Skeletal muscle volume by 3D imaging and long-term survival in esophageal squamous cell carcinoma with neoadjuvant chemotherapy.

Prognostic significance of red cell distribution width in esophageal squamous cell carcinoma

Changes in the expression profiles of microRNAs (miRNAs) have been found in many cancers. The study was aimed to investigate the expression of miR-25, miR-223, and miR-375 in the serum of patients with esophageal squamous cell carcinoma (ESCC) and its effect on survival outcome. We examined the expression levels of miR-25, miR-223, and miR-375 in 20 pairs of ESCC cancer and matched paracancerous tissues, serum samples from 94 healthy volunteers and 194 patients with ESCC using quantitative reverse transcription polymerase chain reaction, and analyzed the relationship between expressions of serum miR-25, miR-223, and miR-375 and ESCC clinicopathological parameters as well as survival. Expressions of miR-25 and miR-223 were significantly increased in ESCC tissues compared with paracancerous tissues (P = 0.008 and 0.009, respectively), whereas the expression of miR-375 was significantly decreased in ESCC tissues compared with paracancerous tissues (P = 0.006). Expressions of serum miR-25 and miR-223 were significantly higher in ESCC patients than those in healthy controls, and, inversely, expression of serum miR-375 was significantly lower in ESCC patients than those in healthy controls (P = 0.007). High expression of serum miR-25 was significantly associated with lymph node metastasis (P = 0.01). Survival analysis showed that high expression of serum miR-223 and low expression of serum miR-375 were associated with poor survival in ESCC patients [hazard ratio (HR) = 1.717, 95% confidence intervals (CI) 1.139-2.588, P = 0.01; HR = 1.750, 95% CI 1.111-2.756, P = 0.016, respectively). Furthermore, Patients with high miR-223 and low miR-375 expression had higher risk of death than those with low miR-223 and high miR-375 expression (HR = 3.599, 95% CI 1.800-7.195, P = 2.92 × 10(-4)). In conclusion, miR-25, miR-223, and miR-375 were abnormally expressed in ESCC tissues and sera. Serum miR-223 and miR-375 are potential prognostic biomarkers for ESCC.

To evaluate effectiveness of concurrent radiotherapy in esophageal cancer patient treated with neoadjuvant therapy. The data of 1026 consecutive esophageal squamous cell carcinoma (ESCC) patients who underwent minimally invasive esophagectomy (MIE) were retrospectively collected. The main inclusion criteria were patients with locally advanced (cT2-4N0-3M0) ESCC who underwent neoadjuvant chemoradiotherapy (NCRT) or neoadjuvant chemotherapy (NCT) followed by MIE, and divided into two groups according to different neoadjuvant strategies. Propensity score matching was performed to improve the comparability between the two groups. After exclusion and matching, 141 patients were enrolled retrospectively: 92 received NCT, and 49 received NCRT. No difference in clinicopathologic characteristics or incidence of adverse events between groups. A shorter operation time (215.7 ± 35.5min) (p < 0.001), less blood loss (111.2 ± 67.7ml) (p = 0.0007) and a greater number of lymph nodes retrieved (33.8 ± 11.7) (p = 0.002) were observed in NCT group than in NCRT group. The incidence of postoperative complications was similar between groups. Although patients in NCRT group had better pathological complete response (16, 32.7%) (p = 0.0026) and ypT0N0 (10, 20.4%) (p = 0.0002) rates, there was no significant difference in 5-year progression-free survival (p = 0.1378) or disease-specific survival (p = 0.1258) between groups. Compared with NCRT, NCT has certain advantages in that it can simplify the surgical procedure and decrease the surgical technique required without compromising the surgical oncological outcomes and long-term survival of patients.

