Overall Survival Of Esophageal Squamous Cell Carcinoma Patients Research Articles

Prognostic value of pretreatment serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio and gamma glutamyltransferase (GGT) in patients with esophageal squamous cell carcinoma

BackgroundThe levels of liver function tests (LFTs) are often used to assess liver injury and non-liver disease-related mortality. In our study, the relationship between pretreatment serum LFTs and overall survival (OS) was evaluated in esophageal squamous cell carcinoma (ESCC) patients.MethodsOur purpose was to investigate the prognostic value of the preoperative alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio and gamma glutamyltransferase (GGT) in ESCC patients. A retrospective study was performed in 447 patients with ESCC, and follow-up period was at least 60 months until death. The prognostic significance of serum LFTs were determined by univariate and multivariate Cox hazard models.ResultsLFTs including ALT, AST, LSR, GGT, TBA and LDH were analyzed. Serum LSR (HR: 0.592, 95% CI = 0.457–0.768, p < 0.001 and GGT (HR: 1.507, 95% CI = 1.163–1.953, p = 0.002) levels were indicated as significant predictors of OS. The 5-year OS among patients with higher LSR levels was longer compared with those patients with decreased LSR levels, not only in the whole cohort but also in the subgroups stratified by pathological stage (T1–T2 subgroup, T3–T4 subgroup, N0 subgroup and M0 subgroup). We also found that patients with a higher GGT might predict worse OS than patients with a normal GGT, not only in the whole cohort but also in the subgroups stratified by pathological stage (T3–T4 subgroup and N1-N2 subgroup).ConclusionsBoth increased levels of LSR and decreased levels of GGT might predict shorter overall survival in ESCC patients. Our findings suggest that serum LSR and GGT levels could be used as a key predictor of survival in patients with ESCC.

Identification and functional characterization of long noncoding RNA NMR as biomarker for metastasis and prognosis in esophageal squamous cell carcinoma.

e15587 Background: Long noncoding RNAs (lncRNA) have been implicated in cancer but most of them remain largely unstudied. Methods: In this study, we identified a NSUN2 methylated lncRNA (NMR), which is significantly upregulated in esophageal squamous cell carcinoma (ESCC), functions as a key regulator of ESCC tumor metastasis and drug resistance. Results: In microarray data of 119 paired ESCC and normal tissues, NMR was significantly overexpressed in ESCC (P &lt; 0.001), and overexpression of NMR indicated poor overall survival of ESCC patients (P = 0.003); in RNA sequencing data of 20 cancer types from TCGA, including 426 head and neck squamous cell carcinoma (HNSC) patients, NMR was significantly upregulated in HNSC tissues (P &lt; 0.01), and patients with higher T stage, N stage, and m stage had significantly higher NMR expression (P &lt; 0.05). Dysregulation of NMR was also validated in an independent cohort with 83 ESCC patients. Consistently, NMR was significantly overexpressed in ESCC (P &lt; 0.001), and high NMR expression was significantly associated with lymph node metastasis and poor overall survival (P &lt; 0.05). Functional experiments demonstrated that NMR could promote tumor cell migration and invasion, inhibit cisplatin-induced apoptosis and increase drug resistance in ESCC cells. Mechanistically, transcription of NMR could be upregulated by NF-κB activation after IL-1β and TNF-α treatment. RNA sequencing after interference highlighted alterations in collagen metabolic process and ERK1 and ERK2 cascade. Further validation proved that NMR could promote the expression of MMP3 and MMP10, at least partially by ERK1/2 pathway. Conclusions: Taken together, these findings suggest that NMR functions as an oncogenic gene in ESCC and may serve as novel biomarker and therapeutic target in ESCC.

Urokinase plasminogen activator secreted by cancer-associated fibroblasts induces tumor progression via PI3K/AKT and ERK signaling in esophageal squamous cell carcinoma.

