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Recent single-arm studies involving neoadjuvant camrelizumab, a PD-1 inhibitor, plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) have shown promising results. This multicenter, randomized, open-label phase 3 trial aimed to further assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy followed by adjuvant camrelizumab, compared to neoadjuvant chemotherapy alone. A total of 391 patients with resectable thoracic LA-ESCC (T1b-3N1-3M0 or T3N0M0) were stratified by clinical stage (I/II, III or IVA) and randomized in a 1:1:1 ratio to undergo two cycles of neoadjuvant therapy. Treatments included camrelizumab, albumin-bound paclitaxel and cisplatin (Cam+nab-TP group; n = 132); camrelizumab, paclitaxel and cisplatin (Cam+TP group; n = 130); and paclitaxel with cisplatin (TP group; n = 129), followed by surgical resection. Both the Cam+nab-TP and Cam+TP groups also received adjuvant camrelizumab. The dual primary endpoints were the rate of pathological complete response (pCR), as evaluated by a blind independent review committee, and event-free survival (EFS), as assessed by investigators. This study reports the final analysis of pCR rates. In the intention-to-treat population, the Cam+nab-TP and Cam+TP groups exhibited significantly higher pCR rates of 28.0% and 15.4%, respectively, compared to 4.7% in the TP group (Cam+nab-TP versus TP: difference 23.5%, 95% confidence interval (CI) 15.1-32.0, P < 0.0001; Cam+TP versus TP: difference 10.9%, 95% CI 3.7-18.1, P = 0.0034). The study met its primary endpoint of pCR; however, EFS is not yet mature. The incidence of grade ≥3 treatment-related adverse events during neoadjuvant treatment was 34.1% for the Cam+nab-TP group, 29.2% for the Cam+TP group and 28.8% for the TP group; the postoperative complication rates were 34.2%, 38.8% and 32.0%, respectively. Neoadjuvant camrelizumab plus chemotherapy demonstrated superior pCR rates compared to chemotherapy alone for LA-ESCC, with a tolerable safety profile. Chinese Clinical Trial Registry identifier: ChiCTR2000040034 ., (© 2024. The Author(s).)

Krüppel-like factor 12 (KLF12) has been characterized as a transcriptional repressor, and previous studies have unveiled its roles in angiogenesis, neural tube defect, and natural killer (NK) cell proliferation. However, the contribution of KLF12 to cancer treatment remains undefined. Here, we show that KLF12 is downregulated in various cancer types, and KLF12 downregulation promotes cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma (ESCC). Mechanistically, KLF12 binds to the promoters of L1 Cell Adhesion Molecule (L1CAM) and represses its expression. Depletion of L1CAM abrogates cisplatin resistance and cancer metastasis caused by KLF12 loss. Moreover, the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) binds to the N-terminal region of KLF12 and ubiquitinates KLF12 at K326 via K33-linked polyubiquitination. Notably, TRIM27 depletion enhances the transcriptional activity of KLF12 and consequently inhibits L1CAM expression. Overall, our study elucidated a novel regulatory mechanism involving TRIM27, KLF12 and L1CAM, which plays a substantial role in cisplatin resistance and cancer metastasis in ESCC. Targeting these genes could be a promising approach for ESCC treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: More than 40% of patients with resectable esophageal squamous cell cancer (ESCC) achieve pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT), who have favorable prognosis and may benefit from an organ-preservation strategy. Our study aims to develop and validate a machine learning model based on MR radiomics to accurately predict the pCR of ESCC patients after nCRT., Methods: In this retrospective multicenter study, eligible patients with ESCC who underwent baseline MR (T2-weighted imaging) and nCRT plus surgery were enrolled between September 2014 and September 2022 at institution 1 (training set) and between December 2017 and August 2021 at institution 2 (testing set). Models were constructed using machine learning algorithms based on clinical factors and MR radiomics to predict pCR after nCRT. The area under the curve (AUC) and cutoff analysis were used to evaluate model performance., Results: A total of 155 patients were enrolled in this study, 82 in the training set and 73 in the testing set. The radiomics model was constructed based on two radiomics features, achieving AUCs of 0.968 (95%CI 0.933-0.992) in the training set and 0.885 (95%CI 0.800-0.958) in the testing set. The cutoff analysis resulted in an accuracy of 82.2% (95%CI 72.6-90.4%), a sensitivity of 75.0% (95%CI 58.3-91.7%), and a specificity of 85.7% (95%CI 75.5-96.0%) in the testing set., Conclusion: A machine learning model based on MR radiomics was developed and validated to accurately predict pCR after nCRT in patients with ESCC., (© 2024. The Author(s).)