Esophageal squamous cell carcinoma (ESCC) has a complex, multifactorial etiology in which environmental, geographical, and genetic factors play major roles. It is the second most common cancer among men and the fourth most common among women in India, with a particularly high prevalence in Northeast India. In this study, an integrative in silico [DAVID, NCG5.0, Oncomine, Cancer Cell Line Encyclopedia, and The Cancer Genome Atlas (TCGA)] approach was used to identify the potential biomarkers by using the available three genomic datasets on ESCC from Northeast India followed by its in vitro functional validation. Fibroblast Growth Factor 12 (FGF12) gene was overexpressed in ESCC. The upregulation of FGF12 was also observed on ESCC of TCGA OncoPrint portal, whereas very low expression of FGF12 gene was mapped in normal esophageal tissue on the GTEx database. Silencing of FGF12 showed significant inhibition in activity of tumor cell proliferation, colony formation, and cell migration. The upregulation of FGF12 showed significantly reduced survival in ESCC patients. The protein interaction analysis of FGF12 found the binding with MAPK8IP2 and MAPK13. High expression of FGF12 along with MAPK8IP2, and MAPK13 proteins correlate with poor survival in ESCC patients. Tissue microarray also showed expression of these proteins in patients with ESCC. These results indicate that FGF12 has a potential role in ESCC and suggest that cancer genomic datasets with application of in silico approaches are instrumental for biomarker discovery research broadly and specifically, for the identification of FGF12 as a putative biomarker in ESCC.

The role of extramural venous invasion (EMVI) in esophageal cancer is still unclear. This study aimed to identify EMVI and assess its impact on survival and recurrences in esophageal squamous cell carcinoma (ESCC). Retrospectively, we reviewed resection specimens of 147 locally advanced ESCC (pT3-T4aN0-3M0) patients who had a curative intended surgery alone at the Cancer Hospital of Shantou University from March 2009 to December 2013. After confirming pT≥3 in hematoxylin-eosin tumor slides, EMVI was evaluated by Verhoeff and Caldesmon staining. The impact of EMVI with other clinicopathological characteristics and survival were analyzed using the χ 2 test, Cox regression, and Kaplan-Meier method. EMVI was present in 30.6% (45/147) of the P ≥T3 ESCCs and associated with lymph-vascular invasion and poor differentiation grade ( P <0.05). Disease-free survival and overall survival in patients with EMVI-absent tumors were about 2.0 times longer than in those with EMVI-present tumors. In pN0 patients, EMVI-presence was associated with poor overall survival (HR 4.829, 95% CI 1.434-16.26, P =0.003) and Disease-free Survival (HR 4.026, 95% CI 0.685-23.32, P =0.018). In pN1-3 patients, EMVI had no additional effect on survival. Conclusions EMVI has an independent adverse prognostic effect on survival in ESCC patients after surgery alone. EMVI should be included in pathology reports as it might contribute to identify high-risk patients for potential additional treatment.

BackgroundMetastasis is still a major cause of poor pathological outcome and prognosis in esophageal squamous cell carcinoma (ESCC) patients. NUAK1 has been reported highly expressed in many human cancers and is associated with the poor prognosis of cancer patients. However, the role of NUAK1 and its underlying signaling mechanism in ESCC metastasis remain unclear.MethodsExpression of NUAK1 in ESCC was detected by real-time quantitative RT-PCR (qRT-PCR), Western blotting and immunohistochemical staining. MTT, colony formation, wound-healing and transwell assays were used to determine the role NUAK1 in vitro. Metastasis was evaluated by use of an experimental pulmonary metastasis model in BALB/c-nu/nu mice. The mechanisms were assessed by using coimmunoprecipitation, immunofluorescence and dual-luciferase reporter gene experiments.ResultsNUAK1 was highly expressed in ESCC tissues compared with the adjacent normal esophageal epithelial tissues. Moreover, the elevated expression of NUAK1 positively correlated with tumor invasion depth, lymph node metastasis, pathological TNM stage, and poor survival in ESCC patients. Further experiments showed that NUAK1 overexpression did not change the cell viability and colony formation of ESCC cells, while remarkably promoted the migration and invasion in vitro and experimental pulmonary metastasis in vivo. Mechanistically, NUAK1 enhanced the transcription level of Slug, which enhanced the migratory and invasive capability of ESCC cells. Consistently, silencing Slug almost completely diminished the migration and invasion of NUAK1-overexpressing ESCC cells. Further studies demonstrated that NUAK1 upregulated the transcription activity of Slug through activating the JNK/c-Jun pathway.ConclusionThese results demonstrated that NUAK1 promoted the metastasis of ESCC cells through activating JNK/c-Jun/Slug signaling, indicating NUAK1 is a promising therapeutic target for metastatic ESCC.

