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Background and Aim: This study aimed to estimate the time to precursor progression and to identify significant predicators. Methods: One hundred thirty-three precursor and 311 normal cases detected in a population- based screening were surveyed for 5.5 years. Precursor progression was defined as worsening of dysplasia or development of a new precursor. Time to precursor progression was estimated by the Kaplan-Meier method. Significant predicators were estimated by Cox proportional regression. Results: Of the 133 precursor cases, 33.08% (44/133) progressed or recurred, 30.08% (40/ 133) persisted, and 36.84% (49/133) regressed; of the 311 normal subjects, 13.50% (42/ 311) developed a precursor. Progression occurred significantly earlier and more frequently with ncreasing histology: with mind dysplasia (mD), 7.8% progressed by 1 year and 23.3% progressed by 5 year; with moderate dysplasia (MD), 18% progressed by 1 year and 70% progressed by 5 years; and with severe dysplasia, 50% progressed by 1 year and 100% progressed by 5 years. The difference between any two groups was significant. In addition, the marginal Lugol-stained mucosa at endoscopic mucosal resection had a progressing risk similar to that of MD, and basal cell hyperplasia was similar to that of mD. Significant predicators for precursor progression included male sex (hazard ratio and 95% CI: 2.74 (1.63-4.60)), age over 50 years (2.31 (1.33-4.02)), family history of upper gastrointestinal cancer (UGIC) (1.56 (1.00-2.45)), multifocal dysplasia (5.11 (3.01-8.68)), and baseline histology. Conclusions: Sex, age, family history of UGIC, multifocal dysplasia, and baseline histology are significant independent predicators for precursor progression. Patients after endoscopic mucosal resection should be continuously surveyed. [ABSTRACT FROM AUTHOR]

Background: Thrombospondin type 1 domain-containing 7A (THSD7A) was reported to play a procancer role in esophageal squamous cell carcinoma (ESCC). The aim of the study was to screen the downstream functional genes of THSD7A and explore their functions in ESCC, based on the reported research into THSD7A function and on gene microarrays.Methods: We adopted quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Celigo high-content screening (HCS) technology to screen the downstream genes of THSD7A. The expression level of target genes was examined by PCR, western blot, and immunohistochemistry (IHC). The effects of these target genes on ESCC malignant biological behavior were performed in vivo and in vitro. The Kaplan-Meier (K-M) survival analysis and Cox regression were used to analyze the prognostic significance of target genes in ESCC patients. Experiments in the literature on liver cancer (LC) were repeated to verify the functions of these genes in different tumors. We further explored the cancer-promoting mechanism of target genes in ESCC by sequencing of the genes' exons.Results: Scavenger receptor class A member 5 (SCARA5) was proved to be the downstream driving gene of THSD7A. SCARA5 promoted cell proliferation and migration but inhibited apoptosis in ESCC. IHC results confirmed that SCARA5 expression in ESCC exceeded that in normal tissues. The K-M survival analysis indicated that SCARA5 expression quantity was not related to prognosis, but tumor volume and T classification were both the independent prognostic factors. Repetition of experiments in LC in the literature confirmed that SCARA5 had exactly opposite functions in EC and LC.Conclusion: SCARA5 was related to the development and occurrence of ESCC. Our findings suggested that it was a potentially diagnostic individualized therapeutic target for ESCC in the future and that its application could possibly be combined with that of upstream THSD7A gene. [ABSTRACT FROM AUTHOR]

By means of glass bottle sampling followed by solid-phase microextraction gas chromatography-mass spectrometry (SPME-GC-MS) technique, the change characteristics of volatile organic compounds (VOCs) in breaths, between before gargling and after gargling, were investigated, respectively, in 41 healthy subjects and 50 esophageal cancer patients. Using an untargeted strategy, 143 VOC chromatographic peaks were enrolled in the statistical analysis. Based on the orthogonal partial least squares discriminant analysis (OPLS-DA), the VOC variations after gargling for each breath test group were obtained according to the combined criteria of variable importance in projection (VIP > 1.5), Wilcoxon signed-rank test (P < 0.05), and fold change (FC > 2.0). When gargled, the levels of indole, phenol, 1-propanol, and p-cresol in the breath of healthy people decreased; meanwhile, for esophageal cancer patients, the declined VOCs in breath were indole, phenol, dimethyl disulfide, and p-cresol. Particularly, these substances were previously reported as breath biomarkers in some diseases such as esophageal, gastric, thyroid, breast, oral, and lung cancers, as well as certain non-cancer disorders. The present work indicates that expiratory VOCs involve the prominent oral cavity source, and in the breath biomarkers study, the potential impact that originates from oral volatiles should be considered. In view of the present results, it is also proposed that gargle pretreatment could eliminate possible interference from the oral cavity VOCs that might benefit breath biomarker investigation. [ABSTRACT FROM AUTHOR]

