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Esophageal squamous cell carcinoma (ESCC) is malignant while the carcinogenesis is still unclear. Here, we perform a comprehensive multi-omics analysis of 786 trace-tumor-samples from 154 ESCC patients, covering 9 histopathological stages and 3 phases. Proteogenomics elucidates cancer-driving waves in ESCC progression, and reveals the molecular characterization of alcohol drinking habit associated signatures. We discover chromosome 3q gain functions in the transmit from nontumor to intraepithelial neoplasia phases, and find TP53 mutation enhances DNA replication in intraepithelial neoplasia phase. The mutations of AKAP9 and MCAF1 upregulate glycolysis and Wnt signaling, respectively, in advanced-stage ESCC phase. Six major tracks related to different clinical features during ESCC progression are identified, which is validated by an independent cohort with another 256 samples. Hyperphosphorylated phosphoglycerate kinase 1 (PGK1, S203) is considered as a drug target in ESCC progression. This study provides insight into the understanding of ESCC molecular mechanism and the development of therapeutic targets.

Esophageal cancer (EC) is one of the most lethal malignancies in humans, and multiple miRNAs have been identified to modulate EC progression by targeting different targets. However, the effect and related mechanism of microRNA-33a-5p (miR-33a-5p) on EC development remain elusive. In this study, we explored the clinical value, function, and possible mechanism of miR-33a-5p in EC. We uncovered that miR-33a-5p and DKK1 are involved in the progression of EC. Significantly, the expression levels of miR-33a-5p were reduced and DKK1 levels were elevated in serum and tissues of clinical EC samples and in EC cell lines. The downregulation of miR-33a-5p and DKK1 upregulation were related to high TNM staging and poor differentiation of patients. The area under the curves (AUCs) of miR-33a-5p and DKK1 for the occurrence of EC were 0.914 and 0.900, respectively. Down-regulation of miR-33a-5p or overexpression of DKK1 indicated a worse prognosis. The miR-33a-5p overexpression or DKK1 depletion induced apoptosis and repressed proliferation, migration, and invasion of EC cells. The repression of miR-33a-5p by inhibitor or DKK1 overexpression presented the conversed effects on EC cells. Mechanically, miR-33a-5p suppressed DKK1 expression, and miR-33a-5p targeted DKK1 to affect the biological behavior of EC through the Wnt/β-catenin pathway. Meanwhile, miR-33a-5p inhibited the tumor growth of EC in vivo. Thus, we concluded that miR-33a-5p inhibited the progression of EC through the DKK1-mediated Wnt/β-catenin pathway. MiR-33a-5p and DKK1 can be used as potential therapeutic targets of EC.

ObjectiveTo analyze changes in volume and position of target regions and organs at risk (OARs) during radiotherapy for esophageal cancer patients.MethodsOverall, 16 esophageal cancer patients who underwent radiotherapy, including 10 cases of intensity-modulated radiation therapy (IMRT) and six of three-dimensional conformal radiotherapy (3D-CRT), were enrolled. The prescription doses for the planning target volumes (PTVs) were as follows: PTV1, 64 Gy/32 fractions; and PTV2, 46 Gy/23 fractions. Repeat computed tomography (CT) was performed for patients after the 5th, 10th, 15th, 20th, and 25th fractions. Delineation of the gross tumor volume (GTV) and OAR volume was determined using five repeat CTs performed by the same physician. The target and OAR volumes and centroid positions were recorded and used to analyze volume change ratio (VCR), center displacement (ΔD), and changes in the distance from the OAR centroid positions to the planned radiotherapy isocenter (distance to isocenter, DTI) during treatment.ResultsNo patient showed significant changes in target volume (TV) after the first week of radiotherapy (five fractions). However, TV gradually decreased over the following weeks, with the rate slowing after the fourth week (40 Gy). The comparison of TV from baseline to 40 Gy (20 fractions) showed that average GTVs decreased from 130.7 ± 63.1 cc to 92.1 ± 47.2 cc, with a VCR of −29.21 ± 13.96% (ppConclusionDuring radiotherapy for esophageal cancer, Targets and OARs change significantly in volume and position during the 2nd–4th weeks. Image-guidance and evaluation of dosimetric changes are recommended for these fractions of treatment to appropriate adjust treatment plans.