Cancer-associated fibroblasts (CAFs) are believed to influence tumor behavior and clinical outcomes. We previously showed that conditioned medium (CM) from CAFs induces proliferation and motility of esophageal squamous cell carcinoma (ESCC) cells. Here, we investigated the molecular mechanisms by which the CAF-secreted proteins induce ESCC development and progression. Using antibody arrays, we identified urokinase plasminogen activator (uPA) as one of the main proteins whose release was increased in CAFs compared to normal fibroblasts (NFs). Immunohistochemical analysis of pathological sections showed that uPA-positive cells were localized at the boundaries of tumor and stroma tissues, in stroma between tumor nests, and within the tumors. Increased stromal uPA levels (132/146 cases) correlated with tumor invasion (p < 0.05) and overall survival of ESCC patients (p < 0.05). In vitro assays showed that uPA promotes ESCC cell proliferation, migration, and invasion via PI3K/AKT and ERK signaling pathways. In vivo, anti-uPA antibody suppressed tumor growth in ESCC xenografts. These results suggest that uPA released from stroma, and especially from CAFs, might be a predictive marker for ESCC diagnosis and prognosis, as well as an effective therapeutic target.

Areca nut is associated with younger age of diagnosis, poor chemoradiotherapy response, and shorter overall survival in esophageal squamous cell carcinoma.

ObjectiveAreca nut chewing is carcinogenic to humans. However, little is known about the impact of areca nut chewing on esophageal squamous cell carcinoma (ESCC).MethodsWe retrospectively reviewed 286 ESCC patients who received surgery or preoperative chemoradiotherapy followed by surgery at our institution. Background characteristics including areca nut chewing history were analyzed. The 4-nitroquinoline 1-oxide (4-NQO)-induced murine ESCC model was used to test the impact of arecoline, a main constituent of areca nut, on ESCC.ResultsCompared to patients without areca nut chewing history, patients with areca nut chewing history had overall a younger age of onset (Mean age: 56.75 versus 52.68 yrs, P<0.001) and significantly worse overall survival than those without areca nut chewing history (P = 0.026). Among patients who received surgery, the overall survival rates were not significantly different between those with or without areca nut chewing history. Among patients who received preoperative chemoradiotherapy followed by surgery, those with areca nut chewing history had a significantly lower pathologic complete response rate (P = 0.002) and lower overall survival rate (P = 0.002) than those without. In the murine ESCC model, the incidence of esophageal invasive squamous cell carcinoma was 40% in mice exposed to concomitant 4-NQO and arecoline treatment for 8 weeks and 6% in mice exposed to 4-NQO only for 8 weeks (P = 0.037).ConclusionsOur results indicate that areca nut chewing history is significantly associated with younger age of onset, poor response to chemoradiotherapy, and shorter overall survival in ESCC patients. Arecoline, a main constituent of areca nut, accelerates esophageal tumorigenesis in the 4-NQO-induced murine ESCC model.

Prognostic and clinicopathologic significance of neutrophil-to-lymphocyte ratio in esophageal squamous cell carcinoma: evidence from a meta-analysis.

PurposeEvidence from an increasing number of studies has demonstrated that the neutrophil-to-lymphocyte ratio (NLR) is a prognostic factor for various cancers. However, it is unclear whether NLR predicts prognosis in esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis to investigate the prognostic and clinicopathologic significance of NLR in patients with ESCC.Patients and methodsSelected studies were identified by searches in PubMed, Embase, and Web of Science databases and filtered using our prepared criteria. The hazard ratio (HR) and odds ratio were chosen as effect measures to assess the prognostic role of NLR and its clinicopathologic significance in ESCC. In total, nine studies containing 2,513 patients were enrolled.ResultsWe demonstrated that elevated NLR was associated with worse overall survival in ESCC patients (pooled HR =1.314; 95% confidence interval, 1.164–1.484; P<0.001). Elevated NLR was also associated with unfavorable characteristics regarding depth of tumor invasion, tumor size, clinical stage, and differentiation degree.ConclusionThe results of our meta-analysis suggest that a high NLR value might represent a poor prognosis and worse clinicopathologic characteristics for patients with ESCC.

Plasma Riboflavin Level is Associated with Risk, Relapse, and Survival of Esophageal Squamous Cell Carcinoma