Background: Tumor budding (TB) and tumor-infiltrating lymphocyte (TIL) are significant predictive indicators of lymph node metastasis (LNM) and unfavorable prognosis in various tumors. Currently, there is no gold standard for TB and TIL evaluation in esophageal squamous cell carcinoma (ESCC). This study aimed to identify the standard of TB and TIL evaluations and build a predictive model for prognosis among patients with pT1b ESCC., Methods: We retrospectively analyzed the prognostic values of TB and TIL in 150 pT1b ESCC cases. Hematoxylin and eosin (H&E) and immunohistochemistry (IHC) of anti-pan cytokeratin (AE1/AE3) were used to analyze the threshold of TB, and intratumoral TIL and peritumoral TIL (pTIL) were evaluated using the receiver operating characteristic curves (ROC)., Results: We found that TB in a three-tiered grading system (low-TB: 0-4; middle-TB: 5-15; high-TB: ≥16) displayed an excellent prognosis prediction for LNM and survival based on IHC staining using a 20× objective lens. Low pTIL level (≤20%) was a significant indicator of LNM and unfavorable prognosis (p < 0.05). Moreover, lower tumor location and lymphovascular invasion (LVI) were correlated with an unfavorable prognosis (p < 0.05). A nomogram developed based on TB, pTIL, LVI, and tumor location showed good discrimination, as shown by the area under the ROC and calibration curves., Conclusion: We therefore recommend identifying TB using a 20× objective lens under IHC staining and TIL adjacent to the tumor. Additionally, a nomogram was built for facilitating individualized prediction of survival for patients with pT1b ESCC., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Introduction: Adjuvant radiotherapy is recommended for pT1b esophageal squamous cell cancer (ESCC) after endoscopic submucosal dissection (ESD). However, it is unclear whether additional radiotherapy can improve patient survival. This study aimed to evaluate the efficacy of adjuvant radiotherapy after ESD for pT1b ESCC., Methods: This was a multicenter, cross-sectional study involving 11 hospitals in China. Between January 2010 and December 2019, patients with T1bN0M0 ESCC treated with or without adjuvant radiotherapy after ESD were included. Survival between groups was compared., Results: Overall, 774 patients were screened, and 161 patients were included. Forty-seven patients (29.2%) received adjuvant radiotherapy after ESD (RT group) and 114 (70.8%) underwent ESD alone (non-RT group). There were no significant differences in overall survival (OS) and disease-free survival (DFS) between the RT and non-RT groups. Lymphovascular invasion (LVI) was the only prognostic factor. In the LVI+ group, adjuvant radiotherapy significantly improved survival (5-year OS: 91.7% vs 59.5%, P = 0.050; 5-year DFS: 92.9% vs 42.6%, P = 0.010). In the LVI- group, adjuvant radiotherapy did not improve survival (5-year OS: 83.5% vs 93.9%, P = 0.148; 5-year DFS: 84.2% vs 84.7%, P = 0.907). The standardized mortality ratios were 1.52 (95% confidence interval 0.04-8.45) in the LVI+ group with radiotherapy and 0.55 (95% confidence interval 0.15-1.42) in the LVI- group without radiotherapy., Discussion: Adjuvant radiotherapy could improve survival in pT1b ESCC with LVI+ other than LVI- after ESD. Selective adjuvant radiotherapy based on LVI status achieved survival rates similar to those of the general population., (Copyright © 2023 by The American College of Gastroenterology.)

Background: Lymphovascular invasion (LVI) is a crucial predictor of lymph node metastasis (LNM). However, few studies have investigated the LVI positivity rate and its clinical significance in pT1b esophageal squamous cell carcinoma (ESCC) using immunohistochemistry and elastin staining., Methods: We collected data from158 patients with pT1b ESCC who had undergone radical esophagectomy. All paraffin blocks of invasive carcinoma from each patient were subjected to HE staining, elastin staining + CK (AE1/AE3) immunohistochemistry (E&IHC), and CD31/D2-40 + CK (AE1/AE3) double immunohistochemistry (D-IHC). The LVI was classified into types, i.e., vascular invasion (VI) and lymphatic vessel invasion (LI), and its location, quantity, and clinical significance were explored., Results: The positivity rates of VI by E&IHC (E-VI), VI by CD31D-IHC (CD31-VI), and LI by D2-40 D-IHC (D2-40-LI) were significantly higher than those obtained by HE staining (P < 0.001, respectively). CD31-VI and E-VI were independent adverse prognostic factors for recurrence-free survival (RFS), and they were significantly associated with poor distant metastasis-free survival and overall survival in pT1b ESCC. Intratumoral LVI was also crucial in pT1b ESCC, and L2 (the count of D2-40-LI was 5 or more) was the strongest predictor for LNM and RFS in pT1b ESCC., Conclusion: E&IHC and D-IHC can dramatically improve the detection rate of LVI in pT1b ESCC, and the classification and grading of LVI can help to improve the prediction of LNM and prognosis., (© 2023. The Author(s).)

Background: A Phase II study was undertaken to evaluate the safety and efficacy of the neoadjuvant socazolimab, a novel PD-L1 inhibitor, in combination with nab-paclitaxel and cisplatin for locally advanced esophageal squamous cell carcinoma (ESCC)., Methods: Sixty-four patients were randomly divided between the Socazolimab + nab-paclitaxel + cisplatin (TP) arm (n = 32) and the control arm (n = 32), receiving either socazolimab (5 mg/kg intravenously (IV), day 1) or a placebo with nab-paclitaxel (125 mg/m 2 IV, day 1/8) and cisplatin (75 mg/m 2 IV, day 1) repeated every 21 days for four cycles before surgery. The primary endpoint was major pathological response (MPR), and the secondary endpoints were pathological complete response (pCR), R0 resection rate, event-free survival (EFS), overall survival (OS), and safety., Results: A total of 29 (90.6%) patients in each arm underwent surgery, and 29 (100%) and 28 (98.6%) patients underwent R0 resection in the Socazolimab + TP and Placebo + TP arms, respectively. The MPR rates were 69.0 and 62.1% (95% Confidence Interval (CI): 49.1-84.0% vs. 42.4-78.7%, P = 0.509), and the pCR rates were 41.4 and 27.6% (95% CI: 24.1-60.9% vs. 13.5-47.5%, P = 0.311) in the Socazolimab + TP and Placebo + TP arms, respectively. Significantly higher incidence rates of ypT0 (37.9% vs. 3.5%; P = 0.001) and T downstaging were observed in the Socazolimab + TP arm than in the Placebo + TP arm. The EFS and OS outcomes were not mature., Conclusions: The neoadjuvant socazolimab combined with chemotherapy demonstrated promising MPR and pCR rates and significant T downstaging in locally advanced ESCC without increasing surgical complication rates., Trial Registration: Registration name (on clinicaltrials.gov): A Study of Anti-PD-L1 Antibody in Neoadjuvant Chemotherapy of Esophageal Squamous Cell Carcinoma., Registration Number: NCT04460066., (© 2023. The Author(s).)

