Impact of deep muscle invasion on nodal status and survival in patients with pT2 esophageal squamous cancer.

BACKGROUND: Whether T2 esophageal squamous cell carcinoma should be subclassified remains controversial. We aimed to investigate the impact of the depth of muscularis propria invasion on nodal status and survival outcomes. METHODS: We identified patients with pT2 esophageal squamous cell carcinoma who underwent primary surgery from January 2009 to June 2017. Clinical data were extracted from prospectively maintained databases. Tumor muscularis propria invasion was stratified into superficial or deep. Binary logistic regression was used to determine risk factors for lymph node metastases. The impact of the depth of muscularis propria invasion on survival was investigated using Kaplan‒Meier analysis and a Cox proportional hazard regression model. RESULTS: A total of 750 patients from three institutes were investigated. The depth of muscularis propria invasion (odds ratio [OR]: 3.95, 95% confidence interval [CI]: 2.46-6.35; p < 0.001) was correlated with lymph node metastases using logistic regression. T substage (hazard ratio [HR]: 1.37, 95% CI: 1.05-1.79; p < 0.001) and N status (HR: 1.51, 95% CI: 1.05-2.17; p < 0.001) were independent risk factors in multivariate Cox regression analysis. The deep muscle invasion was associated with worse overall survival (HR: 1.52, 95% CI: 1.19-1.94; p = 0.001) than superficial, specifically in T2N0 patients (HR: 1.38, 95% CI: 1.08-1.94; p = 0.035). CONCLUSIONS: We found that deep muscle invasion was associated with significantly worse outcomes and recommended the substaging of pT2 esophageal squamous cell carcinoma in routine pathological examination.

Increased resected lymph node stations improved survival of esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) and surgery have been recommended as the standard treatments for locally advanced esophageal squamous cell carcinoma (ESCC). In addition, nodal metastases decreased in frequency and changed in distribution after neoadjuvant therapy. This study aimed to examine the optimal strategy for lymph node dissection (LND) in patients with ESCC who underwent nCRT. METHODS: The hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) were calculated using the Cox proportional hazard model. To determine the minimal number of LNDs (n-LNS) or least station of LNDs (e-LNS), the Chow test was used. RESULTS: In total, 333 patients were included. The estimated cut-off values for e-LNS and n-LNS were 9 and 15, respectively. A higher number of e-LNS was significantly associated with improved OS (HR: 0.90; 95% CI 0.84-0.97, P = 0.0075) and DFS (HR: 0.012; 95% CI: 0.84-0.98, P = 0.0074). The e-LNS was a significant prognostic factor in multivariate analyses. The local recurrence rate of 23.1% in high e-LNS is much lower than the results of low e-LNS (13.3%). Comparable morbidity was found in both the e-LNS and n-LND subgroups. CONCLUSION: This cohort study revealed an association between the extent of LND and overall survival, suggesting the therapeutic value of extended lymphadenectomy during esophagectomy. Therefore, more lymph node stations being sampled leads to higher survival rates among patients who receive nCRT, and standard lymphadenectomy of at least 9 stations is strongly recommended.

Will synchronous esophageal and lung resection increase the incidence of anastomotic leaks? A multicenter retrospective study.