ABSTRACTRiboflavin is an essential micronutrient for normal cellular activity, and deficiency may result in disease, such as cancer. We performed a case-control study to explore the association of riboflavin levels with risk and prognosis of esophageal squamous cell carcinoma (ESCC). Plasma riboflavin levels, as measured by enzyme-linked immunosorbent assay (ELISA), in ESCC patients were significantly lower than in those of healthy controls (7.04 ± 6.34 ng/ml vs. 9.32 ± 12.40 ng/ml; P < 0.05). Moreover, there was an inverse relationship between riboflavin level and risk of ESCC (odds ratio (OR) = 0.97, 95% confidence interval (CI) = 0.95–0.99, P = 0.02). The 5-year relapse-free and overall survival rates were significantly lower when riboflavin levels were ≤0.8 ng/ml than >0.8 ng/ml (relapse-free survival rate: 29.4% vs. 54.8%; overall survival rate: 28.6% vs. 55.6%). Plasma riboflavin level was an independent protective factor for both relapse-free (hazard ratio (HR) = 0.325, 95% CI = 0.161–0.657, P = 0.002) and overall survival of ESCC patients (HR = 0.382, 95% CI = 0.190–0.768, P = 0.007). In conclusion, plasma riboflavin levels are significantly related to risk and prognosis of ESCC patients, suggesting that moderate supplementation of riboflavin will decrease risk and prevent recurrence of ESCC and also improve prognosis of ESCC patients.

TIM-3 promotes the metastasis of esophageal squamous cell carcinoma by targeting epithelial-mesenchymal transition via the Akt/GSK-3β/Snail signaling pathway.

T-cell immunoglobulin and mucin domain-con-taining protein-3(TIM-3), a negative regulator of antitumor immune response, has been demonstrated to be involved in the onset and progression of several types of malignancies. The present study aimed to determine whether and how TIM‑3 plays such a role in esophageal squamous cell carcinoma(ESCC). TIM-3 expression was analyzed by immunohistochemistry and real‑time fluorescence quantitative PCR(qRT‑PCR) in ESCC and matched adjacent normal tissues. Functional experimentsinvitro were performed to elucidate the effect of TIM‑3 knockdown on the proliferation, apoptosis, migration, invasion and epithelial-mesenchymal transition(EMT) in Eca109 and TE‑1 cell lines. Our data revealed that TIM‑3 expression was significantly elevated at both the mRNA and protein levels in ESCC tissues compared with the levels in the matched adjacent normal tissues (both P<0.001). TIM‑3 expression was significantly associated with lymph node metastasis (P=0.008), tumor‑node‑metastasis(TNM) stage (P=0.042) and depth of tumor invasion (P=0.042). In addition, we observed a strong correlation between high TIM‑3 expression and a worse overall survival of ESCC patients (P=0.001). Functional study demonstrated that TIM‑3 knockdown markedly inhibited proliferation, migration and invasion of ESCC cell lines without affecting apoptosis. In addition, TIM‑3 depletion was associated with downregulation of matrix metalloproteinase(MMP)-9 and upregulation of tissue inhibitor of metalloproteinase(TIMP)-1, and with reversion of EMT, as reflected by higher levels of the epithelial marker E‑cadherin and lower levels of the mesenchymal markers N‑cadherin and vimentin. Further study found that TIM‑3 depletion suppressed the signaling pathway involving p‑Akt, p‑GSK‑3β and Snail. Taken together, these results suggest that TIM‑3 is a novel therapeutic target and prognostic biomarker for ESCC and promotes metastasis of ESCC by inducing EMT via, at least partially, the Akt/GSK-3β/Snail signaling pathway.

CD68 and interleukin 13, prospective immune markers for esophageal squamous cell carcinoma prognosis prediction.

PurposeOncology immunity was reported to play a key role in cancer development and progression, so we investigated the prediction role of several immune markers in esophageal squamous cell carcinoma (ESCC) patients after operation in this study.Patients and Methods66 primary ESCC tumor tissues and four sets of tissue microarrays including 705 primary ESCC tumor tissues from four centers were collected and analyzed. Expressions of several immune markers in ESCC tumor tissue were detected with immunohistochemistry staining. Their distribution densities were analyzed with InForm™ 2.0.1 software. All statistic analyses were performed with SPSS16.0 and Stata version 10.0.ResultsSurvival analyses assessed by Kaplan-Meier plots and log-rank tests demonstrated that densities of CD68 and interleukin 13 (IL-13) in tumor stroma were positively correlated with the overall survival of ESCC patients after operation (p < 0.01 for CD68, p < 0.001 for IL-13). Further, a model based on tumor stroma densities of CD68 and IL-13 was constructed and it could significantly classify patients with poor or good prognosis. This model could further identify high-risk group and low-risk group at the same Tumor lymph Nodes Metastases (TNM) stage. Lastly, a more accuracy model based on TNM stage, densities of CD68 and IL-13 was constructed to predict the prognosis of ESCC patient after operation.ConclusionCombining the TNM staging system and densities of CD68 and IL-13 could substantially improve the prognosis prediction accuracy of ESCC patient after operation, which might be an excellent tool for selecting patients for individualized therapy in future.

