Esophageal Squamous Cancer Research Articles

Effect of Adjuvant Radiation Therapy on Survival in Resected Thoracic Esophageal Squamous Cell Carcinoma According to the 8th AJCC Stage System: Pooled Analysis of Two Cancer Centers in China

The objective of this study was to investigate the impact of postoperative radiotherapy on the overall survival (OS) after radical esophagectomy according to the eighth edition of AJCC esophageal cancer staging, using two large hospital-based datasets from two big cancer hospitals in the northern and southern China, individually. A total of 3,811 cases were enrolled in the analysis. The patients who received R0 esophagectomy pathologically were diagnosed with squamous cell carcinoma and with or without postoperative radiotherapy (PORT) were selected. The tumor stage T1b-4aN1-3M0 was determined according to the newly published AJCC 8th staging in all the analysis. The OS was analyzed using the Kaplan-Meier method and compared using the log-rank test. Multivariate Cox regression analysis was used to identify covariates associated with OS. PSM analysis was performed on gender, age, vascular thrombosis, pathological differentiation, and AJCC 8th staging to balance the treatment bias between the surgery group and the postoperative radiotherapy group. The median duration of follow-up was 65.7 months (95% CI: 63.8-67.5 months) using reverse Kaplan–Meier method. The 5-year survival rates of 2725 cases in no PORT group were 83.5%, 66.9%, 57.3%, 50.6%, 29.5%, and 11.3% in IB, IIA, IIB, IIIA, IIIB, and IVA (p < 0.001). Before PSM, PORT did not improve the OS. Further subgroup analysis found that PORT in patients with stage IIB, IIIB, IVA based on the AJCC 8th staging can significantly improve OS. After PSM, 990 patients were included in PORT and no PORT group. PORT could improve the OS significantly (median survival, 52.3 months and 31.0 months, respectively; HR 0.716, 95% CI 0.638-0.804, P<0.001). The subgroup analysis was consistent with that before PSM. PORT in stages IIB, IIIB, and IVA could improve the OS after PSM. Multivariate analysis showed that gender, differentiation, vascular cancer thrombosis, TNM stage and postoperative radiotherapy were independent prognostic factors for both before and after PSM. The prognosis of operable esophageal squamous cell carcinoma cancer can be predicted perfectly by using the AJCC 8th staging. Postoperative radiotherapy after R0 esophagectomy potentially improved the OS for patients with stage IIB, IIIB, and IVA, further prospective studies are needed to confirm these results.

Multivariable Normal Tissue Complication Modeling of Acute Esophageal Toxicity in Esophageal Squamous Cancer Patients Treated with Radio(Chemo)Therapy

To establish a multivariable normal-tissue complication probability (NTCP) model for the Grade ≧2 acute esophageal toxicity (AET) after curative radio(chemo)therapy in patients with esophageal squamous cell carcinoma (ESCC). A cohort of 184 ESCC patients who were treated with definitive radio(chemo)therapy between April 2008 and December 2011 was enrolled in this study. The analysis included clinical and esophageal dose–volume histogram parameters. Clinical parameters included age, sex, weight loss during treatment, alcohol history, tumor site, stage, the length of gross tumor volume, the length of planning target volume (LPTV), the LPTV of the primary tumor (LPTV-P). Dose–volume histogram parameters included V5 to V65 with step of 5Gy, Dmean, and Dmax of the esophagus. Univariate logistic analysis was performed for each available variable.The multivariable logistic regression model was achieved by using of least absolute shrinkage and selection operator (LASSO) with 10-folder cross-validation. Model performance was assessed by the area under the receiver operating characteristic curve. A total of 42 patients (22.83%) developed Grade ≧2 AET. In the univariate analysis, age (>65, OR=0.323, 95%CI=0.144-0.725, p=0.006) and LPTV-P (OR=1.12, 95%CI=1.007-1.246,p=0.036) were associated with Grade≧2 AET. The final LASSO model had enrolled age (>65, OR=0.65), LPTVP (OR=1.02), and tumor site (lower, OR=0.63), The multivariable NTCP model for Grade ≧2 AET was expressed by the multivariable logistic regression formula: NTCP=(1+exp(-S))-1, and S=0.0209×LPTV-P-0.4260×age-0.4586×site-1.2560.The area under the curve was 0.68 (CI=0.5925-0.7688). A multivariable NTCP model including age, LPTVP, tumor site could predict Grade≧2 AET after radio(chemo)therapy for ESCC.

