Identifying LATS2 as a prognostic biomarker relevant to immune infiltrates in human esophageal squamous cell carcinoma.

According to the TIMER database, large tumor suppressor 2 (LATS2) is differentially expressed in various tumors. However, the correlation between LATS2 and esophageal squamous cell carcinoma (ESCC) and the association between LATS2 and immune infiltration in ESCC remain unclear. Our synthetic research on LATS2 in ESCC revealed that the expression was low in esophageal squamous epithelium tissues, revealing the pernicious and adverse prognosis of ESCC. The Kaplan-Meier survival investigation pointed out that low LATS2 expression would result in an adverse prognosis. Biological investigation indicated that LATS2 was engaged in cell migration, adhesion, and junction. To further explore the relationship between LATS2 and tumor immunity, we utilized CIBERSORT to assess immune infiltration. The findings revealed that specimens with lower LATS2 expression showed higher immune infiltration, including T-cell follicular helper cells, M0 macrophages, M1 macrophages, and myeloid dendritic cell resting. An association investigation indicated that LATS2 was negatively relevant to immune checkpoints that restrain operative antitumor immune reactions. We also conducted immunohistochemical staining to explore the link between LATS2 expression and immunophenotype. The indicated association between low LATS2 expression and an immunophenotype is conducive to our understanding of ESCC mini-environments and might offer new indications for enhancing new therapeutic targets.

Early versus the traditional start of oral intake following esophagectomy for esophageal cancer: a systematic review and meta-analysis.

BACKGROUND: Nil by mouth is considered the standard of care during the first days following esophagectomy. However, with the routine implementation of enhanced recovery after surgery, early oral intake is more likely to be the preferred mode of nutrition following esophagectomy. The present study aims to evaluate the safety and effectiveness of early oral intake following esophagectomy for esophageal cancer. METHODS: Comprehensive literature searches were conducted using PubMed, Web of Science, Embase, and Cochrane Library. Weighted mean differences (WMD) and odds ratios (OR) with 95% confidence intervals (CI) were calculated as the effect sizes for continuous and dichotomous variables, respectively. RESULTS: Fourteen studies with a total of 1947 patients were included. Length of hospital stay (WMD = - 3.94, CI: - 4.98 to - 2.90; P < 0.001), the time to first flatus (WMD = - 1.13, CI: - 1.25 to - 1.01; P < 0.001) and defecation (WMD = - 1.26, CI: - 1.82 to - 0.71; P < 0.001) favored the early oral intake group. There was no statistically significant difference in mortality (OR = 1.23, CI: 0.45 to 3.36; P = 0.69). Early oral intake also did not increase the risk of pneumonia and overall postoperative complications. CONCLUSIONS: Current evidence indicates early oral intake following esophagectomy seems to be safe and effective. It may be the preferred mode of nutrition following esophagectomy. However, more high-quality studies are still needed to further validate this conclusion.

Esophagectomy versus definitive chemoradiotherapy as initial treatment for clinical stage I esophageal cancer: a systematic review and meta-analysis.

BACKGROUND: Esophagectomy and definitive chemoradiotherapy are commonly used in the treatment of stage I esophageal cancer (EC). The present study aims to compare the efficacy and safety of esophagectomy and definitive chemoradiotherapy as the initial treatment for clinical stage I EC. METHODS: This study was registered with the International Prospective Register of Systematic Reviews (CRD42020197203). Relevant studies were identified through PubMed, Web of Science, EMBASE, and Cochrane Library from database inception to June 30, 2020. Hazard ratio (HR) with 95% confidence intervals (CI) was employed to compare overall survival (OS) and progression-free survival (PFS). Odds ratio (OR) with 95% CI was employed to compare treatment-related death, complications, and tumor recurrence. RESULTS: A total of 13 non-randomized controlled studies involving 3,346 patients were included. Compared with definitive chemoradiotherapy, esophagectomy showed an improved OS (HR 0.69, 95% CI 0.55-0.86; P < 0.001), PFS (HR 0.47, 95% CI 0.33-0.67; P < 0.001), and a lower risk of tumor recurrence (OR 0.43, 95% CI 0.30-0.61; P < 0.001). There was no significant difference in the incidence of complications (OR 1.11, 95% CI 0.75-1.65; P = 0.60) and treatment-related death (OR 1.15, 95% CI 0.31-4.30; P = 0.84) between the two treatments. CONCLUSIONS: Current evidence shows esophagectomy has superior survival benefits as the initial treatment for clinical stage I EC. It is still the preferred choice for patients with clinical stage I EC. However, future high-quality randomized controlled trials are needed to validate this conclusion.

