• Comprehensive review 
• Esophageal cancer
• Pathological characteristics
• Prevention and Screening
• Treatment advancements

• Humans
• Esophageal Neoplasms/therapy
• Esophageal Neoplasms/diagnosis
• Esophageal Neoplasms/epidemiology
• Esophageal Neoplasms/etiology
• Esophageal Squamous Cell Carcinoma/therapy
• Esophageal Squamous Cell Carcinoma/diagnosis
• Esophageal Squamous Cell Carcinoma/epidemiology
• Adenocarcinoma/therapy
• Adenocarcinoma/diagnosis
• Adenocarcinoma/epidemiology
• Early Detection of Cancer/methods
• Combined Modality Therapy

• Key Project of In-hospital Research Subject
• SZ2020ZD002 Chinese Academy of Medical Sciences
• 82202938 Young Scientists Fund of the National Natural Science Foundation of China
• Chinese Academy of Medical Sciences

• Humans
• Astrocytoma/genetics
• Brain Neoplasms/pathology
• Glioma/metabolism
• Isocitrate Dehydrogenase/genetics
• Mutation
• Proto-Oncogene Proteins c-akt/genetics

• Circulating tumor cells (CTCs)
• c-Kit
• esophageal squamous cell carcinoma
• pathology
• prognosis

• ESCC
• afatinib
• combination
• paclitaxel
• targeted therapy

Epidemiological and experimental evidence indicate that selenium is associated with a reduced risk of some cancers, including esophageal cancer. However, the exact mechanism is still unclear. In the present study, we used esophageal squamous cell carcinoma (ESCC) cell lines and animal models to explore the anti-cancer mechanism of methylseleninic acid (MSA). Firstly, MSA treatment dramatically attenuated Epidermal Growth Factor Receptor (EGFR) protein expression but did not alter mRNA levels in ESCC cells. On the contrary, EGFR overexpression partly abolished the inhibitory effect of MSA. With a microRNA-array, we found MSA up-regulated miR-146a which directly targeted EGFR, whereas miR-146a inhibitor antagonized MSA-induced decrease of EGFR protein. We further used 4-nitroquinoline-1-oxide (4NQO)-induced esophageal tumor mice model to evaluate the inhibitory effect of MSA in vivo. MSA treatment significantly decreased the tumor burden and EGFR protein expression in tumor specimens. Furthermore, MSA treatment inhibited EGFR pathway and subsequntly reduced Interleukin-6 (IL-6) secretion in the supernatant of cancer cell lines. MSA-induced IL-6 suppression was EGFR-dependent. To further evaluate the association of IL-6 and the anti-tumor effect of MSA on esophageal cancer, we established the 4NQO-induced esophageal tumor model in IL-6 knock-out (IL-6 KO) mice. The results showed that IL-6 deficiency did not affect esophageal tumorigenesis in mice, but the inhibitory effect of MSA was abolished in IL-6 KO mice. In conclusion, our study demonstrated that MSA upregulated miR-146a which directly targeted EGFR, and inhibited EGFR protein expression and pathway activity, subsequently decreased IL-6 secretion. The inhibitory effect of MSA on esophageal cancer was IL-6 dependent. These results suggested that MSA may serve as a potential drug treating esophageal cancer.

• EGFR
• ESCC
• IL-6
• MSA
• miR-146a

Osteosarcoma (OTS) is aggressive bone malignancy without well-recognized prognosis biomarker. Tumor mutational burden (TMB) has been proved as effective biomarker in predicting clinical outcomes in several cancer types. However, its prognostic value in OTS remains unknown. In this study, we aim to evaluate the implication of TMB in OTS patients.

To depict the landscape of somatic mutations in OTS, we performed Whole-Exome Sequencing (WES) on 31 OTS tissue samples and corresponding White Blood Cells (WBCs) as matched control. TMB was calculated as the total number of somatic alterations in coding regions normalized to the per sequenced genomic megabase (~30.4Mb in WES). The prognostic values of TMB were evaluated by Kaplan-Meier methods and Cox regression models.