Integrin α5 promotes tumor progression and is an independent unfavorable prognostic factor in esophageal squamous cell carcinoma

The integrin family plays a major role in complex biological events such as differentiation, development, wound healing, and the altered adhesive and invasive properties of tumor cells. The expression and function of integrin α5 in esophageal squamous cell carcinoma (ESCC) are not clear. Here, by using tissue microarrays and immunohistochemical method, integrin α5 expression was retrospectively evaluated in 147 samples of human ESCC. Results showed that expression of integrin α5 was heterogeneous and varied from negative to intense expression in a membrane and cytoplasmic distribution manner. High expression of integrin α5 was significantly correlated with lymph node metastasis (P = .042) and tumor size (P = .042). Kaplan-Meier analysis revealed that high expression of integrin α5 was related to poor overall survival of ESCC patients (P = .018). Multivariate analysis suggested that integrin α5 expression status was an independent prognostic factor for ESCC (P = .003). Moreover, integrin α5 expression was associated with the survival of patients with lymph node metastasis (P = .020), but did not influence the survival of patients without lymph node metastasis. Finally, we found that RNAi-mediated knockdown of integrin α5 led to decreased growth, migration, and invasion of ESCC cells. Combined, integrin α5 might play important roles in the progression of ESCC. Integrin α5 is a novel biomarker to predict the prognosis of ESCC patients.

Genetic variation in SDC2 is associated with the risk of radiation esophagitis in patients with esophageal squamous cell carcinoma receiving radiotherapy

To explore the associations between the genetic variations in the SDC2 gene and overall survival and risk of radiation esophagitis in patients with esophageal squamous cell carcinoma (ESCC). Eleven functional haplotype-tagging single nucleotide polymorphisms (htSNPs) of SDC2 were genotyped in 296 ESCC patients who received radiotherapy alone, and had different response and esophagitis. The associations between genotypes and risk of esophagitis were measured by odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for sex, age, tumor location, staging, radiotherapy mode and total radiation dose. The hazard ratios (HRs) were estimated using Cox proportional hazards regression model. The median survival time (MST) of these patients was 14 months. Of them, 260 (87.8%) had died until the last date of follow-up of 30 June, 2014. Clinical stage (stage IV vs. stage II) and total radiation dose (≥ 60 Gy vs. < 60 Gy) influence the overall survival time of the patient significantly. Cox proportional hazards regression model analysis showed that the subjects with rs61599409 T allele had an decreased hazard ratio as compared with those with C allele (adjusted HR = 0.82, 95% CI, 0.66-1.02), but the difference was not statistically significant (P = 0.071). The rest 10 htSNPs were not associated with the overall survival of ESCC patients treated with radiotherapy. Among this set of patients, 160 (54.1%) suffered from radiation esophagitis. We found that rs17788084 A > T SNP in the 3'-untranslational region of SDC2 was associated with esophagitis risk, with the OR being 0.48 (95% CI = 0.28-0.85, P = 0.011) for the TA or TT genotype compared with the AA genotype. These results suggest that rs17788084 genetic variation in SDC2 is associated with risk of radiation esophagitis and might serve as a potential biomarker for personalized radiotherapy of ESCC.

