Visibility of esophageal squamous cell carcinoma under iodine staining on texture and color enhancement imaging.

Objective: Iodine staining on white light imaging (WLI) is the gold standard for detecting and demarcating esophageal squamous cell carcinoma (ESCC). We examined the effects of texture and color enhancement imaging (TXI) on improving the endoscopic visibility of ESCC under iodine staining. Methods: Twenty ESCC lesions that underwent endoscopic submucosal dissection were retrospectively included. The color difference between ESCC and the surrounding mucosa (ΔEe) on WLI, TXI, and narrow-band imaging was assessed, and ΔEe under 1% iodine staining on WLI and TXI. Furthermore, the visibility grade determined by endoscopists was evaluated on each imaging. Result: The median ΔEe was greater on TXI than on WLI (14.53 vs. 10.71, respectively; p < 0.005). Moreover, the median ΔEe on TXI under iodine staining was greater than the median ΔEe on TXI and narrow-band imaging (39.20 vs. 14.53 vs. 16.42, respectively; p < 0.005 for both). A positive correlation in ΔEe under iodine staining was found between TXI and WLI (correlation coefficient = 0.61, p < 0.01). Moreover, ΔEe under iodine staining on TXI in each lesion was greater than the corresponding ΔEe on WLI. The visibility grade assessed by endoscopists on TXI was also significantly greater than that on WLI under iodine staining (p < 0.01). Conclusions: The visibility of ESCC after iodine staining was greater on TXI than on WLI.

Prognostic modeling and Emerging therapeutic targets Unveiled through single-cell sequencing in esophageal squamous Cell carcinoma.

ESCC presents a significant global health challenge due to its high mortality rates and varying responses to treatment. This underscores the critical need for novel diagnostic and predictive biomarkers to improve treatment outcomes. Initially, we conducted single-cell transcriptome sequencing on a total of 128,688 cells obtained from 10 patients as part of our research. Utilizing machine learning and cross-validation techniques, we developed a model incorporating 12 genes that distinguish malignant cells from non-malignant ones. In vitro, we explored the effects of IGFBP2 knockdown on the proliferation, invasion, and migration of ESCC cells. The clinical relevance of IGFBP2 was confirmed through IHC and Kaplan-Meier survival analyses. Furthermore, using bioinformatics tools such as GSVA and xCell on public databases, we discovered that high expression of IGFBP2 is associated with an immunosuppressive tumor microenvironment in ESCC, characterized by reduced CD8+ T cell infiltration. This was validated then through IHC. In summary, our study integrates single-cell sequencing and sophisticated computational techniques to highlight IGFBP2 as a promising biomarker and therapeutic target in ESCC.

Lymph node metastasis determined miRNAs in esophageal squamous cell carcinoma.

PURPOSE: There is no golden noninvasive and effective technique to diagnose lymph node metastasis (LNM) for esophageal squamous cell carcinoma (ESCC) patients. Here, a classifier was proposed consisting of miRNAs to screen ESCC patients with LNM from the ones without LNM. METHODS: miRNA expression and clinical data files of 93 ESCC samples were downloaded from TCGA as the discovery set and 119 ESCC samples with similar dataset GSE43732 as the validation set. Differentially expressed miRNAs (DE-miRNAs) were analyzed between patients with LNM and without LNM. LASSO regression was performed for selecting the DE-miRNA pair to consist the classifier. To validate the accuracy and reliability of the classifier, the SVM and AdaBoost algorithms were applied. The CCK-8 and wound healing assay were used to evaluate the role of the miRNA in ESCC cells. RESULT: There were 43 DE miRNAs between the LNM+ group and LNM- group. Among them, miR-224-5p, miR-99a-5p, miR-100-5p, miR-34c-5p, miR-503-5p, and miR-452-5p were identified by LASSO to establish the classifier. SVM and AdaBoost showed that the model could classify the ESCC patients with LNM from the ones without LNM precisely and reliably in 2 data sets. miR-224-5p in the classifier as the top contributor to discriminate the two groups of patients based on AdaBoost, promoted ESCC cell proliferation and migration in vitro. CONCLUSION: The classifier based on these 6 miRNAs could classify the ESCC patients with LNM from the ones without LNM successfully.