Tumor microenvironment characterization in esophageal cancer identifies prognostic relevant immune cell subtypes and gene signatures.

Esophageal cancer (ESCA) is a common malignancy in the digestive system with a high mortality rate and poor prognosis. Tumor microenvironment (TME) plays an important role in the tumorigenesis, progression and therapy resistance of ESCA, whereas its role in predicting clinical outcomes has not been fully elucidated. In this study, we comprehensively estimated the TME infiltration patterns of 164 ESCA patients using Gene Set Variation Analysis (GSVA) and identified 4 key immune cells (natural killer T cell, immature B cell, natural killer cell, and type 1 T helper cell) associated with the prognosis of ESCA patients. Besides, two TME groups were defined based on the TME patterns with different clinical outcomes. According to the expression gene set between two TME groups, we built a model to calculate TMEscore based on the single-sample gene-set enrichment analysis (ssGSEA) algorithm. TMEscore systematically correlated the TME groups with genomic characteristics and clinicopathologic features. In conclusion, our data provide a novel TMEscore which can be regarded as a reliable index for predicting the clinical outcomes of ESCA.

Overexpression of cyclin-dependent kinase 1 in esophageal squamous cell carcinoma and its clinical significance.

Cyclin-dependent kinase 1 (CDK1) plays a significant role in certain malignancies. However, it remains unclear whether CDK1 plays a role in esophageal squamous cell carcinoma (ESCC). The aim of this study was to analyze the expression and clinical value of CDK1 in ESCC. CDK1 protein in 151 ESCC tissues and 138 normal esophageal tissues was detected by immunohistochemistry. RNA-seq of eight pairs of ESCC and adjacent esophageal specimens was performed to evaluate the levels of CDK1 mRNA. Microarray and external RNA-seq data from 664 cases of ESCC and 1733 cases of control tissues were used to verify the difference in CDK1 expression between the two groups. A comprehensive analysis of all data was performed to evaluate the difference in CDK1 between ESCC tissues and control tissues. Further, functional enrichment analyses were performed based on differentially expressed genes (DEGs) of ESCC and co-expressed genes (CEGs) of CDK1. In addition, a lncRNA-miRNA-CDK1 network was constructed. The expression of CDK1 protein was obviously increased in ESCC tissues (3.540 ± 2.923 vs. 1.040 ± 1.632, P < 0.001). RNA-seq indicated that the mRNA level of CDK1 was also highly expressed in ESCC tissues (5.261 ± 0.703 vs. 2.229 ± 1.161, P < 0.0001). Comprehensive analysis revealed consistent up-regulation of CDK1 (SMD = 1.41; 95% CI 1.00-1.83). Further, functional enrichment analyses revealed that the functions of these genes were mainly concentrated in the cell cycle. A triple regulatory network of PVT1-hsa-miR-145-5p/hsa-miR-30c-5p-CDK1 was constructed using in silico analysis. In summary, overexpression of CDK1 is closely related to ESCC tumorigenesis.

The Indication of Poor Prognosis by High Expression of ENO1 in Squamous Cell Carcinoma of the Lung.