The lymph node metastasis (LNM) has been well recognized as one of the major risk factors affecting the survival of the patients with esophageal squamous cell carcinoma (ESCC). However, it is a dilemma to determine the LNM status before surgery. The invasive depth (T stage) of ESCC could be determined either with computed tomography or ultrasound endoscopy and may reflect the severity of LNM. Thus, the present study was designed to determine the impact of tumor invasive depth on LNM status and survival in ESCC patients with T1-4N0M0. The enrolled 30,514 ESCC patients in this study were from the ESCC database in Henan Key Laboratory for Esophageal Cancer Research of the First Affiliated Hospital, Zhengzhou University. Of the patients, there were 18346 males with an mean age of 59.2±8.9, and 12168 females with an mean age of 59.7±8.7. All the patients had been performed radical esophagectomy without radiotherapy and chemotherapy before surgery, and the invasive depth records were retrieved from the medical records in hospitals after surgical resection. Based on the 6th version of UICC criteria, the invasive depth (T) was classified as Tis, and T1-4. Of the 30,514 ESCC patients, 20,288 cases were successfully followed until the end of 2015. The Logistic regression method were used to determine the correlation between T stage and LNM status. The Kaplan-Meier method was applied to analyze the survival in different groups. The results showed that, of the 30,514 ESCC patients, there were 3324 (10.9%) patients with Tis+T1, 9616 (31.5%) with T2, 17249 (56.5%) with T3 and 325 (1.1%) with T4. Accordingly, from Tis&amp;T1 to T4, the number of the patients with positive LNM were 554 (16.7%), 3392 (35.3%), 7737 (44.9%) and 205 (63.1%), respectively. Logistic regression analysis indicated the risk of LNM was dramatically increased from 2- to 8-folds with the T stages from Tis&amp;T1 to T4, with OR values of 2.725 (T2: 95%CI: 2.465-3.013), 4.067 (T3: 95%CI: 3.695-4.477) and 8.542 (T4: 95%CI: 6.699-10.892), respectively. Interestingly, seventeen percent of the patients with Tis&amp;T1 stages had occurred positive LNM, indicating that LNM may occur in very early stage of ESCC. Kaplan-Meier analysis showed that T staging was obviously associated with the survival in ESCC patients with negative LNM (P value &amp;lt; 0.05). Overall, the present results indicated a strong correlation between invasive depth and LNM status, suggesting that the invasion depth may be one of crucial markers to reflect the LNM in ESCC. The invasive depth could be used as an promising indicator for LNM status judgment in clinical TNM staging and prognosis for ESCC. [Supported by the Joint Funds of the National Natural Science Foundation of China (U1301227), the General Program of National Natural Science Foundation of China (81472323) and Correspondence to: Li Dong Wang, Email: ldwang2007@126.com] Note: This abstract was not presented at the meeting. Citation Format: Xin Song, Fu You Zhou, Hai Jun Yang, Xue Na Han, Tang Juan Zhang, Lian Qun Zhang, Ning Liu, Jing Li Ren, Zhi Wei Chang, Xin Tian, Hai Ling Wang, Hui Fang Tan, Li Dong Wang. Impact of the invasive depth on lymph node metastasis and survival in Chinese patients with esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3293. doi:10.1158/1538-7445.AM2017-3293