Prediction of lymphovascular invasion in esophageal squamous cell carcinoma by computed tomography-based radiomics analysis: 2D or 3D ?

BACKGROUND: To compare the performance between one-slice two-dimensional (2D) and whole-volume three-dimensional (3D) computed tomography (CT)-based radiomics models in the prediction of lymphovascular invasion (LVI) status in esophageal squamous cell carcinoma (ESCC). METHODS: Two hundred twenty-four patients with ESCC (158 LVI-absent and 66 LVI-present) were enrolled in this retrospective study. The enrolled patients were randomly split into the training and testing sets with a 7:3 ratio. The 2D and 3D radiomics features were derived from the primary tumors' 2D and 3D regions of interest (ROIs) using 1.0 mm thickness contrast-enhanced CT (CECT) images. The 2D and 3D radiomics features were screened using inter-/intra-class correlation coefficient (ICC) analysis, Wilcoxon rank-sum test, Spearman correlation test, and the least absolute shrinkage and selection operator, and the radiomics models were built by multivariate logistic stepwise regression. The performance of 2D and 3D radiomics models was assessed by the area under the receiver operating characteristic (ROC) curve. The actual clinical utility of the 2D and 3D radiomics models was evaluated by decision curve analysis (DCA). RESULTS: There were 753 radiomics features from 2D ROIs and 1130 radiomics features from 3D ROIs, and finally, 7 features were retained to construct 2D and 3D radiomics models, respectively. ROC analysis revealed that in both the training and testing sets, the 3D radiomics model exhibited higher AUC values than the 2D radiomics model (0.930 versus 0.852 and 0.897 versus 0.851, respectively). The 3D radiomics model showed higher accuracy than the 2D radiomics model in the training and testing sets (0.899 versus 0.728 and 0.788 versus 0.758, respectively). In addition, the 3D radiomics model has higher specificity and positive predictive value, while the 2D radiomics model has higher sensitivity and negative predictive value. The DCA indicated that the 3D radiomics model provided higher actual clinical utility regarding overall net benefit than the 2D radiomics model. CONCLUSIONS: Both 2D and 3D radiomics features can be employed as potential biomarkers to predict the LVI in ESCC. The performance of the 3D radiomics model is better than that of the 2D radiomics model for the prediction of the LVI in ESCC.

Number of Resected Lymph Nodes and Survival Status in Node-Negative Esophageal Squamous Cell Carcinoma: A Cohort Study.

Objective: To explore the association between survival status and the number of resected lymph nodes in node-negative esophageal squamous cell carcinoma(ESCC) after surgical treatment. Methods: This was a retrospective observational cohort study and data were obtained from the Surveillance, Epidemiology, and End Results program (SEER) and TaiZhou hospital in China. The data for subjects with negative lymph nodes and no distant metastasis (pN0M0) after post-operative pathology were screened. The nonlinear relationship between resected lymph node number and survival status in node-negative ESCC was conducted using restricted cubic spline regression analysis. The association between the number of resected lymph nodes and survival status in node-negative ESCC was evaluated by Cox proportional hazards regression models. Subgroup analysis based on different subgroups was also performed. Results: A total of 999 subjects were included in the study. Restricted cubic spline regression was used to show a U shaped association between the number of resected lymph nodes and survival status in node-negative ESCC, with low count associated with a decreased survival. To elucidate the association, we adjusted for age, sex, race, T stage, TNM (tumor node metastasis classification), location, grade, chemotherapy, and radiotherapy. As the resected lymph node number increased by one node, the survival status was improved by 2% (Hazard ratio(HR) = 0.98, 95% confidence interval (CI) 0.98-0.99). Sensitivity analysis indicate that the effect size and direction in different subgroups are consistent, the results is stability in SEER. Conclusion: A low count of resected lymph nodes correlated with reduced survival in patients with ESCC, where resecting 25 to 28 or more nodes is considered optimal. Larger prospective studies are warranted to confirm these findings.