Prognostic Significance Of FDG-PET Metrics In Esophageal Squamous Cell Carcinoma

Fluorodeoxyglucose (FDG) avidity as measured by the maximum standard uptake value (SUV) at baseline and after induction chemotherapy (CT) on positron emission tomography (PET) imaging has been shown to be prognostic in patients with esophageal adenocarcinoma; however, the role of FDG PET in esophageal squamous cell carcinoma (SCC) has not been well established. We investigated the prognostic significance of various FDG metrics in a cohort of esophageal SCC patients treated with chemoradiation (CRT). We identified 58 esophageal SCC patients with fully analyzable FDG-PET data at baseline, post-induction CT and post-CRT. All patients received concurrent CRT, of which 53 patients also received induction CT and 11 patients underwent surgery following CRT. Median radiation dose was 5040 cGy (range 5040-5600 cGy). All scans were independently analyzed by a nuclear medicine physician blinded to patient outcome. Using region of interest analysis, max and mean standardized uptake value (SUVmax, SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated for the index lesion and nodes in each patient. Kaplan-Meier analysis was used to evaluate overall survival (OS), disease free survival (DFS), local recurrence free survival (LRFS), and distant metastasis free survival (DMFS). The log-rank test was used to assess correlation between outcomes and FDG-PET metrics. Median follow-up was 3.8 years, with median survival for all patients of 2.9 years. The 3-year OS, DFS, DMFS, and LRFS rates were 49%, 47%, 43%, and 42%, respectively. Using a pre-established cutoff of a 35% decrease in SUVmax from baseline to post-induction PET, 3 yr OS for responders (≥ 35% decrease from baseline) was 52%, whereas nonresponders (< 35% decrease from baseline) had a 3 yr OS of 21% (p = 0.046). Baseline SUVmax, SUVpeak, MTV, and TLG were significantly associated with OS, LRFS, DFS, and DMFS. On post-induction PET, SUVmax, SUVpeak, MTV, and TLG were significantly associated with OS, LRFS, DMFS, and DFS. After completion of CRT, only SUVmax was prognostic for OS, while only SUVmax and TLG were prognostic for DMFS. Baseline and post-induction PET metrics were most prognostic in patients with esophageal SCC. Our data confirms a 35% decrease in SUVmax after induction CT, as established in the adenocarcinoma literature, is also a significant predictor of OS in esophageal SCC patients. This analysis demonstrates that in addition to SUVmax, volumetric PET metrics may also be useful in predicting outcomes.Oral Scientific Abstract 12; TableHazard Ratio for significant PET-metrics based on clinical outcomesHazard Ratio for OS (p-value)Hazard Ratio for DFS (p-value)Hazard Ratio for DMFS (p-value)Hazard Ratio for LRFS (p-value)Baseline SUVmax1.105 (p < 0.001)1.089 (p = 0.002)1.131 (p < 0.001)1.089 (p < 0.001)Post Induction CT SUVmax1.111 (p < 0.001)1.105 (p = 0.001)1.131 (p < 0.001)1.082 (p = 0.004)Post-CRT SUVmax1.161 (p = 0.049)Not Significant1.174 (p = 0.023)Not SignificantBaseline SUVpeak1.115 (p < 0.001)1.115 (p < 0.001)1.152 (p < 0.001)1.095 (p = 0.001)Post Induction CT SUVpeak1.171 (p < 0.001)1.146 (p = 0.003)1.182 (p < 0.001)1.122 (p = 0.005)Baseline MTV1.018 (p = 0.002)1.016 (p = 0.009)1.023 (p < 0.001)1.014 (p = 0.012)Post Induction CT MTV1.02 (p = 0.001)1.017 (p = 0.015)1.024 (p < 0.001)1.015 (p = 0.014)Baseline TLG1.001 (p = 0.021)1.001 (p = 0.023)1.002 (p = 0.001)1.001 (p = 0.044)Post Induction CT TLG1.002 (p = 0.003)1.002 (p = 0.034)1.002 (p = 0.001) and 1.015 (p = 0.043) for Post-CRT TLG1.001 (p = 0.024) Open table in a new tab

Prognostic significance of lymphovascular invasion in patients with esophageal squamous cell carcinoma treated with neoadjuvant chemoradiotherapy.

To investigate the prognostic significance of lymphovascular invasion (LVI) in patients with esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (nCRT). We retrospectively reviewed the charts of 416 consecutive patients with ESCC who underwent surgical resection following nCRT at the Chang Gung Memorial Hospital between 1998 and 2008. After exclusion of patients with non-R0 resection or showing no residual tumor (ypT0Nx), the histological tumor sections of 231 patients were reviewed for LVI. Univariate and multivariate analyses were used to identify the independent predictors of overall survival (OS). LVI was observed in 85 patients (36.8 %). The presence of LVI was related to close circumferential resection margins (CRMs), a greater depth of invasion, poor tumor differentiation, and an increased occurrence of lymph node metastases (LNM). The 5 year OS was significantly lower (10 %) in patients with LVI than in those without (31 %; p < 0.001). By multivariate Cox regression analyses, LVI (hazard ratio [HR] 1.5; p = 0.002) and LNM (HR 1.6; p = 0.007) were identified as independent adverse prognostic factors for OS. The 5 year OS rates according to the number of risk factors present were 35, 21, 20, and 5 for LVI(-)LNM(-), LVI(+)LNM(-), LVI(-)LNM(+), and LVI(+)LNM(+) patients, respectively (p < 0.001). The presence of LVI is independently associated with shorter OS in ESCC patients receiving nCRT. Links between LVI and LNM may provide new clues for the prognostic stratification of esophageal cancer.