BACKGROUND: Reports on combined resection for synchronous lung lesions and esophageal cancer (CRLE) cases are rare and mostly individual cases. Furthermore, the feasibility of CRLE has always been a controversial topic. In the current study, the authors retrospectively analyzed the feasibility of CRLE and established an individualized prediction model for esophageal anastomotic leaks after CRLE by performing a multicenter retrospective study. METHODS: Patients who underwent esophagectomy between January 2009 and June 2021 were extracted from a four-center prospectively maintained database, and those with CRLE at the same setting were matched in a 1:2 propensity score-matched (PSM) ratio to esophagectomy alone (EA) patients. A nomogram was then established based on the variables involved in multivariate logistic regression analysis. Internal validation of the nomogram was conducted utilizing Bootstrap resampling. Decision and clinical impact curve analysis were computed to assess the practical clinical utility of the nomogram. A prognosis analysis for CRLE and EA patients by Kaplan-Meier curves was conducted. RESULTS: Of the 7152 esophagectomies, 216 cases of CRLE were eligible, and 1:2 ratio propensity score-matched EA patients were matched. The incidence of anastomotic leaks following CRLE increased significantly ( P =0.035). The results of the multivariate analysis indicated the leaks varied according to the type of lung resection (anatomic>wedge resection, P =0.016) and site of resected lobe (upper>middle/low lobe; P =0.027), and a nomogram was established to predict the occurrence of leaks accurately (area under the curve=0.786). Although no statistically significant difference in overall survival (OS) was observed in the CRLE group ( P =0.070), a trend toward lower survival rates was noted. Further analysis revealed that combined upper lobe anatomic resection was significantly associated with reduced OS ( P =0.027). CONCLUSION: Our study confirms that CRLE is feasible but comes with a significantly increased risk of anastomotic leaks and a concerning trend of reduced survival, particularly when upper lobe anatomic resections are performed. These findings highlight the need for careful patient selection and surgical planning when considering CRLE.

Vitamin D receptor induces oxidative stress to promote esophageal squamous cell carcinoma proliferation via the p53 signaling pathway.

Background: Esophageal squamous cell carcinoma (ESCC) is a common pathological esophageal cancer with poor prognosis. Vitamin D deficiency reportedly occurs in ESCC patients, and this is related to single nucleotide polymorphism of vitamin D receptor (VDR). Objective: We investigated the effect of VDR on ESCC proliferation, invasion, and metastasis and its potential mechanism. Methods: ESCC and normal tissues were collected from 20 ESCC patients. The ESCC tissue microarray contained 116 pairs of ESCC and normal tissues and 73 single ESCC tissues. VDR expression and its clinicopathological role were determined by real-time quantitative polymerase chain reaction, Western blot, and immunohistochemistry staining. sh-VDR and VDR overexpression were used to validate the effect of VDR on ESCC cell phenotype, and tandem mass tag-based quantitative proteomics and bioinformatics methods identified differential VDR-related proteins. The downstream pathway and regulatory effect were analyzed using ingenuity pathway analysis (IPA). Differentially expressed proteins were verified through parallel reaction monitoring and Western blot. In vivo imaging visualized subcutaneous tumor growth following tail vein injection of VDR-deficient ESCC cells. Results: High VDR expression was observed in ESCC tissues and cells. Gender, T stage, and TNM stage were related to VDR expression, which was the independent prognostic factor related to ESCC. VDR downregulation repressed ESCC cell proliferation, invasion, and migration in vitro and subcutaneous tumor growth and lung metastases in vivo. The cell phenotype changes were reversed upon VDR upregulation, and differential proteins were mainly enriched in the p53 signaling pathway. TP53 cooperated with ABCG2, APOE, FTH1, GCLM, GPX1, HMOX1, JUN, PRDX5, and SOD2 and may activate apoptosis and inhibit oxidative stress, cell metastasis, and proliferation. TP53 was upregulated after VDR knockdown, and TP53 downregulation reversed VDR knockdown-induced cell phenotype changes. Conclusions: VDR may inhibit p53 signaling pathway activation and induce ESCC proliferation, invasion, and metastasis by activating oxidative stress.

Impact of Skeletal Muscle Loss and Sarcopenia on Outcomes of Locally Advanced Esophageal Cancer during Neoadjuvant Chemoradiation.