Plasma-derived Exosomal miR-25-3p and miR-23b-3p as Predictors of Response to Chemoradiotherapy in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Exosomal miRNAs have emerged as promising biomarkers for cancer. However, little is known about the role of exosomal miRNAs in the response prediction of esophageal squamous cell carcinoma (ESCC) patients treated with chemoradiotherapy (CRT). METHODS: In this prospective study, 40 ESCC patients treated by CRT were enrolled from January 2021 to June 2022. Exosomes were isolated from plasma through EXODUS platform. We used small RNA sequencing in 14 samples of ESCC patients (7 responders, 7 non-responders) and the selected exosomal miRNAs were further validated in the extended cohort of 40 ESCC patients by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: In the discovery phase, we identified five significantly differentially expressed exosomal miRNAs from miRNA sequencing data between the responder and non-responder patients. In the extended groups of responders (n = 27) and non-responders (n = 13), only miR-23b-3p (p = 0.035, AUC = 0.708) and miR-25-3p (p < 0.001, AUC = 0.932) were confirmed to have the predictive ability to distinguish non-responders from responders. The patients with low levels of miR-25-3p had a significantly shorter progression-free survival (PFS) than those with high levels (p = 0.035). Multivariate Cox regression analysis revealed that miR-25-3p may serve as an independent predictive biomarker of PFS in ESCC patients received CRT. CONCLUSION: Exosomal miR-25-3p and miR-23b-3p serve as promising biomarkers for predicting the early effectiveness of CRT in locally advanced ESCC patients, whereas miR-25-3p is a novel prognostic marker for ESCC. However, further larger prospective studies are needed to confirm their utility for individualized treatment decision in ESCC.

Examining the relationship between preoperative nutritional and symptom assessment and postoperative atrial fibrillation in esophageal squamous cell carcinoma patients: a retrospective cohort study.

OBJECTIVE: The study aimed to examine the relationship between preoperative nutritional status, symptom burden, and the occurrence of postoperative atrial fibrillation in Esophageal Squamous Cell Carcinoma patients. METHODS: The study, conducted in the Department of Thoracic Surgery at the Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, applied the NRS 2002, SGA and MSAS scoring systems as measures of nutritional status and symptom occurrence in patients diagnosed with ESCC. Univariate and multivariate logistic regression analysis were performed to evaluate the association between nutritional scores, symptom scores, and postoperative complications. RESULTS: The research found a significant correlation between high MSAS scores and postoperative atrial fibrillation. Patients with high symptom burden also tended to have nutritional risk or malnutrition according to the NRS2002 and SGA scores. CONCLUSION: There is a need for healthcare providers to pay attention to ESCC patients' physical and psychological symptoms. Close monitoring of nutritional status and timely nutritional interventions should be integrated into these patients' care plans as they have been found to be related to postoperative complications such as atrial fibrillation.

Landscape of epithelial cell subpopulations in the human esophageal squamous cell carcinoma microenvironment.

Aims: We sought to reveal the landscape of epithelial cell subpopulations in the human esophageal squamous cell carcinoma microenvironment and investigate their parts on esophageal squamous carcinoma (ESCC) development. Background: Epithelial cells play an important role in the occurrence and development of ESCC through multiple mechanisms. While the landscape of epithelial cell subpopulations in ESCC, remains unclear. Objective: Exploring the role of epithelial cell subpopulations in ESCC progression. Methods: Seurat R package was used for single-cell RNA sequencing (scRNA-seq) data filtering, dimensionality reduction, clustering and differentially expressed genes analysis. Cellmarker database was adopted for cell cluster annotation. Functional enrichment analysis was carried out by Gene Ontology (GO) analysis. InferCNV package was conducted for copy number variation (CNV) of epithelial cell subpopulations in all chromosomal regions. Pseudotime trajectory analysis was implemented for exploring differentiation trajectory of epithelial cells subgroups during the cancer progression. CellChat analysis was used for probing the interactions between epithelial cells and NK/T cells. cellular experiments were performed using Quantitative Real-Time Polymerase Chain Reaction (RT-qPCR), Wound-Healing Assay and transwell. Results: 11 major cell subpopulations were identified in ESCC and adjunct tissues. Further reclassification of epithelial cells uncovered 4 subpopulations. Enrichment analysis revealed that highly expressed genes in 4 epithelial cell subpopulations were related to cell proliferation, immune response and angiogenesis. CNV analysis found that UBD + epithelial cells and GAS2L3+ epithelial cells had a higher proportion of CNV. Cell differentiation trajectories disclosed that KRT6C+ and GSTA1+ epithelial cells were in an intermediate state of differentiation, while UBD+ and GAS2L3+ epithelial cells are in an end state of differentiation during ESCC progression. Finally, we found that four epithelial cell subpopulations all inhibited NK/T cells through NECTIN2-TIGIT and CLEC2B-KLRB1. Low ATF3 and DDIT3 mRNA expression inhibited ESCC cell migration and invasion. Conclusion: Here, we obtained a through epithelial cell atlas of ESCC at single-cell resolution, explored the role of epithelial cell in ESCC progression, and unveiled immunosuppressive signals to NK/T cells in promoting ESCC. Our findings expand the comprehension of epithelial cells and offer a theoretical guidance for future anti-epithelial cell treatment of ESCC.