The median age was 16.0 years at diagnosis, and 54.8% of patients were male. The most common genetic alterations were mainly involved in cell cycle and DNA damage response and repair, including H3F3A, TP53, MYC, and CDKN2A/B. The median progression-free survival (PFS) was 775.5 days in TMB-High (defined as third quartile of TMB value, <2.565) versus 351 days in TMB-Low (<2.565). All patients with TMB-High are PFS-Long (>400 days), while 36.4% of all patients with TMB-Low were PFS-Long (P=0.003). TMB were significantly greater in PFS-Long than in PFS-Short (<400 days) (P=0.002). Moreover, the median overall survival (OS) was 1,307 days in TMB-High versus 672.5 days in TMB-Low. Furthermore, TMB-High group had significantly improved PFS (P=0.04) and OS (P=0.03).

TMB-High can be used as prognostic marker for OTS. Our findings demonstrate that TMB may be helpful in combination with traditionally clinicopathologic risk factors to optimize risk stratification and guide treatment decisions.

• osteosarcoma
• overall survival
• progression-free survival
• tumor mutational burden
• whole-exome sequencing

Cancer recurrence is one of the most concerning clinical problems of cholangiocarcinoma (CCA) patients after treatment. However, an identification of predictive factor on Opisthorchis viverrini (OV)-associated CCA recurrence is not well elucidated. In the present study, we aimed to investigate the correlation of twelve targeted protein kinases with CCA recurrence.

Twelve protein kinases, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2, 3, 4 (HER2, HER3, HER4), vascular endothelial growth factor receptor 3 (VEGFR3), vascular endothelial growth factor-C (VEGF-C), erythropoietin-producing hepatocellular carcinoma receptor type-A3 (EphA3), EphrinA1, phosphor-serine/threonine kinase 1 (p-Akt1), serine/threonine kinase 1 (Akt1), beta-catenin and protein Wnt5a (Wnt5a) were examined using immunohistochemistry. Pre-operative serum tumor markers, CA19–9 and CEA were also investigated.

Among twelve protein kinases, EGFR, HER4, and EphA3 were associated with tumor recurrence status, recurrence-free survival (RFS) and overall survival (OS). Multivariate cox regression demonstrated that EGFR, HER4, EphA3 or the panel of high expression of these proteins was an independent prognostic factor for tumor recurrence. The combination of high expression of these proteins with a high level of CA19–9 could improve the predictive ability on tumor recurrence. Moreover, the patients were stratified more accurately when analyzed using the combination of high expression of these proteins with primary tumor (T) or lymph node metastasis (N) status.

EGFR, HER4, EphA3 or the panel of high expression of these proteins is an independent prognostic factor for post-operative CCA recurrence.

• Cancer recurrence
• Cholangiocarcinoma
• Prognostic factor
• Protein kinase
• Tumor marker

Cancer recurrence is the important problem of cholangiocarcinoma (CCA) patients, lead to a very high mortality rate. Therefore, the identification of candidate markers to predict CCA recurrence is needed in order to effectively manage the disease. This study aims to examine the predictive value of cancer stem cell (CSC) markers on the progression and recurrence of CCA patients.

The expression of 6 putative CSC markers, cluster of differentiation 44 (CD44), CD44 variant 6 (CD44v6), CD44 variants 8-10 (CD44v8-10), cluster of differentiation 133 (CD133), epithelial cell adhesion molecule (EpCAM), and aldehyde dehydrogenase 1A1 (ALDH1A1), was investigated in 178 CCA tissue samples using immunohistochemistry (IHC) and analyzed with respect to clinicopathological data and patient outcome including recurrence-free survival (RFS) and overall survival (OS). The candidate CSC markers were also investigated in serum from CCA patients, and explored for their predictive ability on CCA recurrence.