To compare pharmacokinetic parameters and texture features from two dynamic contrast-enhanced (DCE) MR images [golden-angle radial sparse parallel (GRASP) and view-sharing with golden-angle radial profile (VS-GR) reconstruction], and explore their value in assessing response to neoadjuvant chemotherapy (nCT) in esophageal cancer (EC). The study prospectively enrolled 30 EC patients receiving nCT before surgery. DCE-MRI scanning was performed before nCT and within 1 week before surgery. Chemotherapy response was assessed according to RECIST 1.1 and Tumor Regression Grade (TRG). Mann–Whitney U test was utilized for comparing GRASP and VS-GR reconstruction, and the receiver operating characteristic (ROC) was performed for each significant feature to assess its accuracy in predicting response. Among the 30 patients included in this cohort (28 men; average age of 58 ± 8 years), response by RECIST 1.1 demonstrated 18 responders and 12 non-responders. For TRG, no case showed TRG1, 1 patient was TRG2, 3 patients were TRG3, 8 patients were TRG4, and 18 patients were TRG5. A total of 72 pharmacokinetic parameters and texture features were extracted from each tumor. Of those, 29 pre-nCT features and 24 post-nCT features showed statistically significant difference between GRASP and VS-GR reconstruction. One pre-nCT texture feature and 37 post-nCT pharmacokinetic parameters and texture features on VS-GR showed statistically significant differences between responder and non-responders. Both pre- and post-nCT pharmacokinetic parameters and texture features with GRASP reconstruction showed good performance in response groups (AUC > 0.70, P 0.70, P

This randomized phase II trial aims to compare the efficacy and safety of induction chemotherapy followed by definitive chemoradiotherapy (CRT) versus CRT alone in patients with esophageal squamous cell carcinoma (ESCC) unsuitable for surgery (N = 110). The primary outcome was overall response rate (ORR), whereas the secondary outcome was overall survival. This trial did not meet pre-specified endpoints. The ORR was 74.5% in the induction chemotherapy group versus 61.8% in the CRT alone group (P = 0.152). The 3-year overall survival rate was 41.8% in the induction chemotherapy group and 38.1% in the CRT alone group (P = 0.584; hazard ratio, 0.88; 95% CI, 0.54–1.41). Grade 3–5 adverse events were similar. Patients who responded to induction chemotherapy had improved survival in the post-hoc analysis. These results demonstrate no improvement in response rate or survival with the addition of induction chemotherapy to CRT in unselected patients with ESCC. Trial number: NCT02403531., The benefit of induction chemotherapy before definitive chemoradiotherapy (CRT) for patients with esophageal cancer is still uncertain. The results of this phase II randomized trial show that the addition of induction chemotherapy to CRT does not improve the response rate or survival of patients with unresectable esophageal squamous cell carcinoma.

Background: Alantolactone (AL) is a natural compound extracted from the roots of Inula Helenium L, which exerts an anti-tumor effect in a variety of cancer cell lines; however, its effect on esophageal cancer, a common malignancy with poor prognosis, remains unclear. Therefore, we aim to evaluate the effect of AL on esophageal cancer and to explore its underlying mechanism. Objective: This study aims to determine whether AL has an anti-cancer effect on esophageal cancer cells and to explore its underlying mechanism. Methods: The effect of AL on the proliferation and apoptosis of esophageal cancer cells was detected by MTT assay, colony formation assay, crystal violet assay, flow cytometry and hoechst apoptosis staining. The wound healing and Transwell invasion assay were performed to examine the effect of AL on the migration and invasion of esophageal cancer cells. Luciferase reporter system and Western blot were used to study the anti-tumor mechanism of AL on esophageal cancer cells. The subcutaneous murine xenograft model was employed to verify the effects of AL on esophageal cancer cells. Results: MTT assay, colony formation assay and crystal violet assay found that AL inhibited the growth of esophageal cancer cells. Hoechst staining and flow cytometry analysis showed that AL induced apoptosis in esophageal cancer through mitochondrial pathway. Transwell assay and wound healing assays showed that AL inhibited the metastasis and invasion of esophageal cancer cells. Wnt/ β-catenin signaling may contribute to the mechanism of the inhibition. The anti-tumor effect of AL on esophageal cancer cells was validated on murine xenograft model. Conclusion: Our data indicate that AL inhibits proliferation, migration, and invasion of esophageal cancer cells, and promote apoptosis of esophageal cancer cells through the Wnt/β-catenin signaling pathway.