Downregulation of chemokine (C­C motif) ligand 5 induced by a novel 8­hydroxyquinoline derivative (91b1) suppresses tumor invasiveness in esophageal carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a particularly aggressive form of cancer with high mortality. In the present study, a novel 8­hydroxyquinoline derivative (91b1) was investigated for its anticancer activities in ESCC along with its associated mechanisms. The in vitro cytotoxic effect of 91b1 were evaluated across five ESCC cell lines using MTS assay, with cisplatin serving as a comparative standard. Changes in gene expression profile were identified by cDNA microarray and further validated by qualitative PCR and immunostaining. Additionally, protein levels of the most notably downregulated target in archival ESCC samples were also studied. 91b1 demonstrated comparable anticancer effect with cisplatin. Notably, chemokine ligand 5 (Ccl5) was identified as the most substantially downregulated gene, with its suppression at both mRNA and protein expression in ESCC cells, exhibiting a dose­dependent manner. The recombinant human protein of CCL5 enhanced the invasion of ESCC cells using the Transwell assay. The upregulation of CCL5 protein was also detected in 50% of ESCC cell lines. CCL5 was also overexpressed in 76.9% of ESCC specimens. The overall results indicated that 91b1 could effectively induce anticancer effect on ESCC cells through downregulating CCL5 expression with suppression of tumor invasion. Overall, these findings suggested that 91b1 effectively inhibited ESCC cell proliferation and tumor invasion by downregulating CCL5 expression, highlighting its potential as a therapeutic agent for ESCC treatment.

Characteristics of lymph node metastasis and short-term outcome of esophageal squamous-cell carcinoma undergoing minimally invasive esophagectomy: a prospective cross-sectional study (with video).

Introduction: Surgery for esophageal squamous-cell carcinoma (ESCC) presents many potential challenges owing to malignant lymph node metastasis, complex procedures and severe postoperative complications. The appropriate lymphadenectomy for ESCC remains controversial. This study aims to evaluate the characteristics of lymph node metastasis and postoperative complications in patients with ESCC undergoing minimally invasive esophagectomy and extended two-field lymph node dissection. Patients and methods: This prospective, single-center, cross-sectional study was conducted from October 2022 to May 2024. All patients with ESCC who underwent minimally invasive esophagectomy and extended two-field lymph node dissection were selected for this study. Postoperative lymph nodes were divided into upper thoracic, middle thoracic, lower thoracic and abdominal lymph node groups. Results: Seventy-four patients with ESCC, including 49 patients who underwent upfront surgery and 25 patients who received preoperative chemoradiotherapy, were selected. The rate of lymph node metastasis in all patients was 39.2%, with 13.6% of patients having upper thoracic metastasis. The factors affecting the rate of lymph node metastasis included preoperative chemoradiotherapy, tumor stage, poor differentiation, lymphovascular/perineural invasion, and tumor size greater than 2 cm, all of which were significantly different (P<0.05). Common postoperative complications included pneumonia (25.7%), recurrent laryngeal nerve (RLN) palsy (10.8%) and anastomotic leak (4.1%). There were no cases required conversion to open surgery, nor any deaths within 90 days postoperatively. Conclusion: Lymph node metastasis in esophageal squamous-cell carcinoma has a high incidence, occurs in the early stages, and is widely distributed in all regions of the mediastinum and abdomen. Minimally invasive esophagectomy and extended two-field lymph node dissection are feasible and safe, with low complication rates.