Background: It is difficult to distinguish esophageal squamous cell carcinoma with intramural metastases (IM) from multiple primary oesophageal carcinoma (MPEC). Nevertheless, there are significant differences in their prognoses and treatments. Therefore, our study aims to clarify the clinicopathological and prognostic characteristics of these two entities and to provide clues for differential diagnosis., Methods: We retrospectively analyzed 6304 patients who underwent esophagectomy without neoadjuvant therapy. The clinicopathological and prognostic features of patients with IM and MPEC were evaluated. P53 and Rb1 were detected by immunohistochemical (IHC) staining using a tissue microarray., Results: Among the 6304 patients, 127 (2.0%) had IM, and 138 (2.2%) had MPEC. Patients with IM were more likely to have an advanced pT (p < 0.001), pN (p < 0.001), more lymphovascular invasion (p < 0.001) and neural invasion (p < 0.001). Additionally, patients with IM had an extremely poor prognosis compared to those with MPEC, with 5-year overall survival (OS) rates of 18.9% and 56.9%, respectively. Meanwhile, IM was found to be an independent poor prognostic indicator for OS and DFS. In the IM group, all patients showed consistent p53 expression in both primary and IM foci. Of note, Rb1 loss was found in 3 pairs of primary foci and metastases, along with p53 nonsense mutation., Conclusions: Patients with IM had more risk factors and extremely worse prognosis than those with MPEC. It is essential to discriminate IM from MPEC when managing multifocal carcinomas. IHC staining of p53 and Rb1 may aid in differential diagnosis., (© 2022. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Background: pT1b esophageal squamous cell carcinoma (ESCC) patients treated by endoscopic resection (ER) required additional treatment with surgical resection (SR) or chemoradiotherapy (CRT) according to 2020 Japan Gastroenterological Endoscopy Society (JGES) guideline. Given the evidences for this recommendation were largely based on small-size studies, our study collected 166 cases of ER-treated pT1b patients in order to investigate the efficacy of additional SR as compared to ER-alone treatment., Methods: A multi-institutional retrospective study in China was conducted. The pT1b ESCC treated by ER + SR (n = 42) and ER-alone (n = 124) from 2007 to 2018 were recruited. Meanwhile, patients with positive lymphovascular invasion (LVI(+)) and/or with positive vertical margin (VM(+)) were put into high-risk group, and those with both VM(-) and LVI(-) were selected into low-risk group. The clinicopathological parameters, lymph node metastasis (LNM), and survival between ER + SR and ER-alone groups were analyzed., Results: In high-risk group, concurrent LNM revealed in surgically resected specimens accounted for 52.6% cases in ER + SR group. After surgical removal, the incidence of post-resection LNM dropped down to 5.6%. However, in low-risk group, patients with ER + SR treatment did not exhibit any concurrent LNM in surgically resected specimens, and the incidence of their overall LNM was similar to that in ER-alone group (0% vs. 2.8%, p = 1.000). More importantly, these cases demonstrated significantly shorter overall survival (OS) than that in ER-alone group (81.8% and 100.0%, respectively, at 3 years; log-Rank: P = 0.010)., Conclusions: For ER-treated pT1b patients in high-risk group, additional SR is strongly recommended. However, for those in low-risk group, additional SR does not generate much benefit for clearance of LNM, but brings harm to shorten their OS. Therefore, additional SR is not recommended for ER-treated pT1b patient in low-risk group., (© 2022. The Author(s).)

Esophageal basaloid squamous cell carcinoma (bSCC) is a subtype of squamous cell carcinoma (SCC) with a different behavior and poor prognosis. Exploring bSCC's molecular characteristics and treatment strategies are of great clinical significance. We performed multi-omics analysis of paired bSCC and common SCC (cSCC) using whole exome sequencing and a NanoString nCounter gene expression panel. Immunohistochemistry was used for verification of candidate biomarkers. Different treatment response was analyzed on both patients receiving neoadjuvant treatment and late-stage patients. The common genetically-clonal origin of bSCC and cSCC was confirmed. No significant differences between their genetic alterations or mutation spectra were observed. Mutation signature 15 (associated with defective DNA damage repair) was less prominent, and tumor mutational burden (TMB) was lower in bSCC. bSCC with an RNA expression pattern resembling cSCC had a better survival than other bSCCs. Moreover, bSCC showed significant upregulation of expression of genes associated with angiogenesis response, basement membranes, and epithelial-mesenchymal transition, and downregulation of KRT14 (squamous differentiation) and CCL21 (associated with immune response). Immunohistochemistry for SFRP1 was shown to be highly sensitive and specific for bSCC diagnosis (p < 0.001). In addition, bSCC receiving neoadjuvant immuno-chemotherapy had a worse pathological response than bSCC receiving neoadjuvant chemotherapy (but without statistical significance), even in bSCC positive for PD-L1. Our results demonstrated the molecular characteristics of esophageal bSCC as a subtype with a distinct RNA expression pattern and immune characteristics, but no specific genetic mutations. We provided a useful biomarker, SFRP1, for diagnosis. After outcome analysis for six bSCCs with neoadjuvant immunotherapy treatment and four late-stage bSCCs with immunotherapy, we found that immunotherapy may not be an effective treatment option for most bSCCs. This may also provide a clue for the same subtypes of lung and head and neck cancer. Our study highlighted the heterogeneity among bSCC patients, and might explain the conflicting results of bSCC outcomes in existing studies. © 2022 The Pathological Society of Great Britain and Ireland., (© 2022 The Pathological Society of Great Britain and Ireland.)

