutoff value of the PLNR; Pearson's Chi-square (χ2) and Fisher's exact probability tests were used to compare the clinical baseline and characteristics of patients. For continuous variables, Student's t -test and ANOVA were performed to evaluate statistical significance. Clinical outcomes were estimated by using the Kaplan‒Meier method and log-rank test. Furthermore, univariate and multivariate Cox regression models were utilized to analyze independent prognostic factors of ESCC patients., Results: Consequently, advanced ESCC patients were effectively stratified into two groups by prognosis using a PLNR cutoff value of 0.15 (P value = 0.04). The median survival time of patients with PLNR <0.15 (n = 145) was much higher than that of patients (n = 127) in the PLNR ≥0.15 group (20.0 vs. 13.0 months, P value < 0.0001). Notably, the PLNR significantly predicted the prognosis of ESCC patients with stage N1 (P value 0.01) and stage III (P value < 0.001) disease. The multivariate Cox proportional hazard model showed that T stage (HR 1.33, 95 % CI 0.97-1.82), tumor size >45 mm (HR 1.32, 95 % CI 1.02-1.70), N stage (HR 1.41, 95 % CI 0.98-2.01) and PLNR ≥0.15 (HR 1.35, 95 % CI 0.87-1.74) were independent risk factors for prognostic prediction in ESCC patients. Meanwhile, 117 II∼III ESCC patients from Shaanxi Provincial People's Hospital shown that the overall survival with a PLNR <0.15 (n = 96) was significantly longer than that with a PLNR ≥0.15 (n = 21) ., Conclusions: The PLNR is useful for accurately predicting clinical outcomes and determining postoperative strategies., Competing Interests: All authors declared no potential conflicts of interest with respect to the research, author-ship, and/or publication of this article., (© 2023 The Authors.)

Background: Precisely forecasting the prognosis of esophageal squamous cell carcinoma (ESCC) patients is a formidable challenge. Cuproptosis has been implicated in ESCC pathogenesis; however, the prognostic value of cuproptosis-associated long noncoding RNAs (CuRLs) in ESCC is unclear., Methods: Transcriptomic and clinical data related to ESCC were sourced from The Cancer Genome Atlas (TCGA). Using coexpression and Cox regression analysis to identify prognostically significant CuRLs, a prognostic signature was created. Nomogram models were established by incorporating the risk score and clinical characteristics. Tumor Immune Dysfunction and Rejection (TIDE) scores were derived by conducting an immune landscape analysis and evaluating the tumor mutational burden (TMB). Drug sensitivity analysis was performed to explore the underlying molecular mechanisms and guide clinical dosing., Results: Our risk score based on 5 CuRLs accurately predicted poorer prognosis in high-risk ESCC patients across almost all subgroups. The nomogram that included the risk score provided more precise prognostic predictions. Immune pathways, such as the B-cell receptor signaling pathway, were enriched in the datasets from high-risk patients. High TMB in high-risk patients indicated a relatively poor prognosis. High-risk patients with lower TIDE scores were found to benefit more from immunotherapy. High-risk patients exhibited greater responsiveness to Nilotinib, BI-2536, P22077, Zoledronate, and Fulvestrant, as revealed by drug sensitivity analysis. Real-time PCR validation demonstrated significant differential expression of four CuRLs between ESCC and normal cell lines., Conclusions: The above risk score and nomogram can accurately predict prognosis in ESCC patients and provide guidance for chemotherapy and immunotherapy.

Radiotherapy is one of the common treatments for esophageal squamous cell carcinoma (ESCC). Yet, local recurrence led by radioresistance is still not solved. Lobaplatin (LBP) is known to have powerful clinical anti-tumor activities in various tumors, but its effect in radiotherapy is rarely studied. Here we report that LBP is a promising radiosensitizer for ESCC. We treated ESCC cells with LBP and radiation, both separately and in combination. Untreated cells were set as control groups. We found that LBP inhibited ESCC cell growth and enhanced their radiosensitivity. LBP also impeded the tumor growth in vivo . LBP combined with radiation significantly increased ESCC cell apoptosis. Meanwhile, LBP obviously decreased the expression of cancer stem cells biomarker CD271 both in vitro and in vivo . The molecular mechanism was related to the downregulation of Bcl-2/Bax ratio, PI3K and p-AKT (Ser473) expression. Taken together, our findings indicated that LBP could enhance the radiosensitivity of ESCC cells by increasing radiation-induced apoptosis, attenuating cancer stemness and inhibiting PI3K/AKT pathway. These results provide a foundation for the combined therapy of radiation and LBP for ESCC in clinical practice. [ABSTRACT FROM AUTHOR]

Dysregulation of micro (mi)RNA-let-7 has been associated with the development and prognosis of multiple cancer types. Lin28, a RNA-binding protein, plays a conserved role in regulating the maturation of let-7 family proteins. However, few studies have focused on the effects of Lin28/let-7 on Wnt-activated esophageal squamous cell carcinoma (ESCC). Analysis of the expression of let-7a, let-7b and let-7c in clinical tissues revealed that lower let-7a expression was correlated with higher tumor node metastasis staging and recurrence in patients with ESCC. Furthermore, it was demonstrated that let-7a was inversely correlated with the migration and invasion of ESCC cells. In addition, epithelialmesenchymal transition, and the expression of VEGF-C and MMP9 were effectively decreased by let-7a-mimic or siRNALin28 pretreatment. Mechanistically, Lin28 functioned as the key factor in signal transduction, which regulated the expression of let-7a and the downstream genes along the Wnt signaling pathway. Taken together, these findings identified a biochemical and functional association between Lin28/let-7a, and the Wnt pathway in ESCC cells. [ABSTRACT FROM AUTHOR]