Elevated protein level of CD44 and positive expression of CD44v6 and CD44v8-10 were significantly associated with short RFS and OS, while high levels of ALDH1A1 were correlated with a favorable prognosis patient. The elevated CD44v6 level was also correlated with higher tumor staging, whereas a decreasing level of ALDH1A1 was correlated with lower tumor staging. The levels of CD44, CD44v6 and CD44v8-10 were also correlated and were associated with a poor outcome. Furthermore, soluble CD44, CD44v6, CD44v8-10 and EpCAM were significantly increased in the recurrence group for early stage CCA; they also correlated with high levels of the tumor marker CA19-9. Elevated levels of CD44, CD44v6, CD44v8-10 or EpCAM alone or in combination has the potential to predict CCA recurrence.

The overexpression of CD44, CD44v6, CD44v8-10 and EpCAM increases predictability of post-operative CCA recurrence. Moreover, the overexpression of the panel of CSC markers combined with CA19-9 could improve our predictive ability for tumor recurrence in early stage CCA patients. This result may be beneficial for the patients in order to predict the outcome after treatment and may be useful for clinical intervention in order to improve patient survival.

• Cancer recurrence
• Cancer stem cell marker
• Cholangiocarcinoma
• Prognostic factor
• Tumor marker

Background: Esophageal squamous cell carcinoma (ESCC) is the fourth most common cause of cancer death in China. Long noncoding RNAs have emerged as critical regulators in cancer. Long intergenic noncoding RNA-p21, a kind of Long noncoding RNAs, LincRNA-p21 have been discussed dysregulated in several cancers, but its role in ESCC remains unknown. This study investigated the role of LincRNA-p21 in ESCC.

Materials and methods: The LincRNA-p21 expression level and its association with esophageal cancer was determined in 64 tumor tissues of esophageal squamous cell carcinoma patients and cells using quantitative real-time reverse transcription PCR. Fluorescence in situ hybridization of single-RNA molecular probes was used to determine subcellular localization of LincRNA-p21. CCK8 and EdU assays were used for proliferation assay, flow cytometry was performed for apoptosis and cell-cycle distribution, and 24-well Mill cell chamber was made for measuring the abilities of migration and invasion after transfected with lentivirus-expressing LincRNA-p21 in EC109 cells. Then, quantitative real-time reverse transcription PCR and Western blot detected the expression of p21. Further, UC2288, an inhibitor of p21, was used to decrease the level of p21, and flow cytometry was used to detect cell cycle. Finally, screening for differential pathways from microarray analysis and expression of p53 and cyclin D were detected by Western blot.

Results:LincRNA-p21 expression level was remarkably lower in tumor tissues versus nontumor tissues and lower in EC109 cells versus Het-1A cells. Statistical analysis found that LincRNA-p21 might enhance the risk of ESCC. We observed that LincRNA-p21 was expressed both in the nucleus and cytoplasm, and a larger proportion of LincRNA-p21 was observed in the cytoplasm. The results demonstrated that upregulating the expression of LincRNA-p21 could inhibit cell proliferation, migration, invasion, and the transition of cell cycle from G1 and promoted apoptosis of EC109. Then, we found that LincRNA-p21 promotes the expression of p21. Decreasing the level of p21 revealed that cell-cycle arrest was restored. Pathway analysis found p53 pathway was downregulated, and upregulation of LincRNA-p21 inhibited the expression of cyclin D.

Conclusion: Our study suggests that LincRNA-p21 plays as a tumor inhibitor in ESCC development and LincRNA-p21 might induce G1 arrest through p53 signal pathway.