Background: Dietary patterns and symptoms research among Chinese with esophageal squamous cell carcinoma (ESCC) and its precursor lesions is limited, especially as it relates to multiple food consumption and multiple co-occurring symptoms. The aim of our study was to identify the dietary patterns and severity of symptom classes with the risk of esophageal squamous cell carcinoma and its histological precursor lesions, and develop a risk prediction model for different stages of esophageal disease.Methods: We analyzed data from a multicenter cross-sectional study carried out in ESCC high incidence areas between 2017 and 2018, which included 34,707 individuals aged 40-69 years. Dietary patterns and severity of symptom classes were derived by applying a latent class analysis (LCA). A multiple logistic regression model was used to derive the odds ratio (ORs) and corresponding 95% confidence intervals (CIs) for ESCC and the different stages of esophageal disease according to the dietary patterns and severity of symptom classes identified. We built the risk prediction model by using a nomogram.Results: We identified five dietary patterns and three severity of symptom classes. The dietary patterns were classified as follows: "Healthy", "Western", "Lower consumers-combination", "Medium consumers-combination" and "Higher consumers-combination" patterns based on the intake of foods such as red meat, vegetables and fruits. The severity of symptoms was categorized into "Asymptomatic", "Mild symptoms" and "Overt symptoms" classes based on health-related symptoms reported by the participants. Compared to the "Healthy" pattern, the other four patterns were all associated with an increased risk of esophageal disease. Similarly, the other two symptom classes present different degrees of increased risk of esophageal disease compared to the "Asymptomatic". The nomograms reflect the good predictive ability of the model.Conclusion: Among individuals aged 40-69 years in high incidence regions of upper gastrointestinal cancer, the results supplied that subjects with diets rich in livestock and poultry meat and low in fruits and vegetables and subjects with typical symptoms were at increased ESCC risk. The findings highlight the importance of considering food and symptom combinations in cancer risk evaluation. [ABSTRACT FROM AUTHOR]

Abstract: Background: To demonstrate the effect of an inherited predisposition in familial Esophageal Squamous Cell Carcinoma (ESCC) as opposed to the sporadic cancer form. Methods: Differences in age of onset, prevalence rates of double primary ESCC, and post-operative survival rates between ESCC cases with (N = 476) and without (N = 1226)a family history of upper gastrointestinal cancer (FHUGIC, defined as having one or more first- or second-degree relatives with cancer of the esophagus or gastric cardia) were analyzed. Results: Overall, familial ESCC cases show a significantly earlier onset age (51.9 ± 8.2 versus 53.4 ± 8.0, Pt -test = .000), a significantly higher prevalence rate of double primary ESCC (2.73% Versus 1.22%, adjusted with TNM: X MH 2 = 4.029, P = .045), and a worse prognosis than the sporadic cases (P wald = .049). In subgroup analyses, the familial cases showed earlier onset and poor survival at most subgroups as opposed to the sporadic cases, and the difference was greater in early-stage rather than in late-stage groups (Pt-test for difference in onset age in Tis,1N0M0, T2,3N0M0, and T2,3,4N1M0 were .002, .006, and .081 respectively; and P wald for difference in survival in Tis,1N0M0, T2,3N0M0, and in T2,3,4N1M0 were .010, .180, and .520 respectively). Conclusion: These findings suggest the existence of familial as opposed to the sporadic ESCC. By the theory of “two-hit” origin of cancer, these findings also suggest that the “first hit”, a genetic predisposition, is inherited in familial ESCC. [Copyright &y& Elsevier]