Connective tissue growth factor (CTGF, CCN2), a secreted protein, is involved in the development and progression of esophageal squamous cell carcinoma (ESCC). However, it remains unclear how CTGF expression affects the progression of ESCC. Our study implicated differences of CTGF protein status in precancerous lesions, and retrospectively examined the associations of CTGF mRNA and protein levels with clinical prognosis in ESCC patients. Here immunohistochemistry and the quantitative real-time real-time reverse transcription polymerase were performed for predicting the CTGF protein status and mRNA levels in ESCC patients, respectively. Different degrees of CTGF protein status presented in normal human esophageal epithelium and precancerous lesions, and CTGF protein was highly expressed in ESCCs. Survival analysis showed that CTGF protein status was significantly related to poor survival of ESCC patients (P= 0.024), while no significant difference was observed between CTGF mRNA levels and the survival of ESCC patients (P= 0.196). Multivariate Cox analysis demonstrated that CTGF protein status was the independent factor in prognosis of ESCC patients. In that way, CTGF protein status might elevate the progression of ESCC, and would be significant for the diagnosis of precancerous lesions or early ESCC.

Esophageal squamous cell carcinoma (ESCC) is one of the most common cause of cancer-associated mortality. Uncovering novel molecular biomarkers that can predict ESCC development will improve personalized therapy. The goal of the current study was to investigate the expression pattern of miR-483-5p and determine its prognostic value in ESCC. We first analyzed miRNA-seq data obtained from the Cancer Genome Atlas (TCGA) cohort to evaluate the prognostic value of miR-483-5p in ESCC. Then quantitative real-time RT-PCR (qRT-PCR) was carried out to compare the miR-483-5p levels in 80 pairs of ESCC tissues and adjacent non-cancerous tissues. The correlation between miR-483-5p levels and clinical features were determined. For the TCGA cohort, ESCC patients with higher miR-483-5p had significantly shorter overall survival time. The examined ESCC cancer tissues exhibited a remarkable increment in miR-483-5p expression compared with the adjacent normal tissues. miR-483-5p was positively correlated with TNM stage, lymph nodes metastasis and T stage. In addition, upregulate miR-483-5p expression was also found to be significantly associated with poor survival of ESCC patients. Furthermore, miR-483-5p expression was an independent prognostic factor for overall survival and disease free survival in ESCC patients. Our study demonstrates that miR-483-5p might be a tumor promoter of ESCC, which provide a promising prognostic biomarker and therapeutic target.

Protein tyrosine phosphatase receptor type S is a tumor suppressor gene, located at chromosome 19p13.3, frequently inactivated through deletions or epigenetic mechanisms in many types of cancers. In this study, we investigate protein tyrosine phosphatase receptor S (PTPRS) expression level, clinicopathological and prognostic significance in 205 cases of esophageal squamous cell carcinoma (ESCC). Paraffin embedded tissue with immunohistochemistry methods was adopted to exam PTPRS expression in ESCC and paired normal esophageal mucosa tissues on Tissue Microarrays (TMAs). The protein tyrosine phosphatase receptor S was significantly down-regulated in ESCC (58.0%) relative to normal tissues (43.9%) (P=0.006). Statistical analysis revealed that reduced PTPRS expression was significantly associated with TNM stage (P=0.013), invasion depth (P<0.001), local lymph node metastasis (P=0.042) and tumor differentiation (P=0.001). Furthermore, Kaplan-Meier survival analysis revealed that low expression of PTPRS significantly correlated with poor survival of ESCC patients (P=0.002). Cox regression analysis confirmed PTPRS expression as an independent predictor of the overall survival of ESCC patients (HR=1.573, P=0.049). The 5-year overall survival rates in patients with high and low PTPRS expression were 50.6% and 37.2%, respectively. PTPRS deficiency is independently associated with shorter survival and increased recurrence in patients. Our data offer convincing evidence that loss of PTPRS expression may predict an aggressive clinical course in ESCC patients. PTPRS may function as a tumor suppressor and play an important role in ESCC growth and metastasis.