Objective: To evaluate the efficacy and toxicity of concurrent chemoradiotherapy (CRT) in multiple primary cancers (MPC) of the upper digestive tract in esophageal squamous cell carcinoma (ESCC). Methods: In a screening of 1193 consecutive patients diagnosed with ESCC and received radiotherapy, 53 patients presenting synchronous MPC in the upper digestive tract were retrospectively investigated. 53 consecutive patients with esophageal non-multiple primary cancer (NPC), matched by stage, age and sex, served as control. All of the patients received concurrent CRT. The median radiation dose was 60 Gy. Chemotherapy regimens were based on platinum and/or 5-fluorouracil. Clinical outcomes and treatment toxicities were compared. Results: Clinic-pathologic characteristics were well balanced between groups. MPC mostly located in esophagus (43, 81.8%), followed by hypopharynx (8, 15.1%) and stomach (2, 3.8%). In MPC and NPC patients, 94.3% and 96.2% completed the intended treatment. The immediate response rate was 73.6% vs 75.5%, with complete response rate of 11.3% vs 24.5% and partial response rate of 62.3% vs 51.0%. Two-year overall survival (OS), progression-free survival (PFS), locoregional progression-free survival (LRPFS) and distant progression-free survival (DPFS) were 52.2% vs 68.9% (p=0.026), 32.9% vs 54.0% (p=0.032), 60.8% vs 87.8% (p=0.002) and 64.0% vs 70.8% (p=0.22), respectively. Acute grade 3-4 toxicities were observed in 64.2% vs 54.7%, significantly higher in radiation esophagitis (49.1% vs 28.3%, p

Background To compare the value of two dynamic contrast-enhanced Magnetic Resonance Images (DCE-MRI) reconstruction approaches, namely golden-angle radial sparse parallel (GRASP) and view-sharing with golden-angle radial profile (VS-GR) reconstruction, and evaluate their values in assessing response to neoadjuvant chemotherapy (nCT) in patients with esophageal cancer (EC). Methods EC patients receiving nCT before surgery were enrolled prospectively. DCE-MRI scanning was performed after nCT and within 1 week before surgery. Tumor Regression Grade (TRG) was used for chemotherapy response evaluation, and patients were stratified into a responsive group (TRG1 + 2) and a non-responsive group (TRG3 + 4 + 5). Wilcoxon test was utilized for comparing GRASP and VS-GR reconstruction, Kruskal-Wallis and Mann-Whitney test was performed for each parameter to assess response, and Spearman test was performed for analyzing correlation between parameters and TRGs, as well as responder and non-responder. The receiver operating characteristic (ROC) was utilized for each significant parameter to assess its accuracy between responders and non-responders. Results Among the 64 patients included in this cohort (52 male, 12 female; average age of 59.1 ± 7.9 years), 4 patients showed TRG1, 4 patients were TRG2, 7 patients were TRG3, 11 patients were TRG4, and 38 patients were TRG5. They were stratified into 8 responders and 56 non-responders. A total of 15 parameters were calculated from each tumor. With VS-GR, 10/15 parameters significantly correlated with TRG and response groups. Of these, only AUCmax showed moderate correlation with TRG, 7 showed low correlation and 2 showed negligible correlation with TRG. 8 showed low correlation and 2 showed negligible correlation with response groups. With GRASP, 13/15 parameters significantly correlated with TRG and response groups. Of these, 10 showed low correlation and 3 showed negligible correlation with TRG. 11 showed low correlation and 2 showed negligible correlation with TRG. Seven parameters (AUC* > 0.70, P Conclusions In patients with esophageal cancer on neoadjuvant chemotherapy, several parameters can differentiate responders from non-responders, using both GRASP and VS-GR techniques. GRASP may be able to better differentiate these two groups compared to VS-GR. Trial registration for this prospective study: ChiCTR, ChiCTR-DOD-14005308. Registered 2 October 2014.

To assess the role of the MR radiomic signature in preoperative prediction of lymph node (LN) metastasis in patients with esophageal cancer (EC). A total of 181 EC patients were enrolled in this study between April 2015 and September 2017. Their LN metastases were pathologically confirmed. The first half of this cohort (90 patients) was set as the training cohort, and the second half (91 patients) was set as the validation cohort. A total of 1578 radiomic features were extracted from MR images (T2-TSE-BLADE and contrast-enhanced StarVIBE). The lasso and elastic net regression model was exploited for dimension reduction and selection of the feature space. The multivariable logistic regression analysis was adopted to identify the radiomic signature of pathologically involved LNs. The discriminating performance was assessed with the area under receiver-operating characteristic curve (AUC). The Mann-Whitney U test was adopted for testing the potential correlation of the radiomic signature and the LN status in both training and validation cohorts. Nine radiomic features were selected to create the radiomic signature significantly associated with LN metastasis (p < 0.001). AUC of radiomic signature performance in the training cohort was 0.821 (95% CI: 0.7042-0.9376) and in the validation cohort was 0.762 (95% CI: 0.7127-0.812). This model showed good discrimination between metastatic and non-metastatic lymph nodes. The present study showed MRI radiomic features that could potentially predict metastatic LN involvement in the preoperative evaluation of EC patients. • The role of MRI in preoperative staging of esophageal cancer patients is increasing. • MRI radiomic features showed the ability to predict LN metastasis in EC patients. • ICCs showed excellent interreader agreement of the extracted MR features.