Integrated molecular analysis of human cancer has yielded molecular classification for precise management of cancer patients. Here, we analyzed the whole genomic, epigenomic, transcriptomic, and proteomic data of 155 esophageal squamous cell carcinomas (ESCCs). Multi-omics analysis led to the classification of ESCCs into four subtypes: cell cycle pathway activation, NRF2 oncogenic activation, immune suppression (IS), and immune modulation (IM). IS and IM cases were highly immune infiltrated but differed in the type and distribution of immune cells. IM cases showed better response to immune checkpoint blockade therapy than other subtypes in a clinical trial. We further developed a classifier with 28 features to identify the IM subtype, which predicted anti-PD-1 therapy response with 85.7% sensitivity and 90% specificity. These results emphasize the clinical value of unbiased molecular classification based on multi-omics data and have the potential to further improve the understanding and treatment of ESCC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Multifocal esophageal squamous cell carcinomas (ESCCs) can be diagnosed as of multicentric origin (MO) or intramural metastasis (IMM). We aimed here to accurately discriminate MO from IMM and explore the tumor immune microenvironment of multifocal ESCCs. Multifocal ESCCs were identified in 333 ESCC patients, and in 145 patients discrimination between MO and IMM was not possible by histopathological examination. Of the 145 patients, tissues of 14 were analyzed by whole-exome sequencing (WES) of 71 different tumor regions, and MO, IMM, and MO/IMM mixed groups were identified in three, ten, and one cases, respectively, based on the similarity of genomic architecture between or among different tumors from one patient. Further phylogenetic analyses revealed complex clonal evolution patterns in IMM cases, and tumor cells disseminated from the primary tumors to IMM tumors were independent of lymph node metastasis. The NanoString-based assay showed that immune cell infiltrates were significantly enriched, and that the immune and proliferation pathways were more activated, in large tumors than in small ones in MO but not IMM cases. Similarly, PD-L1 expression and the density of paratumoral CD8 + T cells were higher in large tumors than in small tumors in MO. Taken together, through analysis of the genomic and immune landscapes, our study has comprehensively characterized the heterogeneity and clonal relationship of multifocal ESCCs, which may be helpful in distinguishing MO from IMM, and for interpreting the immunotherapy responses for multifocal ESCC patients. © 2022 The Pathological Society of Great Britain and Ireland., (© 2022 The Pathological Society of Great Britain and Ireland.)

Background: Circumferential resection margin (CRM) is very important in esophageal cancer, but its diagnostic criteria has not been unified. The College of American Pathologists (CAP) and the Royal College of Pathologists (RCP) provide two different criteria. The aim of this study is to evaluate the long-term prognostic significance of CRM status with different CRM criteria in esophageal squamous cell carcinoma (ESCC)., Methods: Influence of CRM status according to the CAP and RCP criteria on long-term survival of 838 patients with resected pT3 tumors and without neoadjuvant therapy was analyzed. Patients stratified into three groups on the basis of tumor distance from the CRM (CRM > 1 mm, 0-1 mm, and 0 mm) were also analysed., Results: Positive CRM was found in 59 (7%) patients according to the CAP criteria and 317 (37.8%) patients according to the RCP criteria. Univariate and multivariate survival analysis showed that CRM status, according to three different criteria, was independent prognostic factor. However, subgroup analysis showed that the prognostic value of CRM status was limited to certain metastatic lymph node load. In pN0 subgroup, patients with CRM > 1 mm had better prognosis than patients with CRM 0-1 mm. Patients with CRM 0 mm had worse outcome than patients with CRM > 0 mm in pN1-2 subgroup. But CRM status had no prognosis value in pN3 subgroup., Conclusions: The CRM status is an important prognostic factor in ESCC patients, but this effect was limited to patients without or with less lymph node metastasis (pN0-2). In clinical practice, we recommend the 1 mm-three-tier criteria as it provides more prognostic value than the traditional two-tier criteria., (© 2022. The Author(s).)