• Fluorescence in Situ Hybridization
• G1 arrest
• LincRNA-p21
• esophageal squamous-cell carcinoma
• p53 pathway

Immunohistochemistry studies on p53 inactivation in esophageal cancer are available with inconclusive results. Data on the combined effect of p53 protein accumulation and TP53 genomic deactivation in large scale studies for esophageal cancer are currently lacking. A tissue microarray with 691 esophageal cancer samples was analyzed by p53 immunohistochemistry and fluorescence in situ hybridization (FISH). Nuclear p53 accumulation was observed in 45.9% of patients with adenocarcinoma (AC) and in 40.0% in squamous cell carcinoma (SCC). Heterozygous TP53 deletions occurred in 40.9% in AC and in 19.4% in SCC. Homozygous deletions did not occur at all. High-level p53 immunostaining was associated with shortened overall survival in AC and SCC while TP53 deletions alone showed no correlation with survival. High-level p53 immunostaining in patients with AC was associated with advanced tumor (P=0.019) and Union for International Cancer Control stages (P=0.004), grading (P=0.027) and the resection margin status (P=0.006). Associations between p53 immunostaining and SCC were not found. TP53 deletions were found to be associated with advanced tumor stages (P=0.028) and the presence of lymph node metastasis (P=0.009) in SCC. In conclusion, strong p53 immunostaining, but not TP53 deletion alone, is associated with unfavorable outcomes and may therefore represent a clinically useful molecular marker in esophageal cancer.

• esophageal cancer
• outcome
• p53 expression

• Esophageal squamous cell carcinoma
• Lymphangiogenesis. Tumor microenvironment miR-548k
• Lymphatic metastasis

• Animals
• Cell Line, Tumor
• Chromosomes, Human, Pair 11/genetics
• Esophageal Neoplasms/genetics
• Esophageal Neoplasms/metabolism
• Esophageal Squamous Cell Carcinoma/genetics
• Esophageal Squamous Cell Carcinoma/metabolism
• Esophageal Squamous Cell Carcinoma/pathology
• Female
• Gene Amplification
• Humans
• Lymphatic Metastasis/genetics
• Male
• Mice
• MicroRNAs/genetics
• Neoplasm Transplantation
• Prognosis
• Sequence Analysis, RNA
• Tumor Microenvironment
• Vascular Endothelial Growth Factor C/metabolism

• National 973 Program
• Institut National des Sciences de l'Univers, Centre National de la Recherche Scientifique (FR)
• National Key R&D Program of China
• China Postdoctoral Science Foundation
• National Postdoctoral Program for Innovative Talent
• Special Fund for Science and Technology Development of Guangdong Province (Collaborative Innovation and Platform Building)
• National Key R&D Program of China

• Epigenomics
• Esophageal Cancer
• Genomics

• Acetylation
• Carcinoma, Squamous Cell/genetics
• DNA Copy Number Variations
• DNA Methylation
• Epigenomics
• Esophageal Neoplasms/genetics
• Esophageal Squamous Cell Carcinoma
• Exome/genetics
• Genetic Heterogeneity
• Histones/genetics
• Humans
• Mutation
• Oncogenes/genetics
• RNA/genetics
• RNA Editing

• UL1 TR000124 NCATS NIH HHS
• UL1 TR001881 NCATS NIH HHS

• CDDP
• GLUT1
• PAX5
• esophageal cancer
• methylation

Esophageal squamous cell carcinoma (ESCC) is a highly lethal malignant tumor. Currently, Human papillomavirus (HPV) is suggested as a potential risk factor for esophageal cancer (EC) in addition to the classic risk factors, alcohol and tobacco, but this hypothesis still remains contradictory. We sought to investigate wether HPV and well-known biomarkers (p16 and p53) and patient-related factors that may have impact on survival of ESCC.

We conducted a prospective cohort study. By using multiplex PCR, we determined the prevalence of high risk HPV in ESCC, and evaluated the immunohistochemical expression of p16 and p53, molecular markers related to esophageal carcinogenesis in order to verify the potential influence of these variables in patients’s survival. Survival rates were estimated using Kaplan-Meier methods. A multivariate confirmatory model was performed using Cox proportional hazards regression.