N6-methyladenosine-mediated upregulation of LNCAROD confers radioresistance in esophageal squamous cell carcinoma through stabilizing PARP1.

BACKGROUND: Radiotherapy is a primary therapeutic modality for esophageal squamous cell carcinoma (ESCC), but its effectiveness is still restricted due to the resistance of cancer cells to radiation. Long non-coding RNAs (lncRNAs) and N6-methyladenosine (m6A) have been shown to play significant roles in tumour radioresistance. However, the precise manifestation and role of m6A-modified lncRNAs in ESCC radioresistance remain unclear. METHODS: Bioinformatics analysis was conducted to identify m6A-modified lncRNAs implicated in the radioresistance of ESCC. A series of functional experiments were performed to investigate the function of LNCAROD in ESCC. Methylated RNA immunoprecipitation, chromatin isolation by RNA purification-mass spectrometry, RNA immunoprecipitation, and co-immunoprecipitation experiments were performed to explore the mechanism of m6A-mediated upregulation of LNCAROD expression and the downstream mechanism enhancing the radioresistance of ESCC. The efficacy of LNCAROD in vivo was assessed using murine xenograft models. RESULTS: Herein, we identified LNCAROD as a novel METTL3-mediated lncRNA that enhanced radioresistance in ESCC cells and was post-transcriptionally stabilised by YTHDC1. Moreover, we confirmed that LNCAROD prevented ubiquitin-proteasome degradation of PARP1 protein by facilitating PARP1-NPM1 interaction, thereby contributing to homologous recombination-mediated DNA double-strand breaks repair and enhancing the radiation resistance of ESCC cells. Silencing LNCAROD in a nude mouse model of ESCC in vivo resulted in slower tumour growth and increased radiosensitivity. CONCLUSION: Our findings enhance the understanding of m6A-modified lncRNA-driven machinery in ESCC radioresistance and underscore the significance of LNCAROD in this context, thereby contributing to the development of a potential therapeutic target for ESCC patients.

Integrative analyses of bulk and single-cell RNA-seq reveals the correlation between SPP1+ macrophages and resistance to neoadjuvant chemoimmunotherapy in esophageal squamous cell carcinoma.

Neoadjuvant chemoimmunotherapy (NACI) has significant implications for the treatment of esophageal cancer. However, its clinical efficacy varies considerably among patients, necessitating further investigation into the underlying mechanisms. The rapid advancement of single-cell RNA sequencing (scRNA-seq) technology facilitates the analysis of patient heterogeneity at the cellular level, particularly regarding treatment outcomes. In this study, we first analyzed scRNA-seq data of esophageal squamous cell carcinoma (ESCC) following NACI, obtained from the Gene Expression Omnibus (GEO) database. After performing dimensionality reduction, clustering, and annotation on the scRNA-seq data, we employed CellChat to investigate differences in cell-cell communication among samples from distinct efficacy groups. The results indicated that macrophages in the non-responder exhibited stronger cell communication intensity compared to those in responders, with SPP1 and GALECTIN signals showing the most significant differences between the two groups. This finding underscores the crucial role of macrophages in the efficacy of NACI. Subsequently, reclustering of macrophages revealed that Mac-SPP1 may be primarily responsible for treatment resistance, while Mac-C1QC appears to promote T cell activation. Finally, we conducted transcriptome sequencing on ESCC tissues obtained from 32 patients who underwent surgery following NACI. Utilizing CIBERSORT, CIBERSORTx, and WGCNA, we analyzed the heterogeneity of tumor microenvironment among different efficacy groups and validated the correlation between SPP1+ macrophages and resistance to NACI in ESCC using publicly available transcriptome sequencing datasets. These findings suggest that SPP1+ macrophages may represent a key factor contributing to resistance against NACI in ESCC.