Coexpression of ANXA2, SOD2 and HOXA13 predicts poor prognosis of esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is the main type of esophageal cancer, and is the sixth leading cause of cancer-related mortality among all types of cancers. Previously, we found that the homeobox A13 gene (HOXA13) plays a crucial role in the carcinogenesis of ESCC and both Annexin A2 (ANXA2) and superoxide dismutase 2 (SOD2) were its potential targets. Samples from 258 patients from two independent cohorts were collected. RT-qPCR and immunohistochemistry (IHC) were used to detect the expression levels of HOXA13, ANXA2 and SOD2. Kaplan‑Meier survival curve analysis and Cox proportional hazards regression model were employed to determine their prognostic significance. Results showed that ESCC tissues had higher ANXA2 and SOD2 mRNA and protein levels than the non-cancerous tissues. ANXA2 and SOD2 were found to be positively correlated with HOXA13 expression not only at the mRNA level but also at the protein level. In both the study cohort and the validation cohort, the median overall survival time of patients with high expression of HOXA13, ANXA2 and SOD2 was shorter than the survival time of the patients with low expression. The Cox proportional hazards model revealed that both TNM stage and coexpression of HOXA13/ANXA2/SOD2 are independent predictors of overall survival of ESCC patients. In conclusion, the present study demonstrated that ANXA2 and SOD2 are potential target genes of HOXA13 and their coexpression predicts the poor prognosis of ESCC patients.

Association of mu-opioid receptor expression with lymph node metastasis in esophageal squamous cell carcinoma

The mu-opioid receptor (MOR), a membrane-bound G protein-coupled receptor, is the main target for opioids in the nervous system. MOR1 has been found in several types of cancer cells and reported to be involved in tumor progression and metastasis. However, the expression and clinical significance of MOR1 in esophageal squamous cell carcinoma (ESCC) remain unclear. In our study, the expression of MOR1 was confirmed in ESCC cell lines (KYSE180, KYSE150, and EC109) by Western blot. MOR1 was also detected on tissue microarrays of ESCC samples in 239 cases using immunohistochemical staining. We found that MOR1 was mainly located in the cytoplasm and occasionally occurred in the membrane or nucleus of ESCC cells. Moreover, results indicated that MOR1 expression in the cytoplasm was associated with lymph node metastasis (R = 0.164, P = 0.008, Kendall's tau-b-test). No more associations were found between MOR1 expression status and other clinical parameters. However, no statistical significant differences were found between MOR1 expression in the cytoplasm, nucleus/membrane, and the overall survival of ESCC patients (P = 0.848; P = 0.167; P = 0.428, respectively, log-rank test). Our results suggest that the cytoplasmic MOR1 may be a high-risk factor for lymph node metastasis of ESCC patients. We also hypothesize that MOR1 agonists used in ESCC patients should be prudent, and opioid receptor antagonists may be novel therapeutic drugs for ESCC patients.

Analysis of EHMT1 expression and its correlations with clinical significance in esophageal squamous cell cancer

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy, requiring effective biomarkers for prognosis and therapeutic responsiveness. Histone H3K9 methyltransferases (EHMT1 and EHMT2) are global genome organizers, which are crucial for maintaining the balance state of cells in a tissue-specific manner. It was previously suggested that EHMT1 expression is a predictor of prognosis in several malignant tumors; however, the prognostic significance of EHMT1 expression in ESCC has not been determined. A cohort of 50 ESCC cases and 46 paired normal esophageal tissue samples were evaluated to assess the levels of EHMT1 expression by immunohistochemistry and reverse transcription-polymerase chain reaction. The SPSS software package was used for statistical data analysis. A significantly upregulated EHMT1 expression was observed in squamous preinvasive lesions and ESCC compared to the matched normal esophageal epithelia (52.0 vs. 21.7%, respectively). The expression of EHMT1 was correlated with tumor grade (G), depth of invasion (T) and lymph node metastasis (N) in ESCC. EHMT1 overexpression was found to be associated with poor cancer-specific survival in squamous cell carcinomas (χ2=3.922, P=0.048). The expression of EHMT1 was identified as an independent prognostic factor for overall survival in ESCC patients. In conclusion, EHMT1 expression is upregulated in ESCC and early preinvasive esophageal squamous lesions and the overexpression of EHMT1 is associated with poor prognosis in ESCC. Therefore, the expression of EHMT1 may be an effective prognostic biomarker for ESCC.