BACKGROUND: The impact of changes in skeletal muscle and sarcopenia on outcomes during neoadjuvant chemoradiotherapy (NACR) for patients with esophageal cancer remains controversial. PATIENTS AND METHODS: We retrospectively analyzed the data of patients with locally advanced esophageal squamous cell cancer who received NACR followed by esophagectomy between June 2013 and December 2021. The images at third lumbar vertebra were analyzed to measure the cross-sectional area and calculate skeletal muscle index (SMI) before and after NACR. SMI less than 52.4 cm2/m2 for men and less than 38.5 cm2/m2 for women were defined as sarcopenia. The nonlinearity of the effect of percent changes in SMI (ΔSMI%) to survival outcomes was assessed by restricted cubic splines. RESULTS: Overall, data of 367 patients were analyzed. The survival outcomes between sarcopenia and non-sarcopenia groups had no significant differences before NACR. However, patients in post-NACR sarcopenia group showed poor overall survival (OS) benefit (P = 0.016) and poor disease-free survival (DFS) (P = 0.043). Severe postoperative complication rates were 11.9% in post-NACR sarcopenia group and 5.0% in post-NACR non-sarcopenia group (P = 0.019). There was a significant non-linear relationship between ΔSMI% and survival outcomes (P < 0.05 for non-linear). On the multivariable analysis of OS, ΔSMI% > 12% was the independent prognostic factor (HR 1.76, 95% CI 1.03-2.99, P = 0.039) and significant difference was also found on DFS analysis (P = 0.025). CONCLUSIONS: Patients with post-neoadjuvant chemoradiotherapy sarcopenia have worse survival and adverse short-term outcomes. Moreover, greater loss in SMI is associated with increased risks of death and disease progression during neoadjuvant chemoradiotherapy, with maximum impact noted with SMI loss greater than 12%.

The influence of minimally invasive esophagectomy on wound infection in patients undergoing esophageal cancer surgery: A meta-analysis.

The impacts of minimally invasive esophagectomy (MIE) in comparison with open esophagectomy (OE) on postoperative complications, wound infections and hospital length of stay in patients with esophageal carcinoma (ESCA) using meta-analysis to provide reliable evidence for clinical practice. A search strategy was developed and computer searches were performed on Embase, Web of Science, PubMed, Cochrane Library, Wanfang, China Biomedical Literature Database and China National Knowledge Infrastructure databases for clinical studies that reported the effects of MIE in comparison with OE in patients with ESCA. The retrieval time was from their inception to October 2023. Two authors independently performed literature screening, and data extraction and literature quality evaluation were performed separately for the included studies. Meta-analysis was performed using Stata 17.0 software. Overall, 26 studies with 2427 ESCA patients were included in this study, of which 1203 were in the MIE group and 1224 were in the OE group. The results showed that, compared with OE, ESCA patients who underwent MIE were less likely to develop postoperative wound infections (odds ratio [OR] = 0.31, 95% confidence intervals [CIs]: 0.20-0.49, p < 0.001) and complications (OR = 0.23, 95% CI: 0.18-0.30, p < 0.001) and have a shorter hospital stay (standardized mean difference = -1.93, 95% CI: -2.38 to -1.48, p < 0.001). MIE has advantages over OE in terms of shorter hospital stay and reduced incidence of postoperative wound infections and complications.

Mendelian randomization analysis of atopic dermatitis and esophageal cancer in East Asian and European populations.

Background: Emerging observational studies showed an association between atopic dermatitis (AD) and gastrointestinal cancers. However, it remains unclear whether this association is causal, particularly in the case of cancers like esophageal cancer, which exhibit ancestral genetic traits. Methods: To assess the potential causal relationship between AD and esophageal cancer across diverse ancestral backgrounds, we conducted a 2-sample Mendelian randomization study. Independent genetic instruments for AD from the FinnGen consortium (N case = 7024 and N control = 198 740), BioBank Japan (N case = 2385 and N control = 209 651) and Early Genetics and Lifecourse Epidemiology (EAGLE) eczema consortium (N case = 18 900 and N control = 84 166, without the 23andMe study) were used to investigate the association with esophageal cancer in the UK Biobank study (N case = 740 and N control = 372 016) and BioBank Japan esophageal cancer sample (N case = 1300 and N control = 197 045). Results: When esophageal cancer extracted from East Asian ancestry was used as a outcome factor, AD data extracted from BioBank Japan (OR = 0.90, 95% CI: 0.83-0.98), FinnGen consortium (OR = 0.86, 95% CI: 0.77-0.96), and EAGLE consortium (OR = 0.92, 95% CI: 0.81-1.06) were negatively associated with esophageal cancer susceptibility. However, AD as a whole did not show an association with esophageal cancer from European ancestry. Conclusion: This study provides support for a causal relationship between AD and esophageal cancer in East Asian populations but not between AD and esophageal cancer from European ancestry. The specific associations between esophageal cancer and AD appear to exhibit significant disparities between the East Asian and European regions.