The purpose of this study is to investigate the significance of alpha-enolase (ENO1) expression in squamous cell carcinoma of the lung (LUSC), its prognostic value, and prospective molecular mechanism. Using multiplatforms data, including in-house immunohistochemistry, in-house real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), in-house microarray, and public high-throughput data, the expression significance and prognostic role of ENO1 in LUSC tissues were analyzed comprehensively. With the combination of all eligible cases, compared with 941 non-LUSC lung tissues, ENO1 was significantly overexpressed in 1163 cases of LUSC (standardized mean difference (SMD) = 1.23, 95% confidence interval (CI) = 0.76-1.70, P < 0.001). ENO1 also displayed a great ability to differentiate LUSC tissues from non-LUSC lung tissues (AUC = 0.8705) with the comprehensive sensitivity being 0.88 [0.83-0.92], and comprehensive specificity being 0.89 [0.84-0.94]). Moreover, in 1860 cases of LUSC with survival information, patients with higher expression of ENO1 had poorer prognosis (hazard ratio (HR) = 1.20, 95% CI = 1.01-1.43, P = 0.043). ENO1 and its related genes mainly participated in the pathways of cell division and proliferation. In conclusion, the upregulation of ENO1 could affect the carcinogenesis and unfavorable outcome of LUSC.

Minimal invasive versus open esophagectomy for patients with esophageal squamous cell carcinoma after neoadjuvant treatments.

BACKGROUND: Although previous studies have discussed whether the minimally invasive esophagectomy (MIE) is superior to open surgery, the data concerning esophageal squamous cell carcinoma (ESCC) patients underwent neoadjuvant treatment followed by radical resection is limited. The purpose of our study was to compare the short- and long-term clinical outcomes of the two surgical approaches in treating ESCC patients. METHODS: Between January 2010 and December 2016, ESCC patients who had received neoadjuvant therapy and underwent Mckeown esophagectomy at our institute were eligible. The baseline characteristics, pathological data, short-and long-term outcomes of these patients were collected and compared based on the surgical approach. RESULTS: A total of 195 patients was included in the current study. Compared to patients underwent open surgery, patients underwent MIE had shorter operative time and less intraoperative bleeding (390 min vs 330 min, P = 0.001; 204 ml vs 167 ml, P = 0.021). In addition, the risk of anastomotic leakage was decreased in MIE group (20.0% vs 3.3%, P < 0.001), while the occurrence of other complications did not have statistical significance between two groups. Overall survival (OS) and disease-free survival (DFS) was no difference in patients received neoadjuvant chemotherapy between the two approaches. For the patients underwent neoadjuvant chemoradiotherapy, OS was significantly better in the MIE group (log rank = 6.197; P = 0.013). CONCLUSION: Minimally invasive Mckeown esophagectomy is safe and feasible for ESCC patients who underwent neoadjuvant therapy. MIE approach presented better perioperative results than open esophagectomy. The effect of surgical approaches on survival was depending on the scheme of neoadjuvant treatment.

Clinical significance of transcription factor RUNX2 in lung adenocarcinoma and its latent transcriptional regulating mechanism.

RUNX family transcription factor 2 (RUNX2) overexpression has been found in various human malignancies. However, the expression levels of RUNX2 mRNA and protein in lung adenocarcinoma (LUAD) were not investigated. This study aims to thoroughly analysis the expression level and potential mechanisms of RUNX2 mRNA in LUAD. We applied in-house immunohistochemistry, high-throughput RNA-sequencing, and gene microarrays to comprehensively investigate the expression level of RUNX2 in LUAD. A pool standard mean difference (SMD) and summary receiver operating characteristic curves (SROC) were calculated to assess the integrated expression value of RUNX2 in LUAD. The hazard ratios (HRs) were integrated to evaluate the overall prognostic effect of RUNX2 on the LUAD patients. The differentially expressed genes (DEGs) of LUAD, the potential target genes of RUNX2, and its co-expressed genes were overlapped to obtain a set of specific genes for GO and KEGG enrichment analyses. RUNX2 overexpression in LUAD was validated using a large number of cases (2 418 LUAD and 1 574 non-tumor lung samples). The pooled SMD was 0.85 (95 % CI: 0.64-1.05) and the area under the curve (AUC) of the SROC was 0.86 (95 %CI: 0.83-0.89). The integrated HR was 1.20 [1.04-1.38], indicating that increased expression of RUNX2 was an independent risk factor for the poor survival of the LUAD patients. RUNX2 and its transcriptionally regulates potential target genes may promote cell proliferation and drug resistance of LUAD by modulating the cell cycle and MAPK signaling pathways. RUNX2 can provide new research directions for targeted drug therapy and drug resistance for LUAD treatment.