Background: The treatment strategies for T1 oesophageal squamous cell carcinoma (ESCC) patients with or without lymph node metastasis (LNM) are different. Given the advantages of the minimally invasive, sensitive and real-time detection, liquid biopsy has become an important cancer diagnostic and prognostic tool., Methods: MiRNA array and small-RNA sequencing were performed. Then, 222 formalin-fixed and paraffin-embedded tumour samples and 229 pretreatment serum samples from T1 ESCC patients were used to verify and evaluate the results., Results: We demonstrated that serum miR-20b-5p could predict LNM in T1 ESCC patients. The AUC for serum miR-20b-5p was higher (0.827) than those for lymphovascular invasion (LVI) (0.751, P = 0.2128), invasion depth (0.662, P = 0.0027) and tumour differentiation grade (0.634, P = 0.0019). A nomogram for predicting LNM with three independent significant predictors (miR-20b-5p, LVI and invasion depth) was constructed with a concordance index of 0.931. Serum miR-20b-5p was also significantly correlated with disease-free survival (P < 0.001). An algorithm of improved T1 ESCC treatment strategy after biopsy and/or after endoscopic resection based on serum miR-20b-5p level was constructed., Conclusions: This study suggests that serum miR-20b-5p is a potential biomarker for predicting LNM and can be helpful for precise clinical decision-making strategies and improve treatment outcomes for T1 ESCC patients., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Currently, there are insufficient indicators for the reliable assessment of treatment response following neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal squamous cell carcinoma (ESCC). Considering the essential role of protein-coding and non-coding RNAs in gene regulation and cellular processes, we systematically explored the molecular features and clinical significance of mRNA and lncRNA in 249 pretreatment biopsies from four hospitals in three districts with a high incidence of ESCC patients in China., Methods: During the discovery phrase, 13 differentially expressed genes were identified and validated between samples with a complete pathological response (pCR) and those with an incomplete pathological response (+ T cells infiltration, suggesting that PD-L1 and IDO1 are negatively correlated with a high signature score and further associated with pCR and a better prognosis., Conclusion: The present study identified a promising three-gene-based predictive signature that has powerful clinical implications for the identification of pCR and a good prognosis among patients with ESCC. Further immune-related exploration may provide an opportunity for future therapeutic combination., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Purpose: The optimal mode of neoadjuvant treatment for esophageal squamous cell carcinoma (ESCC) has not been well characterized. Our study compared neoadjuvant chemotherapy (NCT) with neoadjuvant chemoradiotherapy (NCRT) for patients with ESCC., Methods: Data from ESCC patients receiving NCRT or NCT combined with esophagectomy between 2010 and 2018 from the National Cancer Center in China were retrospectively collected. Long-term survival, pathological response, and perioperative mortality and morbidity were compared between the NCRT and NCT groups. A Cox proportional hazards model and propensity score matching (PSM) were used to minimize bias due to potential confounding., Results: Out of 327 eligible patients with ESCC in our study, 90 patients were identified in each group by PSM. The complete pathologic response (pCR) rate in the NCRT group was markedly higher than that in the NCT group (before PSM: 35.1% vs. 6.0%; after PSM: 38.9% vs. 5.6%; both P < 0.001). The rates of 30-day or 90-day mortality were comparable between the two groups, but the NCRT group had a longer postoperative hospital stay (P < 0.001 before PSM and P = 0.012 after PSM) and more postoperative complications (P < 0.001 before PSM and P = 0.014 after PSM), especially, anastomotic leaks (P = 0.001 before PSM and P = 0.013 after PSM). No significant differences in 5-year overall survival (OS) (P = 0.439) or 5-year relapse-free survival (RFS) (P = 0.611) were noted between unmatched groups, but the trend favored NCRT in the propensity score-matched group (77.3% vs. 61.3%; hazard ratio [HR] 1.57; 95% confidence interval [CI] 0.86-2.87; P = 0.141 for OS, and 77.8% vs. 60.5%; HR 1.72; 95% CI 0.95-3.11; P = 0.073 for RFS). Multivariate analysis showed that only ypT and ypN stages were independent predictors of OS before and after PSM (both P < 0.05)., Conclusion: There was no difference in survival between the NCT and NCRT groups, although a trend favored NCRT related to the significantly higher pCR rates. Prospective head-to-head clinical trials to compare these two types of neoadjuvant therapies in ESCC are warranted., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Oesophageal cancer (EC) ranks high in both morbidity and mortality. A non-invasive and high-sensitivity diagnostic approach is necessary to improve the prognosis of EC patients., Methods: A total of 525 serum samples were subjected to lipidomic analysis. We combined serum lipidomics and machine-learning algorithms to select important metabolite features for the detection of oesophageal squamous cell carcinoma (ESCC), the major subtype of EC in developing countries. A diagnostic model using a panel of selected features was developed and evaluated. Integrative analyses of tissue transcriptome and serum lipidome were conducted to reveal the underlying mechanism of lipid dysregulation., Results: Our optimised diagnostic model with a panel of 12 lipid biomarkers together with age and gender reaches a sensitivity of 90.7%, 91.3% and 90.7% and an area under receiver-operating characteristic curve of 0.958, 0.966 and 0.818 in detecting ESCC for the training cohort, validation cohort and independent validation cohort, respectively. Integrative analysis revealed matched variation trend of genes encoding key enzymes in lipid metabolism., Conclusions: We have identified a panel of 12 lipid biomarkers for diagnostic modelling and potential mechanisms of lipid dysregulation in the serum of ESCC patients. This is a reliable, rapid and non-invasive tumour-diagnostic approach for clinical application., (© 2021. The Author(s), under exclusive licence to Cancer Research UK.)

Primary small cell carcinoma of the esophagus (PSCCE) is a lethal neuroendocrine carcinoma. Previous studies proposed a genetic similarity between PSCCE and esophageal squamous cell carcinoma (ESCC) but provided little evidence for differences in clinical course and neuroendocrine differentiation. We perform whole-exome sequencing, RNA sequencing and immunohistochemistry profiling on 46 PSCCE cases. Integrated analyses enable the discovery of multiple mechanisms of RB1 disruption in 98% (45/46) of cases. The transcriptomic landscape of PSCCE closely resembles small cell lung cancer (SCLC) but differs from ESCC or esophageal adenocarcinoma (EAC). Distinct gene expression patterns regulated by ASCL1 and NEUROD1 define two molecular subtypes, PSCCE-A and PSCCE-N, which are highly similar to SCLC subtypes. A T cell excluded phenotype is widely observed in PSCCE. In conclusion, PSCCE has genomic alterations, transcriptome features and molecular subtyping highly similar to SCLC but distinct from ESCC or EAC. These observations are relevant to oncogenesis mechanisms and therapeutic vulnerability.