CTHRC1 promotes colorectal cancer progression by recruiting tumor-associated macrophages via up-regulation of CCL15.

Tumor-associated macrophages (TAMs) represent a key factor in the tumor immune microenvironment (TME), exerting significant influence over tumor migration, invasion, immunosuppressive features, and drug resistance. Collagen triple helix repeat containing 1 (CTHRC1), a 30 KDa protein which was secreted during the tissue-repair process, is highly expressed in several malignant tumors, including colorectal cancer (CRC). Previous studies demonstrated that CTHRC1 expression in TAMs was positively correlated to M2 macrophage polarization and liver metastasis, while our discovery suggesting a novel mechanism that CTHRC1 secreted from cancer cell could indirectly interplay with TAMs. In this study, the high expression level of CTHRC1 was evaluated in CRC based on GEO and TCGA databases. Further, CTHRC1 was detected high in all stages of CRC patients by ELISA and was correlated to poor prognosis. Multispectral imaging of IHC demonstrated that M2 macrophage infiltration was increased accompanied with CTHRC1 enrichment, suggesting that CTHRC1 may have chemotactic effect on macrophages. In vitro, CTHRC1 could have chemotactic ability of macrophage in the presence of HT-29 cell line. Cytokine microarray revealed that CTHRC1 could up-regulate the CCL15 level of HT-29, pathway analysis demonstrated that CTHRC1 could regulate CCL15 by controlling the TGFß activation and Smad phosphorylation level. In vivo, knocking down of CTHRC1 from CT-26 also inhibits tumor formation. In conclusion, CTHRC1 could promote the chemotactic ability of macrophages by up-regulating CCL15 via TGFß/Smad pathway; additionally, a high level of CTHRC1 could promote macrophage's M2 polarization. This discovery may be related to tumor immune tolerance and tumor immunotherapy resistance in CRC. KEY MESSAGES: CTHRC1 promotes CRC progression by up-regulating CCL15 via TGF-ß/Smad pathways to further recruit tumor-associated macrophages. By the means of autocrine or paracrine, CTHRC1 can indeed promote macrophage chemotaxis and enhance the infiltration of macrophages in tumor tissues but in the presence of tumor cells. CAFs were another source of CTHRC1, indicating CTHRC1 can infiltrate tumor islet as well as the stomal and be secreted from both tumor cells and CAFs. This study validated CTHRC1 as a potential immune therapy target CRC.

Deep Learning in Barrett's Esophagus Diagnosis: Current Status and Future Directions.

Barrett's esophagus (BE) represents a pre-malignant condition characterized by abnormal cellular proliferation in the distal esophagus. A timely and accurate diagnosis of BE is imperative to prevent its progression to esophageal adenocarcinoma, a malignancy associated with a significantly reduced survival rate. In this digital age, deep learning (DL) has emerged as a powerful tool for medical image analysis and diagnostic applications, showcasing vast potential across various medical disciplines. In this comprehensive review, we meticulously assess 33 primary studies employing varied DL techniques, predominantly featuring convolutional neural networks (CNNs), for the diagnosis and understanding of BE. Our primary focus revolves around evaluating the current applications of DL in BE diagnosis, encompassing tasks such as image segmentation and classification, as well as their potential impact and implications in real-world clinical settings. While the applications of DL in BE diagnosis exhibit promising results, they are not without challenges, such as dataset issues and the "black box" nature of models. We discuss these challenges in the concluding section. Essentially, while DL holds tremendous potential to revolutionize BE diagnosis, addressing these challenges is paramount to harnessing its full capacity and ensuring its widespread application in clinical practice.

Causal relationship between lung diseases and risk of esophageal cancer: insights from Mendelian randomization.