The present study aimed to understand the expression characteristics of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2) in individuals of Uygur, Han and Kazak ethnicity with esophageal carcinoma in Xinjiang (China) and their interrelation analysis, and to investigate the expression differences in these genes between esophageal carcinoma and pericarcinoma tissue samples, and between the three ethnic groups. The expression levels of EGFR and VEGFR-2 from 119 pairs of esophageal carcinoma tissue and corresponding pericarcinoma tissue from Uygur, Han and Kazak patients with esophageal carcinoma were detected by immunohistochemistry following surgical resection, and an additional five carcinoma in situ specimens were also tested. The relative expression was analyzed among the ethnic groups and clinicopathological parameters. The positive rate of EGFR in esophageal carcinoma tissue from patients of Uygur, Han and Kazak heritage was 70.73, 68.42 and 67.5%, respectively. For VEGFR-2 the positive rate was 73.17, 68.42 and 67.5%, respectively. No significant difference was detected in their expression between the three ethnic groups (P>0.05); however, EGFR and VEGFR-2 overexpression were correlated with lymph node metastasis (P

Background Data on cervical esophageal cancer (CEC) based on modern radiotherapy technique are rare. We aimed to analyze the clinical efficacy and failure pattern of patients with CEC who underwent definitive chemoradiotherapy. Methods Between February 2002 and October 2013, 102 patients with CEC treated with definitive chemoradiotherapy were retrospectively analyzed. All patients received concurrent platinum-based chemotherapy with conformal radiotherapy (50–70Gy in 25–35 fractions, 5 fractions per week over 5–7weeks). Overall survival (OS), progression-free survival (PFS) and loco-regional failure-free survival (LRFFS) were calculated. Results The 3-year OS, PFS and LRFFS rates for the entire sample were 39.3%, 33.6% and 35.3%, respectively. During follow-up, 32, 26, and 41 patients had developed local, regional, and distant failure, respectively. Sex and hoarseness were independent prognostic indicators for OS ( P =0.011, P P =0.008, P =0.001; respectively). Hoarseness was the only independent prognostic factor for LRFFS ( P =0.002). Conclusions Distant metastasis was the most common failure pattern in CEC patients undergoing definitive chemoradiotherapy. Hoarseness was an independent prognostic factor for OS, PFS, and LRFFS.

Purpose: To compare the T staging of potentially resectable esophageal cancer using free-breathing radial VIBE (r-VIBE) and breath-hold Cartesian VIBE (C-VIBE), with pathologic confirmation of the T stage. Materials and Methods: Fifty patients with endoscopically proven esophageal cancer and indeterminate T1/T2/T3 stage by CT scan were examined on a 3-T scanner. The MRI protocol included C-VIBE at 150 seconds post–IV contrast, immediately followed by a work-in-progress r-VIBE with identical spatial resolution (1.1 mm × 1.1 mm × 3.0 mm). Two independent readers assigned a T stage on MRI according to the 7th edition of UICC-AJCC TNM Classification, and postoperative pathologic confirmation was considered the gold standard. Interreader agreement was also calculated. Results: The T staging agreement between both VIBE techniques and postoperative pathologic T staging was 52% (26/50) for C-VIBE, 80% (40/50) for r-VIBE for reader 1, and 50% (25/50), 82% (41/50) for reader 2, respectively. For the esophageal cancer with invading lamina propria, muscularis mucosae, or submucosa (T1 stage), r-VIBE achieved 86% (12/14) agreement for both readers 1 and 2. For invasion of muscularis propria (T2 stage), r-VIBE achieved 83% (25/30) for both readers 1 and 2, whereas for the invasion of adventitia (T3 stage), r-VIBE could only achieve agreement in 50% (3/6) and 67% (4/6) for readers 1 and 2, respectively. Conclusion: Contrast-enhanced free-breathing r-VIBE is superior to breath-hold CVIBE in T staging of potentially resectable esophageal cancer, especially for T1 and T2.