Twelve (13.8%) of 87 patients were HPV-DNA positive. Positive reactions of p16 and p53 were 10.7% and 68.6%, respectively. Kaplan-Meier analysis indicated that men (p = 0.025) had poor specific-cancer survival and a shorter progression-free survival (p = 0.050) as compared to women; III or IV clinical stage (p < 0.019) had poor specific-cancer survival and a shorter progression-free survival (p < 0.001) compared to I and II clinical stage; not submitted to surgery (<0.001) and not submitted to chemoradiotherapy (p = 0.039) had a poor specific-cancer survival, as well. The multivariate analysis showed that HPV, p16 and p53 status are not predictive parameters of progression-free and specific-cancer survival.

HPV infection and p53 and p16 expression are not prognostic factors in ESCC.

• Esophageal cancer
• Human Papillomavirus
• Survival

• Esophageal squamous cell carcinoma
• Immunohistochemical markers
• Prognosis
• Survival

• Biomarkers, Tumor/genetics
• Carcinoma, Squamous Cell/epidemiology
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/pathology
• Esophageal Neoplasms/epidemiology
• Esophageal Neoplasms/genetics
• Esophageal Neoplasms/pathology
• Esophageal Squamous Cell Carcinoma
• Female
• Humans
• Male
• Neoplasm Proteins/genetics
• Prognosis

• CC2016 Arthritis Research UK
• National Natural Science Foundation of China

Esophageal squamous cell carcinoma (ESCC) is a highly malignant tumor associated with a poor prognosis, and the molecular mechanisms underlying its formation and progression remain poorly understood. KIAA1522 is upregulated in various tumor tissues, but its function is unknown. Alterations in KIAA1522 expression and its implication in ESCC are currently unclear. In this study, an immunohistochemical analysis of ESCC tissues showed that KIAA1522 was highly expressed in 46% (157/342) of ESCC specimens and that its expression was inversely correlated with the degree of differentiation (P=0.03). Furthermore, small interfering RNA-mediated silencing of KIAA1522 revealed that overexpression of this protein reinforced malignant cell proliferation and anoikis resistance of ESCC cells in vitro. More importantly, KIAA1522 depletion significantly suppressed the growth of ESCC xenograft tumors and lung metastasis of ESCC cells in nude mice. At the molecular level, inhibition of KIAA1522 expression markedly reduced the phosphorylated extracellular signal-regulated kinase (ERK) levels in both suspended and adherent ESCC cells, suggesting that KIAA1522 might promote cell proliferation and survival via the ERK cascade. Taken together, these data suggest that upregulation of KIAA1522 might enhance tumorigenicity and metastasis of ESCC cells through potentiating the ERK activity. Thus, aberrant expression of KIAA1522 plays oncogenic roles in ESCC and might serve as a novel molecular target in ESCC treatment.

• KIAA1522
• anoikis
• esophageal squamous cell carcinoma
• extracellular signal-regulated kinase
• metastasis
• tumor growth

Esophageal cancer is the sixth leading cause of cancer death worldwide, and patients who are treated with surgery alone, without neoadjuvant therapies, experience frequent relapses. Whether postoperative therapies could reduce the recurrence or improve overall survival is still controversial for these patients. The purpose of our review is to figure out the value of postoperative adjuvant therapy and address the disputes about target volume delineation according to published data. Based on the evidence of increased morbidity and disadvantages on patient survival caused by postoperative chemotherapy or radiotherapy (RT) alone provided by studies in the early 1990s, the use of postoperative adjuvant therapies in cases of esophageal squamous cell carcinoma has diminished substantially and has been replaced gradually by neoadjuvant chemoradiation. With advances in surgery and RT, accumulating evidence has recently rekindled interest in the delivery of postoperative RT or chemoradiotherapy in patients with stage T3/T4 or N1 (lymph node positive) carcinomas after radical surgery. However, due to complications with the standard radiation field, a nonconforming modified field has been adopted in most studies. Therefore, we analyze different field applications and provide suggestions on the optimization of the radiation field based on the major sites of relapse and the surgical non-clearance area. For upper and middle thoracic esophageal carcinomas, the bilateral supraclavicular and superior mediastinal areas remain common sites of recurrence and should be encompassed within the clinical target volume. In contrast, a consensus has yet to be reached regarding lower thoracic esophageal carcinomas; the “standard” clinical target volume is still recommended. Further studies of larger sample sizes should focus on different recurrence patterns, categorized by tumor locations, refined classifications, and differing molecular biology, to provide more information on the delineation of target volumes.