BACKGROUND: An increasing number of cohort studies have indicated a correlation between lung diseases and esophageal cancer, but the exact causal relationship has not been definitively established. Therefore, the objective of this study is to assess the causal relationship between lung diseases and esophageal cancer. METHODS: Single-nucleotide polymorphisms (SNPs) related to lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and idiopathic pulmonary fibrosis (IPF), along with outcomes data on esophageal cancer, were extracted from public genome-wide association studies (GWAS). A two-sample Mendelian randomization (MR) analysis was then performed using publicly available GWAS data to investigate the potential causal relationship. The effect estimates were primarily calculated using the fixed-effects inverse-variance-weighted method. RESULTS: Totally, 81 SNPs related to asthma among 218,792 participants in GWAS. Based on the primary causal effects model using MR analyses with the inverse variance weighted (IVW) method, asthma was demonstrated a significantly related to the risk of esophageal cancer (OR 1.0006; 95% CI 1.0003-1.0010, p = 0.001), while COPD (OR 1.0306; 95% CI 0.9504-1.1176, p = 0.466), lung cancer (OR 1.0003, 95% CI 0.9998-1.0008, p = 0.305), as well as IPF (OR 0.9999, 95% CI 0.9998-1.0000, p = 0.147), showed no significant correlation with esophageal cancer. CONCLUSIONS: The two-sample MR analysis conducted in this study revealed a positive causal relationship between asthma and esophageal cancer. In contrast, esophageal cancer demonstrated no significant correlation with COPD, lung cancer, or IPF. Further large-sample prospective studies are needed to validate these findings and to provide appropriate recommendations regarding esophageal cancer screening among patients with asthma.

Pararespiratory and paradigestive lymph node metastases in esophageal squamous cell carcinoma: predicting survival and refining the N staging system.

BACKGROUND: The site of lymph node metastasis (LNM) may affect the prognosis of patients with esophageal squamous cell carcinoma (ESCC). To investigate the prognoses of pararespiratory and paradigestive LNM and to propose a novel N (nN) staging system that integrates both the LNM site and count. METHODS: This study was a multicenter, large-sample, retrospective cohort study that included ESCC patients with LNM between January 2014 and December 2019 from three Chinese institutes. Patients were set into training (two institutes) and external validation (one institute) cohorts. The primary outcomes were survival differences in LNM site and the development of novel nodal staging system. The overall survival (OS) of patients with pararespiratory LNM only (Group A), paradigestive LNM only (Group B), and both sites (Group C) was evaluated by Kaplan-Meier. Cox proportional hazards models were used to identify the independent prognostic factors. An nN staging system considering both the LNM site and count was developed and evaluated by the area under the receiver operating characteristic curve (AUC). RESULTS: In total, 1313 patients were included and split into training (n = 1033) and external validation (n = 280) cohorts. There were 342 (26.0%), 568 (43.3%) and 403 (30.7%) patients in groups A, B and C, respectively. The OS of patients with pararespiratory and patients with paradigestive LNM presented significant differences in the training and validation cohorts (P < 0.050). In the training cohort, LNM site was an independent prognostic factor (hazard ratio: 1.58, 95% confidence intervals: 1.41-1.77, P < 0.001). The nN staging definition: nN1 (1-2 positive pararespiratory/paradigestive LNs), nN2 (3-6 pararespiratory LNs or 1 pararespiratory with 1paradigestive LN), nN3 (3-6 LNs with ≥ 1 paradigestive LN), nN4 (≥ 7 LNs). Subsets of patients with different nN stages showed significant differences in OS (P < 0.050). The prognostic model of the nN staging system presented higher performance in the training and validation cohorts at 3-year OS (AUC, 0.725 and 0.751, respectively) and 5-year OS (AUC, 0.740 and 0.793, respectively) than the current N staging systems. CONCLUSIONS: Compared to pararespiratory LNM, the presence of paradigestive LNM is associated with worse OS. The nN staging system revealed superior prognostic ability than current N staging systems.

Efficacy and safety of PD-1/PD-L1 inhibitor combined with chemotherapy versus chemotherapy alone in the treatment of advanced gastric or gastroesophageal junction adenocarcinoma: a systematic review and meta-analysis.