Background: Esophageal squamous cell carcinoma (ESCC) and leiomyoma are common tumors. The coexistence of these two tumors can be classified into two types: the overlying type and the separate type. The overlying type is rare., Methods: We report 12 cases of the overlying type treated by endoscopic submucosal dissection (ESD). They underwent pre-ESD endoscopic examination with white-light imaging, iodine staining, narrow-band imaging, endoscopic ultrasound, and biopsy. The clinical, endoscopic and pathologic characteristics were reviewed., Results: Among the 12 patients, 3 were female and 9 were male. The age range was 49-76 years. They accounted for 4.0% of 300 cases of esophageal leiomyoma and 1.3% of 955 cases of superficial ESCC or high-grade dysplasia treated by endoscopic resection. After endoscopic examination and biopsy, ESCC or high-grade dysplasia, combined with leiomyoma was considered in four cases; leiomyoma was considered but without the squamous lesion (underdiagnosis) in another case; and leiomyoma was mistaken for submucosal ESCC (overdiagnosis) in the other seven cases. ESD specimens showed that nine cases were intramucosal or submucosal ESCC, and three cases were high-grade dysplasia, overlying leiomyoma originating from the muscularis mucosae or muscularis propria. The 12 cases were successfully treated by ESD, with no recurrence during follow-up., Conclusions: We must keep in mind that ESCC or high-grade dysplasia can occur overlying leiomyoma. These cases are rare but should not be neglected, especially in high-risk areas for ESCC. These patients can receive appropriate treatment if overdiagnosis or underdiagnosis can be avoided.

Recent years have seen rapid advances in the field of molecular and genomic pathology that have not only improved understanding of esophageal carcinogenesis and tumor immune environment in general but also have reshaped pathology practice and clinical management. In this article, we provide updates on three topics (1) human epidermal growth factor receptor 2, the first and most important biomarker in targeted therapy of esophageal cancer; (2) programmed death 1/programmed death ligand 1, recent biomarkers that have shown promise in treating both esophageal adenocarcinoma and esophageal squamous cell carcinoma; and (3) human papillomavirus involvement in esophageal carcinogenesis, one of the most debated topics in the field, discussed here with a renewed understanding from recent genomic and molecular data., (© 2020 New York Academy of Sciences.)

No clinically available biomarkers can predict pathological complete response (pCR) for esophageal squamous cell carcinomas (ESCCs) with neoadjuvant chemoradiotherapy (nCRT). Considering that antitumor immunity status is an important determinant for nCRT, we performed an integrative analysis of immune-related gene profiles from pretreatment biopsies and constructed the first individualized immune signature for pCR and outcome prediction of ESCCs through a multicenter analysis. During the discovery phase, 14 differentially expressed immune-related genes (DEIGs) with greater than a twofold change between pCRs and less than pCRs (

Esophageal squamous cell carcinoma (ESCC) patients with a synchronous or metachronous lung tumor can be diagnosed with lung metastasis (LM) or a second primary tumor (SPT), but the accurate discrimination between LM and SPT remains a clinical dilemma. This study aimed to investigate the feasibility of using the whole-exome sequencing (WES) technique to distinguish SPT from LM. Methods: We performed WES on 40 tumors from 14 patients, including 12 patients with double squamous cell carcinomas (SCCs) of the esophagus and lung (lymph node metastases were sequenced as internal controls) diagnosed as LM according to pathological information and 2 patients with paired primary ESCC and non-lung metastases examined as external controls. Results: Shared genomic profiles between esophageal (T) and lung (D) tumors were observed in 7 patients, suggesting their clonal relatedness, thus indicating that the lung tumors of these patients should be LM. However, distinct genomic profiles between T and D tumors were observed in the other 5 patients, suggesting the possibility of SPTs that were likely formed through independent multifocal oncogenesis. Conclusions: Our data demonstrate the limitations and insufficiency of clinicopathological criteria and that WES could be useful in understanding the clonal relationships of multiple SCCs., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Despite great progress in surgery and other treatments, the prognosis of patients with esophageal squamous cell carcinoma (ESCC) is still very poor. HER2 has strong therapeutic implications in certain cancers, such as breast cancer and gastric cancer. However, literature on the frequency of HER2 expression in ESCC is scarce. In the present study, HER2 protein expression, HER2 gene amplification and the relationship between HER2 status and clinicopathological characteristics were evaluated in a large cohort of Chinese ESCC patients., Methods: A total of 857 consecutive ESCC patients who received radical esophagectomy without neoadjuvant therapy between January 2014 and October 2015 were included in this retrospective study. HER2 protein expression was analyzed by immunohistochemistry (IHC), and its correlation with clinicopathological parameters was assessed. In addition, 65 cases, including 13 HER2 overexpression (3+) cases and 52 HER2 equivocal (2+) cases from the 857-case cohort, and another 104 ESCC cases, including 1 HER2 overexpression (3+) case, 3 HER2 equivocal (2+) cases and 100 HER2 negative (1+/0) cases, were selected to construct tissue microarrays (TMAs). Dual-color in situ hybridization (DISH) was performed on the TMAs to assess HER2 gene amplification and the relationship with clinicopathological parameters., Results: We found HER2 overexpression (3+) status in 1.5% (13/857) of cases and HER2 equivocal (2+) status in 6.1% (52/857) of cases. HER2 IHC expression was significantly associated with gender (P = 0.028). However, there were no significant correlations between HER2 IHC expression and age, tumor differentiation, pT stage, pN stage, pM stage and pTNM stage (P > 0.05). Regarding the 169 cases analyzed by DISH, 14 (of 14, 100%) HER2 overexpression (3+) cases, 10 (of 55, 18.2%) HER2 equivocal (2+) cases, and 0 (of 100, 0%) HER2 negative (1+/0) cases showed HER2 gene amplification. HER2 gene amplification was not significantly associated with clinicopathological characteristics such as age, gender, tumor differentiation, pT stage, pN stage, pM stage and pTNM stage (P > 0.05)., Conclusions: Approximately 1.5% of the Chinese ESCC patients had HER2 overexpression based on IHC. IHC and DISH had a high concordance rate. These results provide valuable insight for the future treatment of ESCC.