• adjuvant therapy
• delineation of clinical target volume
• postoperative locoregional recurrence
• postoperative radiation
• thoracic esophageal squamous cell carcinoma

The prognostic value of p53 protein expression in esophageal cancer has been evaluated, but the results remain inconclusive and no consensus has yet been achieved. This meta-analysis was conducted to quantitatively assess the prognostic significance of p53 expression in esophageal cancer.

Publications that assessed the clinical or prognostic significance of p53 expression in esophageal cancer and were published before July 1, 2015 were identified by searching the PubMed and EMBASE databases. A meta-analysis was performed to clarify the association between p53 expression and the clinical outcomes.

A total of 36 publications met the criteria and included 4577 cases. Analysis of these data showed that p53 expression in esophageal cancer was significantly associated with poorer 5-year survival (RR = 1.30, 95 % CI: 1.11–1.51, P = 0.0008). Subgroup analyses according to histological type, continent of the patients, and cut-off value revealed the similar results. The results also indicated that p53 expression was highly associated with advanced TNM stages (I/II vs. III/IV, OR = 0.74, 95 % CI: 0.55–0.99, P = 0.04), lymph node metastasis (OR = 0.77, 95 % CI: 0.66–0.90, P = 0.001), and distant metastasis (OR = 0.46, 95 % CI: 0.26–0.80, P = 0.006). However, p53 expression in the included studies was not significantly associated with tumor size (≤ 5 cm vs. > 5 cm, OR = 1.13, 95 % CI: 0.92–1.40, P = 0.24), tumor location (upper + middle vs. lower, OR = 0.91, 95 % CI: 0.70–1.17, P = 0.45), grade of differentiation (well + moderate vs. poor, OR = 1.10, 95 % CI: 0.90–1.34, P = 0.35), and the depth of invasion (T1/T2 vs. T3/T4, OR = 0.86, 95 % CI: 0.71–1.03, P = 0.09).

This meta-analysis showed that p53 expression may be a useful biomarker for predicting poorer prognosis in patients with esophageal cancer.

• Esophageal cancer
• Meta-analysis
• Prognosis
• p53

• cancer of alimentary tract
• periostin
• signaling pathways
• therapy

BACKGROUND. Aggressive tumor cells can form perfusable networks that mimic normal vasculature and enhance tumor growth and metastasis. A number of molecular players have been implicated in such vasculogenic mimicry, among them the receptor tyrosine kinase EphA2, which is aberrantly expressed in aggressive tumors. Here we study the role and regulation of EphA2 in vasculogenic mimicry in prostate cancer where this phenomenon is still poorly understood.

METHODS. Vasculogenic mimicry was characterized by tubules whose cellular lining was negative for the endothelial cell marker CD34 but positive for periodic acid-Schiff staining, and/or contained red blood cells. Vasculogenic mimicry was assessed in 92 clinical samples of prostate cancer and analyzed in more detail in three prostate cancer cell lines kept in three-dimensional culture. Tissue samples and cell lines were also assessed for total and phosphorylated levels of EphA2 and its potential regulator, Phosphoinositide 3-Kinase (PI3K). In addition, the role of EphA2 in vasculogenic mimicry and in cell migration and invasion were investigated by manipulating the levels of EphA2 through specific siRNAs. Furthermore, the role of PI3K in vasculogenic mimicry and in regulating EphA2 was tested by application of an inhibitor, LY294002.