Background: Despite research efforts, the causative factors that contribute to esophageal squamous cell carcinoma (ESCC) in high-risk areas have not yet been understood. In this study, we, therefore, aimed to describe the risk factors associated with ESCC and its precursor lesions.Methods: We performed an endoscopic examination of 44,857 individuals aged 40-69 years from five high incidence regions of China in 2017-2018. Participants were classified as 4 groups of normal control, esophagitis, low-grade intraepithelial neoplasia (LGIN) and high-grade intraepithelial neoplasia/esophageal squamous cell carcinoma (HGIN/ESCC) using an unconditional logistic regression determine risk factors.Results: We identified 4890 esophagitis, 1874 LGIN and 437 HGIN/ESCC cases. Crude odds ratios (ORs) and adjusted odds ratios were calculated using unconditional logistic regression. Drinking well and surface water, salty diet, and positive family history of cancer were the common risk factors for esophagitis, LGIN and HGIN/ESCC. History of chronic hepatitis/cirrhosis was the greatest risk factor of esophagitis (adjusted OR 2.96, 95%CI 2.52-3.47) and HGIN/ESCC (adjusted OR 1.91, 95%CI 1.03-3.22). Pesticide exposure (adjusted OR 1.20, 95%CI 1.05-1.37) was essential risk factor of LGIN.Conclusions: Among individuals aged 40-69 years in high incidence regions of upper gastrointestinal cancer, the results provided important epidemiological evidence for the prevention of different precancerous lesions of ESCC. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the association between tumor protein 53 (TP53) gene deletion and protein expression and clinical features in esophageal squamous cell carcinoma (ESCC), and to evaluate the predictive value of these two characteristics in the prognosis of ESCC. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were performed to detect the expression of p53 protein and gene deletion in ESCC tissue samples from different ethnic groups in Xinjiang, in order to analyze their association with clinicopathological characteristics and patient prognosis, as well as the sensitivity and specificity of the two methods. In addition, the results were further validated by tissue microarray from a different region. The positive rate of p53 protein expression was 54.5% (201/369) in the multi-ethnic group, and was significantly different between sex (P=0.026) and between tumor differentiation groups (P=0.032). FISH demonstrated that the TP53 gene deletion rate was 31.8% (68/214), which was significantly different between different tumor differentiation (P=0.002), lymph node metastasis (P=0.005) and vascular invasion (P<0.001) groups. The survival rate of patients with TP53 gene deletion was significantly lower than those without TP53 gene deletion (P<0.05). The positive rate of p53 protein expression in the tissue microarray was 58.1% (68/117), which was significantly different between the depth of invasion groups (P=0.011). The TP53 gene deletion rate was 47.9% (56/117), which significantly differed according to lymph node metastasis (P=0.003) and TNM stage (P=0.01). In addition, the total concordance rates of the two methods were 60.3 and 64.1%, respectively. There were also significant differences in the positive rate of TP53 gene deletion and protein expression in different stages of ESCC (P<0.05), which increased gradually with the progression of ESCC. The deletion of the TP53 gene in esophageal cancer was associated with poor prognosis and may be an important biomarker for evaluating the prognosis of patients with ESCC. The combination of FISH and IHC methods could significantly improve the detection rate of TP53 gene abnormalities and the accuracy of prognostic assessment of ESCC. [ABSTRACT FROM AUTHOR]

MicroRNA (miR) signatures may aid the diagnosis and prediction of cancer; therefore, miRs associated with the prognosis of esophageal squamous cell carcinoma (ESCC) were screened. miR‑sequencing (seq) and mRNA‑seq data from early‑stage ESCC samples were downloaded from The Cancer Genome Atlas (TCGA) database, and samples from subjects with a >6‑month survival time were assessed with Cox regression analysis for prognosis‑associated miRs. A further two miR expression datasets of ESCC samples, GSE43732 and GSE13937, were downloaded from the Gene Expression Omnibus database. Common miRs between prognosis‑associated miRs, and miRs in the GSE43732 and GSE13937, datasets were used for risk score calculations for each sample, and median risk scores were applied for the stratification of low‑ and high‑risk samples. A prognostic scoring system of signature miRs was subsequently constructed and used for survival analysis for low‑ and high‑risk samples. Differentially‑expressed genes (DEGs) corresponding to all miRs were screened and functional annotation was performed. A total of 34 prognostic miRs were screened and a scoring system was created using 10 signature miRs (hsa‑miR‑140, ‑33b, ‑34b, ‑144, ‑486, ‑214, ‑129‑2, ‑374a and ‑412). Using this system, low‑risk samples were identified to be associated with longer survival compared with high‑risk samples in the TCGA and GSE43732 datasets. Age, alcohol and tobacco use, and radiotherapy were prognostic factors for samples with different risk scores and the same clinical features. There were 168 DEGs, and the top 20 risk scores positively‑correlated and the top 20 risk scores negatively‑correlated DEGs were significantly enriched for six and 10 functional terms, respectively. ‘Tight junction’ and ‘melanogenesis’ were two significantly enriched pathways of DEGs. miR‑214, miR‑129‑2, miR‑37a and miR‑486 may predict ESCC patient survival, although further studies to validate this hypothesis are required. [ABSTRACT FROM AUTHOR]