Conversion surgery for esophageal and esophagogastric junction cancer.

As a result of the recent advances in first-line treatment including chemotherapy, radiation therapy, targeted therapy, and immune checkpoint inhibitor immunotherapy (ICI) for locally advanced/metastatic initially unresectable esophageal and esophagogastric junction cancer, surgery aiming at cure after initial treatment, so-called "conversion surgery" has become more common in this field. Several studies have indicated encouraging survival outcomes for patients after conversion surgery with R0 resection. However, various issues, such the utility and the safety of conversion surgery remain unclear. In this review, we will focus on the surgical treatment for initially unresectable esophageal and esophagogastric junction cancer after first- or later- line treatment and review recent evidence regarding the safety and the efficacy of conversion surgery. Multidisciplinary treatment including surgery may serve as a novel treatment strategy for esophageal and esophagogastric junction cancer, thus provide a curative treatment option and potentially contribute to better prognosis for initially untreatable diseases.

Impact of baseline steroids on the efficacy of neoadjuvant immunochemotherapy in locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Immunochemotherapy involving the combination of programmed cell death 1/programmed cell death ligand 1 inhibitors with chemotherapy has advanced the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). The use of corticosteroids as pretreatment might reduce immunotherapy efficacy. AIM: To investigate the impact of baseline corticosteroid use on neoadjuvant immunochemotherapy (nIC) outcomes in locally advanced ESCC patients. METHODS: Patients with locally advanced ESCC who received nIC at Sun Yat-sen University Cancer Center and the Third Affiliated Hospital of Sun Yat-sen University were included. Patients were divided into dexamethasone and antihistamine groups on the basis of the administered pretreatment. Antiallergic efficacy and safety were evaluated, as well as its impact on short-term efficacy [complete pathological response (pCR), major pathological response (MPR)] and long-term efficacy [overall survival (OS), progression-free survival (PFS)] of nIC. RESULTS: From September 2019 to September 2023, 142 patients were analyzed. No severe treatment-related adverse events or deaths were observed. Allergy occurrence was greater in the antihistamine group (P = 0.014). Short-term efficacy was not significantly different: The pCR rates were 29.9% and 40.0%, and the MPR rates were 57.9% and 65.7% in the dexamethasone and antihistamine groups, respectively. The long-term efficacy was not significantly different: The 2 years OS rates were 95.2% and 93.5%, and the 2 years PFS rates were 90.3% and 87.8%. Subgroup analysis revealed no difference in OS between the 20 mg dexamethasone group and the < 20 mg dexamethasone group, but PFS was significantly greater in the 20 mg dexamethasone group (93.9% vs 56.4%, P = 0.001). CONCLUSION: Dexamethasone or antihistamines can be used before nIC in locally advanced ESCC without affecting short- or long-term efficacy. Administering 20 mg dexamethasone before nIC may improve PFS in ESCC.

Integrated analyses reveal IDO1 as a prognostic biomarker coexpressed with PD-1 on tumor-associated macrophages in esophageal squamous cell carcinoma.

Background: Inhibition of indolamine-2,3-dioxygenase 1 (IDO1) has been proposed as a promising strategy for cancer immunotherapy; however, it has failed in clinical trials. Macrophages in the tumor microenvironment (TME) contribute to immune escape and serve as potential therapeutic targets. This study investigated the expression pattern of IDO1 in TME and its impact on prognosis and therapeutic response of patients with esophageal squamous cell carcinoma (ESCC). Methods: RNA sequencing data from 95 patients with ESCC from The Cancer Genome Atlas (TCGA) database were used to explore the prognostic value of IDO1. Bioinformatics tools were used to estimate scores for stromal and immune cells in tumour tissues, abundance of eight immune cell types in TME, and sensitivity of chemotherapeutic drugs and immune checkpoint (IC) blockage. The results were validated using digitalized immunohistochemistry and multiplexed immunofluorescence in ESCC tissue samples obtained from our clinical center. Results: TCGA and validation data suggested that high expression of IDO1 was associated with poor patient survival, and IDO1 was an independent prognostic factor. IDO1 expression positively correlated with macrophages in TME and PDCD1 within diverse IC genes. Single-cell RNA sequencing data analysis and multiplexed immunofluorescence verified the coexpression of IDO1 and PD-1 in tumor-associated macrophages (TAMs). Patients with high IDO1 expression showed increased sensitivity to various chemotherapeutic drugs, while were more likely to resist IC blockage. Conclusion: This study identifies IDO1 as an independent prognostic indicator of OS in patients with ESCC, reveals a compelling connection of IDO1, PD-1, and TAMs, and explores the sensitivity of patients with high IDO1 expression to chemotherapeutic drugs and their resistance to IC blockade. These findings open new avenues for potential targets in ESCC immunotherapy.