RESULTS. Immunohistochemistry of prostate cancers showed a significant correlation between vasculogenic mimicry and high expression levels of EphA2, high Gleason scores, advanced TNM stage, and the presence of lymph node and distant metastases. Likewise, two prostate cancer cell lines (PC3 and DU-145) formed vasculogenic networks on Matrigel and expressed high EphA2 levels, while one line (LNCaP) showed no vasculogenic networks and lower EphA2 levels. Specific silencing of EphA2 in PC3 and DU-145 cells decreased vasculogenic mimicry as well as cell migration and invasion. Furthermore, high expression levels of PI3K and EphA2 phosphorylation at Ser897 significantly correlated with the presence of vasculogenic mimicry and in vitro inhibition of PI3K by LY294002 disrupted vasculogenic mimicry, potentially through a reduction of EphA2 phosphorylation at Ser897.

CONCLUSIONS. The expression levels of PI3K and EphA2 are positively correlated with vasculogenic mimicry both in vivo and in vitro. Moreover, phosphorylation levels of EphA2 regulated by PI3K are also significantly associated with vasculogenic mimicry in vivo. Based on its functional implication in vasculogenic mimicry in vitro, EphA2 signaling may be a potential therapeutic target in advanced prostate cancer.

• EphA2
• PI3K.
• Prostate cancer
• Vasculogenic mimicry

• CDC25C
• Esophageal cancer
• RNA interference
• Radiosensitivity

• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/pathology
• Cell Line, Tumor
• Cell Proliferation
• Down-Regulation/genetics
• Esophageal Neoplasms/genetics
• Esophageal Neoplasms/metabolism
• Esophageal Neoplasms/pathology
• Esophageal Squamous Cell Carcinoma
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• HEK293 Cells
• Humans
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Radiation Tolerance/genetics
• Transfection
• Tumor Stem Cell Assay
• cdc25 Phosphatases/genetics
• cdc25 Phosphatases/metabolism

Background: Epidermal growth factor receptor (EGFR), c-Met, and human epidermal growth factor receptor 2 (HER2) are overexpressed in a variety of human cancers, and may serve as biomarkers for disease prognosis. We examined whether high expression of these molecular markers correlates with poor disease prognosis in esophageal squamous cell cancer (ESCC). Materials and Methods: Expression of EGFR, c-Met, and HER2 protein was detected by immunohistochemistry (IHC) in 180 paraffin-embedded tissue samples from stage IIB-IIIC ESCC patients. The overall survival (OS) rates were calculated according to the Kaplan-Meier method, and the log-rank test was used to evaluate differences between survival curves. The Cox proportional hazards model was used for univariate and multivariate analyses. Results: The median survival of all patients was 46 months. There was no significant difference in OS in terms of HER2 and EGFR status (P = 0.177 and P=0.061, respectively). However, there was a significant difference in OS between c-Met high expression patients and c-Met low expression or negative patients (median: 41.9 months vs. 56.7 months; P = 0.001). Multivariate analysis also showed that, of the covariates analyzed, c-Met high expression was the only prognostic factor for OS (HR: 0.459 [95 % confidence interval: 0.287-0.733]; P = 0.001). Patients with ESCC that had concurrent overexpression of EGFR and c-Met had significantly worse survival than ESCC that displayed overexpression of either EGFR or c-Met individually or that did not have overexpression of either protein (P=0.000). Conclusions: Overexpression of HER2 and EGFR individually is not significantly associated with poor prognosis in ESCC. High expression of c-Met may be indicative of a poorer prognosis in ESCC. In order to promote efficient and rapid development of therapeutic methods in ESCC, further studies are necessary to explore the role of c-Met.