Ras-association (RA) domain family number 6 (RASSF6) is a member of the Ras-association domain protein family. It is epigenetically inactive and negatively regulates the malignant progression of some tumors. However, its precise role in esophageal squamous cell carcinoma (ESCC) has not been reported. In this study, we performed immunohistochemistry (IHC) assay. The results show that RASSF6 is upregulated in ESCC and that the elevated expression level of RASSF6 is associated with lymph node metastasis and poor survival of ESCC patients. Consistent with the clinical observations, the upregulation of RASSF6 greatly promotes ESCC cell proliferation, migration and invasion as well as the cell cycle transition to G1/S phase in vitro. According to models in vivo, the downregulation of RASSF6 considerably inhibits ESCC tumor growth and lung metastasis. Mechanistically, RASSF6 negatively regulates the tumor suppressor tripartite-motif-containing protein 16 (TRIM16) by promoting its ubiquitination-dependent degradation and eventually activates pathways associated with the cell cycle and epithelial-mesenchymal transition (EMT). Together, these results indicate that the RASSF6-TRIM16 axis is a key effector in ESCC progression and that RASSF6 serves as a potential target for the treatment of ESCC., (Copyright © 2019 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.)

Metabolic activities are often accompanied by cell-cycle progression, yet known connections between these two processes remain limited. Here, we identified the isocitrate dehydrogenase 3β (IDH3β) as a novel substrate of anaphase-promoting complex/cyclosome (APC/C)-CDH1 and an important regulator of the cell cycle. In esophageal squamous cell carcinoma (ESCC), IDH3β was posttranslationally upregulated in late G 1 phase, and overexpression of IDH3β accelerated G 1 -S transition, contributing to the promotion of cell proliferation in vitro and in vivo . α-Ketoglutarate (α-KG), a crucial metabolite in tricarboxylic acid (TCA) cycle, was dependent on IDH3β level and partially accounted for IDH3β-mediated cell growth. IDH3β expression increased PFKFB3 protein levels and enhanced glucose uptake, and high expression of IDH3β correlated with poor survival in patients with ESCC, suggesting a potential application of IDH3β in prognosis. Overall, our results highlight a new molecular connection between cell-cycle regulation and the TCA cycle in ESCC. SIGNIFICANCE: These findings show that IDH3β is an APC/C-CDH1 substrate and is expressed in a cell-cycle-dependent manner, highlighting novel molecular cross-talk between the TCA cycle and cell cycle in cancer cells. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/13/3281/F1.large.jpg., (©2019 American Association for Cancer Research.)

Background and Aims: Radiofrequency ablation (RFA) is an accepted treatment for flat Barrett's neoplasia. Less is known about RFA for esophageal squamous cell neoplasia (ESCN). Our group has reported several prospective studies of RFA for ESCN in China with promising results through 12 months of follow-up. In this cohort study we aimed to evaluate longer term outcomes after RFA for ESCN., Methods: Patients with flat unstained lesions (USLs) on Lugol's endoscopy containing moderate-/high-grade intraepithelial neoplasia (MGIN/HGIN) or mucosal cancer were treated with RFA every 3 months until complete remission (CR; no MGIN or a worse histologic grade). Patients with CR at 12 months (CR12) were included for follow-up and underwent annual Lugol's endoscopy with biopsy sampling and re-RFA for flat USLs. The clinical course of patients with persistent ESCN at 12 months (treatment failures) is also reported., Results: Among the 78 patients in CR12, 67 (86%) had sustained CR during a median of 48 months (interquartile range, 48-48) of follow-up and 5 endoscopies (interquartile range, 4-6). Recurrence occurred in 7 of 78 patients (9%; MGIN, n = 6; HGIN, n = 1); all lesions were managed with RFA. Four other patients (5%) had progression (to HGIN, n = 1; submucosal esophageal squamous cell carcinoma, n = 3). During follow-up protocol violations occurred in 46 of 78 patients (59%). Of the 12 treatment failures, progression occurred in 6. Overall, 2 patients developed subepithelial disease that was not visible after Lugol's endoscopy. Based on post-hoc analysis, the pink-color sign at baseline (a pink color change after Lugol's endoscopy) significantly predicted failure after RFA., Conclusions: RFA is relatively easy to apply and can efficiently treat large areas with ESCN. Despite protocol violations that may have interfered with the efficacy of RFA in 59% of patients, most patients with CR12 had sustained CR during follow-up. However, some patients progressed to advanced disease and 2 developed subepithelial disease, not visible after Lugol's endoscopy. Based on currently available data, we advise the restriction of the use of RFA for flat MGIN and HGIN without the pink-color sign on Lugol's chromoendoscopy. (Clinical trial registration number: NCT02047305.)., (Copyright © 2019 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: Programmed death ligand 1 (PD-L1) is a ligand for the inhibitory programmed cell death protein 1 (PD-1), which are targeted by several anti-PD-1 and PD-L1 drugs for a variety of human cancers. However, only a few studies have evaluated PD-L1 expression in esophageal squamous cell carcinoma (ESCC) with a large Chinese cohort. Our present study is to evaluate the association of PD-L1 expression with clinicopathological features on ESCC., Methods: Using tissue microarray and immunohistochemistry, PD-L1 expression on tumor cells and tumor-infiltrating immune cells was studied in 378 advanced ESCC patients without neoadjuvant chemoradiotherapy. Its correlation with clinicopathological parameters was analyzed., Results: PD-L1 was expressed on 29.9% (113/378) ESCC tumor cells and 40.2% (152/378) tumor-infiltrating immune cells. PD-L1 expression in tumor cells was significantly correlated with age, degree of differentiation, T stage, N stage and metachronous hematogenous metastasis, and PD-L1 expression in tumor-infiltrating immune cells was significantly associated with N stage (P < 0.05). Patients with PD-L1 expression in tumor cells had poor disease-free survival (Hazard ratio [HR] = 1.436, P = 0.009). There was a positive association between tumor cells and tumor-infiltrating immune cells for PD-L1 expression (r = 0.16, P = 0.002). However, PD-L1 expression in tumor-infiltrating immune cells was not significantly correlated with disease-free survival and overall survival., Conclusions: PD-L1 expression in tumor cells and tumor infiltrating immune cells is not only an indicator for immunotherapy, but also significantly related with age, differentiation, stage, metastasis and disease free survival.