High microvessel and lymphatic vessel density predict poor prognosis in patients with esophageal squamous cell carcinoma.

Background: Microangiogenesis and lymphangiogenesis are essential for tumor growth in the tumor microenvironment, contributing to tumor invasion and metastasis. Limited literature exists on these processes in esophageal squamous cell carcinoma (ESCC). Therefore, the purpose of this study is to explore the impacts of microangiogenesis and lymphangiogenesis on the occurrence, progression, and prognosis assessment of ESCC. Methods: Surgical specimens and paraffin-embedded human tissues were procured from ESCC patients, encompassing 100 ESCC tissues and 100 cancer-adjacent normal (CAN) tissues. CD34 and D2-40 were utilized as markers for microvessel endothelial cells and lymphatic vessel endothelial cells, respectively. Microvascular density (MVD) and lymphatic vessel density (LVD) were evaluated through immunohistochemical quantification. Results: We found that tumor tissues in ESCC patients had significantly higher MVD and LVD than cancer-adjacent normal (CAN) tissues. High MVD and LVD were associated with lymph node metastasis and advanced tumor clinical stages. Additionally, both high MVD and high LVD were strongly linked to poorer prognosis among cancer patients. Furthermore, a positive correlation was found between high MVD and high LVD (p < 0.05). The presence of these markers individually indicated a worse prognosis, with their combined assessment showcasing enhanced prognostic value. Conclusions: Overall, the increased MVD and LVD indicates higher invasion and metastasis of ESCC, closely correlating with unfavorablefor poor prognosis of ESCC patients.

Comparison of pathologic response and survival outcomes between neoadjuvant chemoradiotherapy (nCRT) and neoadjuvant immunochemotherapy (nICT) in patients with locally advanced esophageal squamous cell carcinoma: a propensity score-matched analysis.

BACKGROUND: In locally advanced, operable esophageal squamous cell carcinoma (ESCC), neoadjuvant immunochemotherapy (nICT) has shown results that are somewhat comparable to those of standard neoadjuvant chemoradiotherapy (nCRT). The impact of these neoadjuvant treatments on survival outcomes, however, has yet to be elucidated. METHODS: This study included 489 patients with locally advanced ESCC who underwent surgery at Sichuan Cancer Hospital after receiving neoadjuvant treatment between June 2017 and September 2023. Patients were categorized into nCRT and nICT groups based on whether they received neoadjuvant treatment. To mitigate potential biases and balance covariates between the two cohorts, 1:2 propensity score matching (PSM) was conducted using a caliper width of 0.05. RESULTS: After PSM, the baseline characteristics of the 360 patients remained balanced between the two groups. The findings indicated a superior pathological response in the nCRT group, as evidenced by significantly greater rates of complete response (32.87% vs 14.58%, P < 0.001) and favorable tumor regression grade (TRG), as well as reduced ypT stages and less perineural and angioinvasion, despite comparable ypN stages. Despite the improvement in complete pathological response (pCR) in the nCRT group, the 3-year disease-free survival (DFS) and overall survival (OS) rates did not significantly differ between the groups (DFS: 58.32% vs 56.16%, P = 0.67; OS: 69.96% vs 71.99%, P = 0.99). Crucially, The nICT group showed a lower incidence of grade 3 and 4 adverse events in Leukopenia (2.8% vs 29%; P < 0.001) and Neutropenia (2.8% vs 24%; P < 0.001) during neoadjuvant treatment, comparing with nCRT group. CONCLUSIONS: Our preliminary findings suggest that nICT followed by surgery offers comparable survival rates to nCRT, despite being less effective in pathologic outcomes. Nonetheless, nICT is a safe and feasible strategy for locally advanced ESCC, warranting further exploration to understand its impact on long-term survival.