Background: There is increasing evidence that immunotherapy (programmed cell death-1 (PD-1) inhibitor) combined with chemotherapy is superior to chemotherapy alone in neoadjuvant therapy for patients with previously untreated, unresectable advanced, or metastatic esophageal adenocarcinoma (EAC)/gastric/gastroesophageal junction adenocarcinoma (GEA). However, the results of recent studies have been contradictory. Therefore, the aim of this article is to evaluate the efficacy and safety of PD-1 inhibitors combined with chemotherapy in neoadjuvant therapy through meta-analysis. Method: We comprehensively reviewed the literature and clinical randomized controlled trials (RCTs) by February 2022 by searching Medical Subject Headings (MeSH) and keywords such as "esophageal adenocarcinoma" or "immunotherapy" in several databases, including the Embase, Cochrane, PubMed, and ClinicalTrials.gov websites. Two authors independently selected studies, extracted data, and assessed the risk of bias and quality of evidence by using standardized Cochrane Methods procedures. The primary outcomes were 1-year overall survival (OS) and 1-year progression-free survival (PFS), estimated by calculating the 95% confidence interval (CI) for the combined odds ratio (OR) and hazard ratio (HR). Secondary outcomes estimated using OR were disease objective response rate (DORR) and incidence of adverse events. Results: Four RCTs with a total of 3,013 patients researching the efficacy of immunotherapy plus chemotherapy versus chemotherapy alone on gastrointestinal cancer were included in this meta-analysis. The results showed that immune checkpoint inhibitor plus chemotherapy treatment was associated with an increased risk of PFS (HR = 0.76 [95% CI: 0.70-0.83]; p < 0.001), OS (HR = 0.81 [95% CI: 0.74-0.89]; p < 0.001), and DORR (relative ratio (RR) = 1.31 [95% CI: 1.19-1.44]; p < 0.0001) when compared with chemotherapy alone in advanced, unresectable, and metastatic EAC/GEA. However, immunotherapy combined with chemotherapy increased the incidence of adverse reactions such as alanine aminotransferase elevation (OR = 1.55 [95% CI: 1.17-2.07]; p = 0.003) and palmar-plantar erythrodysesthesia (PPE) syndrome (OR = 1.30 [95% CI: 1.05-1.63]; p = 0.02). Nausea (OR = 1.24 [95% CI: 1.07-1.44]; p = 0.005) and white blood cell count decreased (OR = 1.40 [95% CI: 1.13-1.73]; p = 0.002), and so on. Fortunately, toxicities were within acceptable limits. Meanwhile, for patients with a combined positive score (CPS) ≥1, compared with chemotherapy alone, immunotherapy combined with chemotherapy had a better overall survival rate (HR = 0.81 [95% CI: 0.73-0.90]; p = 0.0001). Conclusion: Our study shows that immunotherapy plus chemotherapy has an obvious benefit for patients with previously untreated, unresectable advanced, or metastatic EAC/GEA when compared with chemotherapy alone. However, a high risk of adverse reactions may occur during immunotherapy plus chemotherapy, and more studies focusing on the treatment strategies of untreated, unresectable advanced, or metastatic EAC/GEA are warranted. Systematic review registration: www.crd.york.ac.uk, identifier CRD42022319434.

MTHFD1L confers a poor prognosis and malignant phenotype in esophageal squamous cell carcinoma by activating the ERK5 signaling pathway.

MTHFD1L, a key enzyme of folate metabolism, is seldom reported in cancer. In this study, we investigate the role of MTHFD1L in the tumorigenicity of esophageal squamous cell carcinoma (ESCC). ESCC tissue microarrays (TMAs) containing 177 samples from 109 patients were utilized to evaluate whether MTHFD1L expression, determined using immunohistochemical analysis, is a prognostic indicator for ESCC patients. The function of MTHFD1L in the migration and invasion of ESCC cells was studied with wound healing, Transwell, and three-dimensional spheroid invasion assays in vitro and a lung metastasis mouse model in vivo. The mRNA microarrays and Ingenuity pathway analysis (IPA) were used to explore the downstream of MTHFD1L. Elevated expression of MTHFD1L in ESCC tissues was significantly associated with poor differentiation and prognosis. These phenotypic assays revealed that MTHFD1L significantly promote the viability and metastasis of ESCC cell in vivo and in vitro. Further detailed analyses of the molecular mechanism demonstrated that the ESCC progression driven by MTHFD1L was through up-regulation ERK5 signaling pathways. These findings reveal that MTHFD1L is positively associated with the aggressive phenotype of ESCC by activating ERK5 signaling pathways, suggesting that MTHFD1L is a new biomarker and a potential molecular therapeutic target for ESCC.