The abnormal function of O(6)-methylguanine-DNA methyltransferase (MGMT) is reported to be associated with the occurrence of various tumors and malignant tumor progression. However, little evidence is available to describe its role in esophageal carcinogenesis. To address this issue, we constructed a stable MGMT-silenced esophageal cancer cell line by RNA interference, and exposed the cells to N-methyl-N-nitro-N-nitrosoguanidine (MNNG) to investigate the role that MGMT plays in toxicity. During this time, we also observed the malignant behavior of cells in vitro and in vivo. In addition, two-dimensional electrophoresis and mass spectrometry were used to detect and confirm the proteins that were differentially expressed in the MGMT-deficient and MGMT-proficient cells, which might be responsible for the malignant alteration of cells. Results showed that the IC(50) of MGMT-deficient and MGMT-proficient cells exposed to MNNG was 30 μM and 65 μM, respectively, and MGMT-deficient cells had more aggressive motility and invasive abilities compared with MGMT-proficient cells. Nineteen differentially expressed proteins were detected between the MGMT-deficient and MGMT-proficient cells, 14 of which were identified, including the membrane-cytoskeleton linker protein, Ezrin, which was confirmed by both mass spectrometry and western blot analysis. The correlation between MGMT, Ezrin expression, and the malignant behavior of one normal epithelial esophageal cell line and seven esophageal cancer lines is discussed. In conclusion, loss of MGMT expression leads EC109 esophageal cancer cells to have increased malignant behavior, which may correlate with its high Ezrin protein expression.

In the report, we describe a case of refractory benign esophageal strictures from esophageal cancer after an operation for the placement of three partially covered self-expanding metal stents (SEMSs), which were all embedded in the esophageal wall. Using the stent-in-stent technique, the three embedded SEMSs were successfully removed without significant complications. To the best of our knowledge, few cases of the successful removal of multiple embedded esophageal SEMSs have been reported in the literature. This case also highlights that the stent-in-stent technique is effective for removing multiple embedded esophageal SEMSs.

Modified Heller's myotomy is still the first choice for achalasia and the assessment of surgical outcomes is usually made based on the subjective sensation of patients. This study was to objectively assess the long-term outcomes of esophageal myotomy for achalasia using esophageal manometry, 24-hour pH monitoring, esophageal scintigraphy and fiberoptic esophagoscopy.From February 1979 to October 2000, 176 patients with achalasia underwent modified Heller's myotomy, including esophageal myotomy alone in 146 patients, myotomy in combination with Gallone or Dor antireflux procedure in 22 and 8 patients, respectively. Clinical score, pressure of the lower esophageal sphincter (LES), esophageal clearance rate and gastroesophageal reflux were determined before and 1 to 22 years after surgery.After a median follow-up of 14 years, 84.5% of patients had a good or excellent relief of symptoms, and clinical scores as well as resting pressures of the esophageal body and LES were reduced compared with preoperative values (P0.001). However, there was no significant difference in DeMeester score between pre- and postoperative patients (P=0.51). Esophageal transit was improved in postoperative patients, but still slower than that in normal controls. The incidence of gastroesophageal reflux in patients who underwent esophageal myotomy alone was 63.6% compared to 27.3% in those who underwent myotomy and antireflux procedure (P=0.087). Three (1.7%) patients were complicated with esophageal cancer after surgery.Esophageal myotomy for achalasia can reduce the resting pressures of the esophageal body and LES and improve esophageal transit and dysphagia. Myotomy in combination with antireflux procedure can prevent gastroesophageal reflux to a certain extent, but further randomized studies should be carried out to demonstrate its efficacy.

Cancer treatment situation in tumor hospitals in China has its own unique characteristics which are not found in other parts of the world. Because of the huge population and high incidence rates of esophageal and stomach cancer[1-5], the number of cancer patients waiting for admission is inconceivably large. It is estimated that there are about 1.6-2.0 million new cases per year in China. In 1999, the Hebei Tumor Hospital had 6884 carcinoma patients hospitalized, among them there were 1035 esophageal cancer and 1057 stomach cancer patients. Because of the financial problem and most peasants have not joined the medical care insurance plan. Therefore, they are not benefited by the ideal treatment regimen after being diagnosed with TNM staging. Hebei Tumor Hospital was established in 1958 to provide medical care to cancer patients in the central and southern parts of Hebei Province. It has 621 beds. The southern part of Hebei Province around Chixian is adjacent to Linxian of Henan Province, both Chixian and Linxian counties have the highest incidence rates of esophageal cancer which are 135/100000. Besides, stomach carcinoma is another major cancer in this region. With a view to standardize the therapy of esophagus and stomach cancer, the authors reviewed the national and international standard treatment and recent progress in this field, and the therapeutic modalities given in this hospital from 1981 to 1997, and hope this analysis may benefit the development of standardized therapy for the above two malignances in clinical management.