Purpose Various malnutrition and inflammation criteria were associated with prognosis of esophageal squamous cell carcinoma (ESCC) patients. Nonetheless, the interplay of clinicopathological features, malnutrition, and inflammation criteria with overall survival in ESCC patients remains unclear. Methods We retrospectively reviewed medical records of 205 patients diagnosed with ESCC between 2007 and 2012, and evaluated the status of participant malnutrition and inflammation, including body mass index < 18.5 kg/m2, body weight loss > 5.0%, serum albumin level < 3.5 g/dl, neutrophil-to-lymphocyte ratio > 3.5, platelet-to-lymphocyte ratio > 20, prognostic nutrition index < 40, blood total lymphocyte count < 1600 cells/mm3, and grades of body mass index-adjusted body weight loss (combined BMI-BWL). We assessed the association of clinicopathological features, nutritional status, and inflammation condition with overall survival using univariate and multivariate Cox regression analyses. Results The mean overall survival of ESCC patients was 28.8 mo,. The multivariate logistic regression model after adjustment for clinicopathological variables, malnutrition status, inflammation condition, and co-morbid status found that tumor stage and grades of combined BMI-BML served as equally important prognostic factors for overall survival. Conclusions Advanced tumor stage and high grades of combined BMI-BWL were independent prognostic factors for overall survival in ESCC patients.

BackgroundEarly detection of esophageal squamous cell carcinoma (ESCC) recurrence is a key element for follow‐up care and surveillance. The aim of this study is to detect the level of circulating exosomes (CEs) in ESCC patient and clarify its clinical significance.MethodsIn this study, 200 serum samples of ESCC patients were obtained from the Zhejiang Cancer Hospital Biospecimen Repository. Total CEs were purified by selectively capturing epithelial cell adhesion molecule positive exosomes, using magnetic‐bead technique. enzyme‐linked immunosorbent assay (ELISA) was performed to measure the concentration level of CEs. The oncogenic potential of CEs was analyzed in vitro.ResultsSerum concentration of CEs was significantly higher in ESCC patients than in healthy controls (P < 0.01). Receiver‐operating characteristic curve analysis demonstrated that CEs concentration could distinguish patients with ESCC from healthy individuals with a sensitivity of 75% and a specificity of 85%. Kaplan‐Meier analysis demonstrated that the increased CEs concentration was associated with poor overall survival (P = 0.01) and progression free survival (P = 0.03) in ESCC patients. Multivariate cox regression analysis revealed that CEs concentration was an independent prognostic marker for overall survival in ESCC patients (P < 0.01). Results from transwell and wound scratching experiments showed that the CEs could promote cell migration and invasion.ConclusionsThis study clearly demonstrates that CEs from ESCC patients are stable enough to be measured and their levels in ESCC patients are significantly upregulated. Circulating exosomes could serve as a novel noninvasive biomarker for detection of ESCC. Their involvement in carcinogenesis must be further established.