Expression of epidermal growth factor receptor is an independent prognostic factor for esophageal squamous cell carcinoma.

BackgroundThe overall survival of patients with esophageal squamous cell carcinoma (ESCC) remains poor. Prognostic predictions in ESCC are usually based on histological assessment of tumor invasion and lymph node metastasis, but a biomarker with better predictive accuracy could be more useful. Because overexpression of epidermal growth factor receptor (EGFR) has been associated with poor prognosis, this study investigated whether EGFR is an independent prognostic factor for overall survival and disease-free survival of ESCC patients.MethodsESCC tissue specimens from 243 patients obtained during surgical resection between 1980 and 1997 were retrieved for immunohistochemical analysis of EGFR expression.ResultsThe data showed that EGFR protein was overexpressed in 187 of 243 (77%) ESCC tissues. Elevated expression was associated with higher pathologic tumor stages (P = 0.001), lymph node metastasis (P = 0.002), and higher Union for International Cancer Control (UICC) stage (P <0.0001), as well as poorer disease-free survival and overall survival of ESCC patients (P <0.0001). A multivariate analysis showed that overexpression of EGFR protein was an independent factor for disease-free survival (P = 0.003) and overall survival (P = 0.001) of these patients. Subgroup analysis of patients with stage IIA (UICC 2002) showed that EGFR overexpression was associated with poorer disease-free survival (P = 0.007) and overall survival (P = 0.010) of the patients in univariate analyses.ConclusionsThe current study demonstrated that EGFR overexpression was an independent prognostic factor for overall survival and disease-free survival of ESCC patients. However, targeting of EGFR activity using gefitinib or erlotinib could be useful for clinical treatment of ESCC patients.

Expression of Six1 and Six4 in esophageal squamous cell carcinoma and their correlation with clinical prognosis

Six1 and Six4 are expressed in several tumors, and associated with tumor progress and poor prognosis. The aim of this study was to investigate the expression of Six1 and Six4 in esophageal squamous cell carcinoma (ESCC), and to evaluate their correlation with the clinicopathological factors and prognosis. Tissue microarray technology and immunohistochemical method (EnVision) were used to detect the expression of Six1 and Six4 in the tumor tissues and corresponding adjacent normal epithelium of esophagus from 292 ESCC patients. Among the 292 ESCC patients, the positive rates of Six1 and Six4 protein expression in tumor tissues were 72.9% (213/292) and 56.2% (164/292), respectively, significantly higher than the expression rate of 33.2% (97/292) and 32.5% (95/292) in adjacent normal epithelium of esophagus (P < 0.05). Chi square test showed that the expression of Six1 protein was related to tumor size, depth of tumor invasion and patient survival status; higher Six4 protein expression level was related to poor differentiation and increased depth of invasion. Single factor Log-rank analysis revealed that gender, TNM stage, Six1 protein expression level were related to the overall survival of ESCC patients (P < 0.05), while the five-year survival rate was significantly higher in the Six1-negative group than the Six1-positive group [51.9% (41/79) vs. 43.7% (93/213)]. Multi-factor Cox proportional risk model analysis showed that TNM stage and positive expression of Six1 were independent prognostic factors for ESCC patients (P < 0.05). Six1 and Six4 are highly expressed in ESCC. Their expression levels are closely related to the progress and prognosis of ESCC. Over-expression of Six1 is related to poor prognosis in ESCC patients. Thus, Six1 could be used as an important prognostic indicator for ESCC patients.

Autophagy-related proteins LC3 and Beclin-1 impact the efficacy of chemoradiation on esophageal squamous cell carcinoma