Esophageal squamous cell carcinoma (ESCC) is one of the most malignant tumors in China with a poor prognosis. Most ESCC patients were diagnosed at advanced stages, losing the opportunity for surgical excision. Hence, it remains a pressing work to identify biomarkers for early detection, prognosis prediction and targeting therapies in ESCC. Interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, and is involved in the post-translational modification (PTMs) of multiple proteins. However, the molecular functions of ISG15 in ESCC remain unclear. In this work, we found that ISG15 was aberrantly expressed in ESCC tissues and cell lines. Enhanced protein level of ISG15 promoted cellular malignant phenotypes including proliferation, migration, invasion and tumor formation in vivo. Consistently, reduction of ISG15 attenuated the cellular malignant phenotype in ESCC cell lines. Furthermore, gene-expression profiles suggested that the differentially expressed ISG15 affected the expression of a panel of genes enriched in the cell adherens junction, such as c-MET. Notably, as a secreted protein, the concentration of ISG15 was elevated in ESCC plasma than healthy individuals, acting as a potential diagnostic marker. Taken together, our results suggested a tumor promotion role of ISG15 in ESCC via c-MET/Fyn/β-catenin pathway., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological type of esophageal cancer worldwide, with a high mortality and poor prognosis due to advanced stage at diagnosis. Surgical resection after neoadjuvant therapy is the main treatment for ESCC. With the rise of immunotherapy, immunotherapy on ESCC has been shown to improve outcomes, especially the immune checkpoint inhibitors (ICIs). As the efficacy of immunotherapy for ESCC is limited, it is helpful to screen patients who may benefit from immunotherapy by looking for predictive biomarkers of efficacy of immunotherapy. In this paper, based on the current literature on immunotherapy and related biomarkers, we review the research progress on predictive markers of ICIs for ESCC, in hopes of providing assistances for the precise treatment and prognosis determination.

Intramural metastasis (IM) is defined as metastatic tumor from the primary tumor to the digestive tracts through the intramural lymphatic system. It can occur in esophageal, gastric and colorectal carcinomas, especially in esophageal squamous cell carcinoma. The combination of histological morphological evaluation and molecular pathology can assist in the identification of IM and multiple primary carcinomas (MPCs). IM is usually associated with a poor prognosis and also affects the treatment. This article reviews the anatomical and histological basis, clinicopathological characteristics, treatment and prognosis of IM in ESCC, the identification of IM and MPCs and how to improve the detection rate of IM, to guide accurate diagnosis and treatment.

There is no cost-effective, accurate, and non-invasive method for the detection of esophageal squamous cell carcinoma (ESCC) in clinical practice. We aimed to investigate the diagnostic potential of tumor-educated platelets in ESCC. In this study, seventy-one ESCC patients and eighty healthy individuals were enrolled and divided into a training cohort (23 patients and 27 healthy individuals) and a validation cohort (48 patients and 53 healthy individuals). Next-generation RNA sequencing was performed on platelets isolated from peripheral blood of all participants, and a support vector machine/leave-one-out cross validation (SVM/LOOCV) approach was used for binary classification. A diagnostic signature composed of ARID1A, GTF2H2 , and PRKRIR discriminated ESCC patients from healthy individuals with 91.3% sensitivity and 85.2% specificity in the training cohort and 87.5% sensitivity and 81.1% specificity in the validation cohort. The AUC was 0.924 (95% CI, 0.845–0.956) and 0.893 (95% CI, 0.821–0.966), respectively, in the training cohort and validation cohort. This 3-gene platelet RNA signature could effectively discriminate ESCC from healthy control. Our data highlighted the potential of tumor-educated platelets for the noninvasive diagnosis of ESCC. Moreover, we found that keratin and collagen protein families and ECM-related pathways might be involved in tumor progression and metastasis of ESCC, which might provide insights to understand ESCC pathobiology and advance novel therapeutics. [ABSTRACT FROM AUTHOR]

Background: Current strategies are insufficient to predict pathologically complete response (pCR) for esophageal squamous cell carcinomas (ESCCs) before treatment. Here, we aim to develop a novel long noncoding RNA (lncRNA) signature for pCR and outcome prediction of ESCCs through a multicenter analysis for a Chinese population. Methods: Differentially expressed lncRNAs (DELs) between pCRs and less than pCR (

Summary Humans with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a T cell-driven autoimmune disease caused by impaired central tolerance, are susceptible to chronic fungal infection and esophageal squamous cell carcinoma (ESCC). However, the relationship between autoreactive T cells and chronic fungal infection in ESCC development remains unclear. We find that kinase-dead Ikk α knockin mice develop APECED-like phenotypes, including impaired central tolerance, autoreactive T cells, chronic fungal infection, and ESCCs expressing specific human ESCC markers. Using this model, we investigated the link between ESCC and fungal infection. Autoreactive CD4 T cells permit fungal infection and incite tissue injury and inflammation. Antifungal treatment or autoreactive CD4 T cell depletion rescues, whereas oral fungal administration promotes, ESCC development. Inhibition of inflammation or epidermal growth factor receptor (EGFR) activity decreases fungal burden. Fungal infection is highly associated with ESCCs in non-autoimmune human patients. Therefore, autoreactive T cells and chronic fungal infection, fostered by inflammation and epithelial injury, promote ESCC development. [ABSTRACT FROM AUTHOR]