The present study aimed to understand the expression characteristics of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2) in individuals of Uygur, Han and Kazak ethnicity with esophageal carcinoma in Xinjiang (China) and their interrelation analysis, and to investigate the expression differences in these genes between esophageal carcinoma and pericarcinoma tissue samples, and between the three ethnic groups. The expression levels of EGFR and VEGFR-2 from 119 pairs of esophageal carcinoma tissue and corresponding pericarcinoma tissue from Uygur, Han and Kazak patients with esophageal carcinoma were detected by immunohistochemistry following surgical resection, and an additional five carcinoma in situ specimens were also tested. The relative expression was analyzed among the ethnic groups and clinicopathological parameters. The positive rate of EGFR in esophageal carcinoma tissue from patients of Uygur, Han and Kazak heritage was 70.73, 68.42 and 67.5%, respectively. For VEGFR-2 the positive rate was 73.17, 68.42 and 67.5%, respectively. No significant difference was detected in their expression between the three ethnic groups (P>0.05); however, EGFR and VEGFR-2 overexpression were correlated with lymph node metastasis (P<0.05). VEGF expression was also correlated with the expression of VEGFR-2 in esophageal carcinoma tissues. EGFR was positive in carcinoma in situ samples, while VEGFR-2 was negative. The overexpression of EGFR is therefore an early event and may have a significant role in the progression of esophageal carcinoma pathogenesis. EGFR overexpression may correlate with the expression of VEGFR-2 in esophageal cancer. These results may aid the early diagnosis of esophageal cancer, and the development of individual target treatment in the future. [ABSTRACT FROM AUTHOR]

Aims Esophageal cancer ( EC) is one of the most prevalent and deadly cancers worldwide. Along with nutrition, smoking and alcohol consumption, human papillomavirus ( HPV) infection is one of the major risk factors, which is modulated by host immune response. This study is aimed at elucidating how HPV modifies host immune system in the EC pathogenesis. Methods The HPV and HLA- DQB1 levels in primary esophageal squamous cell (ESC) cancer cells from Han, Khazak and Uygur patients were analyzed by quantitative real-time PCR and immunoblotting. The ability of HPV16 E6/E7 to transform normal primary ESCs was investigated by infecting ESC with pMSCVpuro-carried E6 or E7. The shRNA against HPV16 E6 or E7 was delivered by adenovirus into esophageal squamous cell carcinoma ( ESCC) cells with high HPV content. The DNA methylation level of HLA- DQB1 was measured by methylation-specific PCR. Results The HLA- DQB1 expression level was correlated with the levels of HPV and inversely related to DNA methylation level of HLA- DQB1. Overexpressing HPV16 E6 or E7 alone was enough to transform normal primary ESCs. However, single knockdown of either E6 or E7 in ESC cancer cells did not reduce HLA- DQB1 expression. Conclusions Oncogenic HPV E6 and E7 genes promoted ESCC pathogenesis by upregulating susceptible HLA- DQB1 via DNA demethylation. [ABSTRACT FROM AUTHOR]

Abstract: Background: To find a genetic component in gastric cardia adenocarcinomas (GCA). Methods: Age at onset (AO) and rate of another synchronous primary upper gastrointestinal carcinoma (RASPUGIC) were compared among the three GCA groups with positive (N = 766), negative (N = 2167), and missing family history of upper gastrointestinal cancer (FHUGIC) (N = 198). These 3131 GCAs were diagnosed on 3128 primary GCA patients of a consecutive surgical cohort treated from 1973 through 1994 at the Department of Thoracic Surgery in the 4th Hospital of Hebei Medical University in a high-risk region in northern China. Results: Overall, GCAs of positive FHUGIC showed a significantly younger AO and a significantly higher RASPUGIC than the negative group (54.68 ± 7.35 vs 55.94 ± 7.47 years old, Pt-test = 0.000; 3.1% vs 1.3%, χ2 = 11.02, P = 0.001). The difference in AO and RASPUGIC between the positive and the negative FHUGIC GCAs is significant or nearly significant in most subgroups; minimizing the possibility of a false association due to bias or confounding (e.g. significant stage-specific differences in AO between familial and sporadic GCAs observed in the subgroup of T2,3N0M0 (P = 0.000) and T2,3,4N1M0 (P = 0.03) exclude the possibility of ascertainment bias towards an earlier diagnosis in familial cases), and the association between FHUGIC and RASPUGIC is statistically significant for GCAs of younger AO (<55 yr old, RASPUGIC 3.8% vs 1.6% vs 1.1% for the positive, negative and missing FHUGIC GCAs respectively, χ2 = 6.50, P = 0.04), but not significant for the later onset GCAs (≥55 yr old, RASPUGIC 2.5%, 1.1%, 1.9% for the positive, negative and missing FHUGIC respectively, χ2 = 4.22, P = 0.12). Conclusion: These findings suggest a genetic component in GCA in the Chinese high-risk region, and genetic predisposition may determine the age at onset and number of primary upper gastrointestinal cancer. [Copyright &y& Elsevier]