Integrated expression analysis revealed RUNX2 upregulation in lung squamous cell carcinoma tissues.

This study aimed to investigate the clinicopathological significance and prospective molecular mechanism of RUNX family transcription factor 2 (RUNX2) in lung squamous cell carcinoma (LUSC). The authors used immunohistochemistry (IHC), RNA-seq, and microarray data from multi-platforms to conduct a comprehensive analysis of the clinicopathological significance and molecular mechanism of RUNX2 in the occurrence and development of LUSC. RUNX2 expression was significantly higher in 16 LUSC tissues than in paired non-cancerous tissues detected by IHC (P < 0.05). RNA-seq data from the combination of TCGA and genotype-tissue expression (GTEx) revealed significantly higher expression of RUNX2 in 502 LUSC samples than in 476 non-cancer samples. The expression of RUNX2 protein was also significantly higher in pathologic T3-T4 than in T1-T2 samples (P = 0.031). The pooled standardised mean difference (SMD) for RUNX2 was 0.87 (95% CI, 0.58-1.16), including 29 microarrays from GEO and one from ArrayExpress. The co-expression network of RUNX2 revealed complicated connections between RUNX2 and 45 co-expressed genes, which were significantly clustered in pathways including ECM-receptor interaction, focal adhesion, protein digestion and absorption, human papillomavirus infection and PI3K-Akt signalling pathway. Overexpression of RUNX2 plays an essential role in the clinical progression of LUSC.

The Significance of Negative Lymph Nodes in Esophageal Cancer After Curative Resection: A Retrospective Cohort Study.

OBJECTIVE: The impact of negative lymph nodes (NLNs) count on prognosis in esophageal cancer (EC) was analyzed using two institutions surgical database. METHODS: We conducted a retrospective study of 768 EC patients treated by surgical resection between January 2010 and December 2012. The effects of the NLNs count on prognosis was analyzed. Cox regression model was conducted to determine the significant prognostic elements. RESULTS: The number of NLNs was studied as a categorical variable based on the quartiles (Q1: ≤15, Q2: 16-21, Q3: 22-30, Q4: ≥31). And a better overall survival (OS) was observed with increasing number of NLNs (HR= 0.762; 95% CI, 0.596-0.974 for Q2, HR= 0.666; 95% CI, 0.516-0.860 for Q3 and HR= 0.588; 95% CI, 0.450-0.768 for Q4) (all P<0.05). Multivariate regression analysis revealed that the NLNs count was an independent prognostic factor. Besides, for patients in T2 or T3 stage, a high number of NLNs was found to be significantly associated with a favorable OS (log rank P<0.001). CONCLUSION: A higher number of NLNs is independently related to the better OS in EC patients after surgical resection.

The Clinical Significance and Potential Molecular Mechanism of PTTG1 in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the major histological type of esophageal cancers worldwide. Transcription factor PTTG1 was seen highly expressed in a variety of tumors and was related to the degree of tumor differentiation, invasion, and metastasis. However, the clinical significance of PTTG1 had yet to be verified, and the mechanism of abnormal PTTG1 expression in ESCC was not clear. In this study, the comprehensive analysis and evaluation of PTTG1 expression in ESCC were completed by synthesizing in-house immunohistochemistry (IHC), clinical sample tissue RNA-seq (in-house RNA-seq), public high-throughput data, and literature data. We also explored the possible signaling pathways and target genes of PTTG1 in ESCC by combining the target genes of PTTG1 (displayed by ChIP-seq), differentially expressed genes (DEGs) of ESCC, and PTTG1-related genes, revealing the potential molecular mechanism of PTTG1 in ESCC. In the present study, PTTG1 protein and mRNA expression levels in ESCC tissues were all significantly higher than in non-cancerous tissues. The pool standard mean difference (SMD) of the overall PTTG1 expression was 1.17 (95% CI: 0.72-1.62, P < 0.01), and the area under curve (AUC) of the summary receiver operating characteristic (SROC) was 0.86 (95% CI: 0.83-0.89). By combining the target genes displayed by ChIP-seq of PTTG1, DEGs of ESCC, and PTTG1-related genes, it was observed that PTTG1 may interact with these genes through chemokines and cytokine signaling pathways. By constructing a protein-protein interaction (PPI) network and combining ChIP-seq data, we obtained four PTTG1 potential target genes, SPTAN1, SLC25A17, IKBKB, and ERH. The gene expression of PTTG1 had a strong positive correlation with SLC25A17 and ERH, which suggested that PTTG1 might positively regulate the expression of these two genes. In summary, the high expression of PTTG1 may play an important role in the formation of ESCC. These roles may be completed by PTTG1 regulating the downstream target genes SLC25A17 and ERH.