• C-MET
• Epidermal growth factor receptor
• Esophageal squamous cell carcinoma
• Human epidermal growth factor receptor 2.

AIM: To evaluate the prognostic role of p53 status and its relationship with clinicopathologic characteristics in esophagus squamous cell carcinoma (ESCC).

METHODS: A systematic search of PubMed, SCI-Ex-panded, EMBASE, the Cochrane library, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Database (CBM), and science and technology periodical database (VIP) was performed. Related references were also searched for additional clinical studies. Two reviewers independently performed screening of identified studies and data extracting according to inclusion and exclusion criteria. The quality assessment was conducted on the basis of the Newcastle-Ottawa Quality Assessment Scale (NOS). The evaluation of the publication bias of the included studies and data synthesis were performed with RevMan 5.3. A fixed-effect or random effects model was adopted according to heterogeneity.

RESULTS: A total of 85 studies involing 8825 cases met the inclusion criteria. The experimental group (4608 cases) was positive for either p53 gene mutation or protein expression, and the control group (4217 cases) was negative for either p53 gene mutation or protein expression. The pooled hazard ratio (HR) for OS was 1.35 (95%CI: 1.23-1.47, P < 0.00001; heterogeneity: P = 0.39, I² = 5%). The pooled risk ratio (RR) for the 5-year and 3-year survival rates was 0.73 (95%CI: 0.62-0.87, P = 0.0003; heterogeneity: P = 0.001, I² = 50%) and 0.87 (95%CI: 0.74-1.02, P = 0.09; heterogeneity: P = 0.28, I² = 18%). p53 gene mutation or protein expression was significantly associated with poorer T stage (RR = 1.09, P = 0.004), N stage (RR = 1.24, P < 0.00001), M stage (RR = 1.65, P < 0.00001), TNM stage (RR = 1.25, P < 0.00001) and differentiation degree (RR = 1.06, P = 0.03). However, there were no association between P53 status and vascular invasion, tumor location, size, age or gender in ESCC (P>0.05).

CONCLUSION: p53 gene mutation or protein expression abnormality is a marker of poor prognosis in patients with ESCC. Meantime, patients with P53 abnormalities are associated with higher depth of invasion, higher rate of lymph node metastasis and distant metastasis, later TNM stage, and poorer grade of differentiation.

• Esophagus squamous cell carcinoma
• P53
• Prognosis
• Clinicopathologic characteristics
• Systematic review

• barrett esophagus
• proto-oncogene proteins c-bcl-6
• tumor suppressor protein p53

• Animals
• Apoptosis
• Barrett Esophagus/metabolism
• Carcinoma/metabolism
• Cell Proliferation
• Dimethylnitrosamine/analogs & derivatives
• Esophageal Neoplasms/metabolism
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• In Situ Nick-End Labeling
• Male
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Proto-Oncogene Proteins c-bcl-6/metabolism
• Rats
• Rats, Wistar
• Tumor Suppressor Protein p53/metabolism
• Vascular Endothelial Growth Factor A/metabolism

• Cancer heterogeneity
• Cultured tumor cells
• Driver mutation
• Drug side effects
• Esophageal squamous cell carcinoma
• Exceptional responder
• High-throughput nucleotide sequencing
• Neoplasm drug resistance
• Personalized medicine
• Xenograft model

• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Carcinoma, Squamous Cell/drug therapy
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/metabolism
• Esophageal Neoplasms/drug therapy
• Esophageal Neoplasms/genetics
• Esophageal Neoplasms/metabolism
• Esophageal Squamous Cell Carcinoma
• Genetic Predisposition to Disease
• Genomics
• Humans
• Molecular Diagnostic Techniques
• Molecular Targeted Therapy
• Phenotype
• Precision Medicine
• Predictive Value of Tests
• Risk Factors
• Signal Transduction/drug effects
• Treatment Outcome

• U54 CA156735 NCI NIH HHS