Longer interval between neoadjuvant chemoradiotherapy and surgery is associated with improved pathological response, but does not accurately estimate survival in patients with resectable esophageal cancer.

Neoadjuvant chemoradiotherapy (nCRT) has been shown to reduce tumor burden and achieve tumor regression in patients with esophageal cancer (ESC). However, the most beneficial time interval between the administration of nCRT and surgery remains unclear. Therefore, the aim of the present study was to explore the association of the duration of time between nCRT and surgery with the prognosis of patients with ESC. Patients with ESC who received nCRT following surgical resection (n=161) were reviewed and divided into the prolonged time interval group (time interval ≥66 days) and the short time interval group (time interval <66 days), according to the median value. Subsequent analysis revealed that the prolonged time interval group achieved a higher pathological complete response (pCR) rate compared with the short time interval group (49.4 vs. 26.3%; P=0.003). Furthermore, multivariate logistic regression analysis showed that it was possible to independently estimate a higher pCR rate based on a prolonged time interval (odds ratio, 2.131; P=0.042). However, no association between a prolonged time interval and disease-free survival (DFS) was detected using Kaplan-Meier curves (P=0.252) or multivariate Cox regression (P=0.607) analyses. Similarly, no association was identified between a prolonged time interval and overall survival (OS; P=0.946) based on Kaplan-Meier curve analysis, and subsequent multivariate Cox regression analyses showed that the time interval also failed to independently estimate OS (P=0.581). Moreover, female sex (P=0.001) and a radiation dose ≥40 Gy (P=0.039) served as independent factors associated with a higher pCR rate, and the pCR rate was an independent predictor of favorable DFS (P=0.002) and OS (P=0.015) rates. In conclusion, the present study revealed that a prolonged time interval from nCRT to surgery was associated with a higher pCR rate, but it failed to estimate the survival profile of patients with ESC.

Identification of m6a-related signature genes in esophageal squamous cell carcinoma by machine learning method.

Background: We aimed to construct and validate the esophageal squamous cell carcinoma (ESCC)-related m6A regulators by means of machine leaning. Methods: We used ESCC RNA-seq data of 66 pairs of ESCC from West China Hospital of Sichuan University and the transcriptome data extracted from The Cancer Genome Atlas (TCGA)-ESCA database to find out the ESCC-related m6A regulators, during which, two machine learning approaches: RF (Random Forest) and SVM (Support Vector Machine) were employed to construct the model of ESCC-related m6A regulators. Calibration curves, clinical decision curves, and clinical impact curves (CIC) were used to evaluate the predictive ability and best-effort ability of the model. Finally, western blot and immunohistochemistry staining were used to assess the expression of prognostic ESCC-related m6A regulators. Results: 2 m6A regulators (YTHDF1 and HNRNPC) were found to be significantly increased in ESCC tissues after screening out through RF machine learning methods from our RNA-seq data and TCGA-ESCA database, respectively, and overlapping the results of the two clusters. A prognostic signature, consisting of YTHDF1 and HNRNPC, was constructed based on our RNA-seq data and validated on TCGA-ESCA database, which can serve as an independent prognostic predictor. Experimental validation including the western and immunohistochemistry staining were further successfully confirmed the results of bioinformatics analysis. Conclusion: We constructed prognostic ESCC-related m6A regulators and validated the model in clinical ESCC cohort as well as in ESCC tissues, which provides reasonable evidence and valuable resources for prognostic stratification and the study of potential targets for ESCC.