Multiple primary malignancies for squamous cell carcinoma and adenocarcinoma of the esophagus.

BACKGROUND: Patients with esophageal cancer (EC) frequently have multiple primary cancers. We conducted the present study to assess the risk of multiple primary malignancies for patients with squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the esophagus and to investigate the influence of multiple primary tumors on the prognosis of EC patients. METHODS: Using the data of 44,091 EC patients from the Surveillance Epidemiology and End Results (SEER) database, we calculated the standardized incidence ratios (SIRs) for overall multiple primary cancers and cancers at particular sites among EC survivors. The SIRs of esophageal SCC and AC patients were compared using Poisson regression. The Kaplan-Meier (KM) method was used for survival analysis. RESULTS: Multiple primary cancer risk was significantly increased among both esophageal SCC and AC survivors (SIR: 2.28 and 1.57, respectively; P<0.001). Among SCC patients, the highest SIRs were found in the oral cavity and pharynx (SIR: 16.54), esophagus (SIR: 10.02), and larynx (SIR: 10.34). Also, the highest SIRs following AC cases were observed in the esophagus (SIR: 8.81), stomach (SIR: 9.29), and small intestine (SIR: 4.95). SIRs for the oral cavity and pharynx, lung, and larynx were significantly higher among SCC survivors than AC survivors (all P<0.05). KM analysis revealed no significant difference of overall survival (OS) for multiple primary cancers, including those of the esophagus, stomach, oral cavity and pharynx, and lung among EC patients (log rank =2.04; P=0.564), except for prostate cancer (log rank =96.65; P<0.001). CONCLUSIONS: Multiple primary malignancy risk differed by the histological type of esophageal SSC and AC survivor. However, no significant relationship between survival and the multiple primary cancer sites, except for prostate cancer, was observed.

Recurrence and prognostic model for identifying patients at risk for esophageal cancer after surgery.

OBJECTIVE: The aim of this study was to construct a risk model to assess overall survival (OS) and disease-free survival (DFS) in patients with esophageal cancer (EC) after surgery. PATIENTS AND METHODS: A total of 872 consecutive EC patients who had undergone surgery between February 2009 and October 2012 were retrospectively analyzed. The cutoff for risk value (RV) was inferred by receiver operating characteristic curves and the Youden index. A log-rank test was used to compare the survival curves, and a Cox regression analysis was performed to clarify the significant prognostic factors. RESULTS: The area under the curve was 0.688 for OS and 0.645 for DFS. The survival rates were 69.4% (259/373) and 39.1% (195/499), and the rates of recurrence were 19.2% (70/364) and 27.6% (132/479), respectively, for RV<0.218 and RV≥0.218 (c 2=78.83, P<0.001; c 2=9.07, P=0.003; respectively). A multivariate Cox regression analysis identified cases suffering from higher overall mortalities with RV≥0.218 compared to RV<0.218 (HR=1.45; 95% CI, 1.21-2.02; P=0.015); similar results were also found for DFS (HR=1.38; 95% CI, 1.03-1.86; P=0.033). Kaplan-Meier survival curves showed that cases with RV<0.218 had better OS and DFS than cases with RV≥0.218 (log rank = 75.80, P<0.001; log rank = 24.78, P<0.001). CONCLUSION: This model could be applied to an integrated assessment of recurrence and prognostic risk after the surgical treatment of EC.