Autophagy is a bulk protein and organelle degradation process essential for cellular maintenance, cell viability and development. This study investigated the prognostic role of LC3 and Beclin-1, two autophagy-related proteins, in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated with definitive chemoradiation.The data of 150 patients with stages II–IVa ESCC who had undergone definitive concurrent chemoradiation were studied; LC3 and Beclin-1 protein expression was evaluated by immunohistochemistry and western blot. The correlations between LC3 and Beclin-1 expression, the patients’ clinicopathological features, and overall survival were analyzed.Eighty-three patients showed positive LC3 and 84 showed positive Beclin-1 protein expressions, but LC3 and Beclin-1 expression in ESCC was not significantly correlated (P=0.746). LC3 and Beclin-1 expression did not show any association with gender, age, tumor location, and treatment response. The median survival of patients with positive LC3 expression was 23.6 months, while the median survival was 32.0 months in patients with negative LC3 expression (P=0.049). The patients with LC3 and Beclin-1-positive tumors presented much poorer long-term survival. Multivariate analysis showed that clinical stage (P=0.019), treatment response (P=0.002), and LC3 expression level (P=0.021) were independent predictive factors of overall survival in patients with locally advanced ESCC receiving definitive chemoradiation.Patients with LC3 and Beclin-1-negative expression had a better overall survival than those with LC3 and Beclin-1-positive tumors. LC3 expression is an independent prognostic factor for overall survival in ESCC patients treated with definitive chemoradiation.

Overexpression of HSPA2 is correlated with poor prognosis in esophageal squamous cell carcinoma

BackgroundHeat shock-related 70 kDa protein 2 (HSPA2) has been identified as a potential cancer-promoting protein expressed at abnormal levels in a subset of cancers. However, its important role in esophageal squamous cell carcinoma (ESCC) is hardly known by people. The purpose of this study is to assess HSPA2 expression and to explore its role in ESCC.MethodsThirty ESCC samples, paired adjacent non-cancerous tissues and normal esophageal tissues, were collected for HSPA2 detection by quantitative RT-PCR (qRT-PCR) and western blotting. Additionally, the expression of HSPA2 in ESCC and adjacent non-cancerous tissues from 120 patients was analyzed by immunohistochemistry, and correlated with clinicopathological parameters and patients’ outcome.ResultsHSPA2 mRNA and protein were overexpressed in ESCC tissues. Overexpression of HSPA2 was significantly associated with primary tumor, TNM stage, lymph node metastases and recurrence, respectively (all, P <0.05). Kaplan-Meier curves showed that elevated HSPA2 expression was associated with shorter disease-free survival and overall survival in ESCC patients. Cox multivariate regression analysis revealed that overexpression of HSPA2 was an independent prognostic factor in disease-free survival and overall survival for ESCC patients (hazard ratio was 2.115 and 2.210, respectively, P <0.05).ConclusionsOur findings demonstrate that overexpression of HSPA2 may contribute to the malignant progression of ESCC and present a novel prognostic indicator for ESCC patients.

Epidermal growth factor receptor as a prognostic predictor to chemoradiotherapy in the primary lesion of esophageal squamous cell carcinoma.

e15167 Background: Concurrent chemoradiotherapy (CCRT) is standard performed for patients with locally advanced esophageal squamous cell carcinoma (ESCC). Some reports have revealed that patients who responded well to CCRT had favorable outcomes, whereas poor responders conversely showed a worse prognosis. The aim of this study was to identify molecular markers predicting prognosis to CCRT. Methods: Forty-seven patients with locally advanced ESCC who were treated with CCRT were included in the present study.The regimen comprised 5-fluorouracil and cisplatinumcombined with radiation therapy (1.8-2Gy/day). The chemotherapy was repeated every 3 weeks and the total radical radiation dose was 60-64Gy.The clinicopathologic features, patterns of treatment failure, and survival data were compared with the expressions of epidermal growth factor receptor (EGFR), which were determined by immunohistochemistry in biopsy specimens obtained before treatment. Univariate and multivariate analyses were performed to determine the prognostic factors that influence patients survival. Results: Overall the indices of the overexprssions of EGFR (the percentage of immunoreactivetumor cells≥50%) in all patients were 59.6%. EGFR expression was no significantly associated with gender,age,tumor differentiation grade,tumor location,depth of invasion, and metastasis status except for lymph node status (P=0.011). A significant difference was seen in the overall survival between patients with or without EGFR overexpression group(P=0.024). However, overexpression of EGFR was not associated with local recurrence or distant metastasis.In addition, a relationship between overall survival and sex (P=0.021),age (P=0.018),T stage(P=0.035), and tumor location (P=0.023) was detected.Local recurrence was found has a relationship with T stage(P=0.015) and metastasis status (P=0.026),and distant metastasis was found has a relationship with age (P=0.048). Conclusions: EGFR overexpression determined in pretreatment biopsy specimens maybe a clinically useful biomarker for predicting the overall survival of ESCC patients.