Efficacy and toxicity of anlotinib plus camrelizumab versus anlotinib plus S-1 as second-line therapy for advanced esophageal squamous cell carcinoma: A real-world retrospective study.

Background: No data exist on the efficacy and safety of anlotinib plus camrelizumab doublet as second-line therapy for advanced esophageal squamous cell carcinoma (ESCC). Although anlotinib and the programmed death-1 (PD-1) inhibitor camrelizumab are used as treatments for ESCC, the combined use of anlotinib and camrelizumab as a second-line therapy has not been reported. Therefore, this study explored the efficacy and toxicity of anlotinib plus camrelizumab as second-line therapy for advanced ESCC. Methods: Fifty-eight patients with advanced ESCC undergoing second-line therapy, either with anlotinib plus camrelizumab or anlotinib plus S-1, were enrolled and retrospectively analyzed at Jiangsu Province Hospital of Chinese Medicine from January 2020 to December 2021. The primary endpoint was progression-free survival (PFS), with secondary endpoints including the objective response rate (ORR), disease control rate (DCR), and assessment of toxicity. Results: In patients with advanced ESCC, the anlotinib plus camrelizumab group (N = 32) exhibited longer PFS (8.00 vs. 4.53 months, P < 0.001), higher ORR (28.1 vs. 19.2%, P = 0.431), and higher DCR (87.5 vs. 65.4%, P = 0.045) than those in the anlotinib plus S-1 group (N = 26). Treatment-related adverse events (TRAEs) were predominantly grade 1/2 in both groups, with a higher incidence of grade 1/2 skin toxicity in patients treated with anlotinib plus camrelizumab (P = 0.033). Two patients (6.3%) developed grade 1/2 immune-related pneumonia. The incidence of grade 3/4 TRAEs did not differ significantly between the two groups. Multivariable Cox regression analysis identified that the drug regimen (P < 0.001), Eastern Cooperative Oncology Group performance status (P = 0.008), and differentiation grade (P = 0.008) were independent prognostic factors for PFS. Conclusions: Anlotinib plus camrelizumab exhibited promising antitumor efficacy and manageable toxicity when used as a second-line treatment for advanced ESCC.

Phase II Trial of Adjuvant S-1 Following Neoadjuvant Chemotherapy and Surgery in Patients with Locally Advanced Esophageal Squamous Cell Carcinoma: The PIECE Trial.

BACKGROUND: Neoadjuvant chemotherapy followed by surgery (NAC-S) is the standard therapy for locally advanced esophageal squamous cell carcinoma (ESCC) in Japan. OBJECTIVE: The aim of this phase II trial was to assess the efficacy and safety of the addition of adjuvant S-1 after R0 resection in ESCC patients who received NAC-S. PATIENTS AND METHODS: Key eligibility criteria included clinical stage IB-III (without T4 disease) ESCC, age 20-75 years, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients received adjuvant therapy with four cycles of S-1 (80 mg/m2/day) administered orally for 4 weeks of 6-week cycles. The primary endpoint was 3 year relapse-free survival (RFS). If the lower confidence limit for 3 year RFS was >50%, we judged that the primary endpoint of this study was met. RESULTS: A total of 52 patients were enrolled between January 2016 and January 2019. Two patients were excluded from analysis; five patients were determined to have R1 or R2 resection, and seven patients did not receive adjuvant S-1. The 3-year RFS and overall survival rates in the intention-to-treat population were 72.3% (90% confidence interval [CI] 59.9-81.5) and 85.0% (90% CI 73.9-91.6), indicating that the primary endpoint was met. Grade ≥3 adverse events with an incidence ≥10% included neutropenia (13.2%), anorexia (13.2%), and diarrhea (10.5%). There were no treatment-related deaths. CONCLUSION: Adjuvant S-1 after NAC-S showed promising efficacy with a manageable safety profile for patients with resectable ESCC and warrants further evaluation in larger studies.