The purpose of the study is to evaluate the predictive efficacy of secreted protein, acidic and rich in cysteine (SPARC) and the class III β-tubulin (β-tubulin III, TUBB3) in predicting therapeutic effect in patients with locally advanced esophageal squamous cell carcinoma(ESCC) who received nab-paclitaxel plus cisplatin neoadjuvant chemotherapy(CT) followed by surgery. Patients with stage II to III esophageal squamous cell carcinoma of different stages are recruited. The tumor biopsy tissues prior treatment from enrolled patients were examined by SPARC and TUBB3 immunohistochemistry (IHC). Correlations between SPARC/TUBB3 expression and response to chemotherapy and long-term survival in patients received surgical resection was analyzed. A total of 35 patients with stage II to III esophageal squamous cell carcinoma were enrolled. Of the 35 enrolled patients, 30 successfully completed neoadjuvant chemotherapy and underwent R0 resection, 3 refused surgery after chemotherapy, and 2 failed to undergo radical surgery after chemotherapy. Out of patients undergoing surgery, pathological complete response (pCR) was achieved in 6 patients (6/30, 20%). The 1, 2 and 5-year disease free survival (DFS) rates were 70.0%, 36.6% and 33.3%, respectively. The 1, 2 and 5-year overall survival (OS) rates were 83.3%, 63.3% and 36.6%, respectively. SPARC and TUBB3 IHC was performed on the tumor biopsy tissues which were obtained from patients before treatment. Correlation between SPARC/TUBB3 expression and long-term survival in patients was studied. Both the median DFS and OS between SPARC negative samples and SPARC positive staining samples have no statistical difference. However, the median DFS and OS in TUBB3 negative patients was better than those in TUBB3 positive patients (p = 0.002 for DFS, p = 0.001 for OS). In addition, patients with pCR had longer OS and DFS time than those without pCR.COX regression analysis showed that TUBB3 prior treatment and pCR were independent prognostic factors in ESCC patients undergoing sequential surgery after preoperative chemotherapy. TUBB3 negative expression prior treatment and pCR may indicate a better prognosis for stage II and III ESCC patients after nab-paclitaxel plus cisplatin neoadjuvant chemotherapy following radical esophagectomy.

The impact of hospital volume on the long-term survival of esophageal squamous cell carcinoma (ESCC) has not been well assessed in China, especially for stage I-III stage ESCC. We performed a large sample size study to assess the relationships between hospital volume and the effectiveness of ESCC treatment and the hospital volume value at the lowest risk of all-cause mortality after esophagectomy in China. To investigate the prognostic value of hospital volume for assessing postoperative long-term survival of ESCC patients in China. The date of 158,618 patients with ESCC were collected from a database (1973-2020) established by the State Key Laboratory for Esophageal Cancer Prevention and Treatment, the database includes 500,000 patients with detailed clinical information of pathological diagnosis and staging, treatment approaches and survival follow-up for esophageal and gastric cardia cancers. Intergroup comparisons of patient and treatment characteristics were conducted with the X2 test and analysis of variance. The Kaplan-Meier method with the log-rank test was used to draw the survival curves for the variables tested. A Multivariate Cox proportional hazards regression model was used to analyze the independent prognostic factors for overall survival. The relationship between hospital volume and all-cause mortality was assessed using restricted cubic splines from Cox proportional hazards models. The primary outcome was all-cause mortality. In both 1973-1996 and 1997-2020, patients with stage I-III stage ESCC who underwent surgery in high volume hospitals had better survival than those who underwent surgery in low volume hospitals (both P<0.05). And high volume hospital was an independent factor for better prognosis in ESCC patients. The relationship between hospital volume and the risk of all-cause mortality was half-U-shaped, but overall, hospital volume was a protective factor for esophageal cancer patients after surgery (HR<1). The concentration of hospital volume associated with the lowest risk of all-cause mortality was 1027 cases/year in the overall enrolled patients. Hospital volume can be used as an indicator to predict the postoperative survival of ESCC patients. Our results suggest that the centralized management of esophageal cancer surgery is meaningful to improve the survival of ESCC patients in China, but the hospital volume should preferably not be higher than 1027 cases/year. Hospital volume is considered to be a prognostic factor for many complex diseases. However, the impact of hospital volume on long-term survival after esophagectomy has not been well evaluated in China. Based on a large sample size of 158,618 ESCC patients in China spanning 47 years (1973-2020), We found that hospital volume can be used as a predictor of postoperative survival in patients with ESCC, and identified hospital volume thresholds with the lowest risk of death from all causes. This may provide an important basis for patients to choose hospitals and have a significant impact on the centralized management of hospital surgery.

Prognostic Impact of Skeletal Muscle Index and Vitamin D in Diffuse Large B-Cell Lymphoma