Delineate Genomic and Epigenomic Changes in Esophageal Squamous Cell Carcinoma Following Radiation Therapy

Esophageal squamous cell carcinoma (ESCC) is one of the most common lethal cancers worldwide. Radiotherapy is the standard clinical treatment of ESCC. Understanding how radiotherapy affects esophageal squamous cancer cells is a key biological question. We investigated the molecular changes during radiotherapy on the bases of genetic and epigenetic features. We performed whole-exome sequencing and genome-wide DNA methylation profiling of samples collected from different time points during radiotherapy from ESCC patients. We detected the genetic and epigenetic alterations of different samples at sequential time points to compare the pre-treated and treated samples following radiotherapy and explore the mutagenic mechanism shaping the evolution of ESCC. Our study provided several important insights: (i) The genomic changes during radiotherapy follow a gain and loss pattern and the treated samples may acquire mutations in known driver genes. (ii) DNA mismatch repair deficiency induced mutagenesis is enriched in treated ESCC and continues to shape the ESCC evolution following the radiotherapy. (iii) Methylome is also largely edited by ionizing radiation with a global trend towards hypomethylation after radiotherapy. (iv) By analyzing whole-exome sequencing data of 84 primary ESCC tumors, we identified an ESCC related driver gene (MUC16) which has not previously described in ESCC. Our integrated study provides an important molecular foundation for understanding of tumor progression in ESCC during radiotherapy.

Automated Detection of Precancerous Lesion and Early Esophageal Squamous Cancer Using a Deep Learning Model

Introduction: Early detection of esophageal squamous cancer is essential for favorable prognosis of patients. However the ability to detect precancerous lesion and early esophageal squamous cancer is substantially subject to operator experience. We develop an artificial intelligence model(AIM) for automated detection of these lesions, trying to reduce interobserver variability and improve the diagnosis of early esophageal cancer. Methods: We used 1014 narrow band images(NBI) of precancerous lesions and esophageal squamous cancers in 95 cases and 1071 NBI images of non-cancerous lesions in 198 cases from 2017, to train the model. 1478 malignant NBI images in 59 consecutive cases diagnosed as precancerous lesion or esophageal squamous cancer from January 2018 to February 2018 were included to test the mode. 3899 non-cancerous NBI images in 1205 cases dignosed as normal squamous epithelium(821 cases), esophagitis( 109 cases), heterotopic gastric mucosa(154 cases), esophageal varices(69 cases) and submucosal tumor (52 cases) from 2018 were also tested. AI hot zone image was generated for any input endoscopic image. The red color indicates high possibility of cancerous lesion, while the blue color indicates noncancerous lesion. When AIM detected any precancerous lesion or esophageal squamous cancer, a blue spot was displayed to indicate the lesion of interest. Results: Among 59 cases, 32 cases (total 35 lesions) were diagnosed as precancerous lesion or early esophageal squamous cancer by endoscopic submucosal dissection or surgery. The rest 27 cases(total 29 lesions) were diagnosed as cancerous lesions by biopsy including early and advanced esophageal cancer. The sensitivity of AIM for precancerous lesion and early esophageal squamous cancer images in 32 cases was 97.1%. The sensitivity of AIM for all malignant images in 59 cases was 97.8%. The specificity of AIM for all non-cancerous images was 76.2%. Conclusion: AIM demonstrated high diagnostic accuracy for precancerous lesion and early esophageal cancer. False positive rate was high under current mode. Future effort is warranted to build a more accurate mode.317_A Figure 1. patient characteristic and AI test result317_B Figure 2. AI result of cancerous image317_C Figure 3. AI result of non-cancerous image

Safety and efficacy of preoperative chemotherapy followed by esophagectomy versus upfront surgery for resectable esophageal squamous cell carcinoma.

Neoadjuvant chemotherapy (NAC) followed by esophagectomy has become a standard treatment for esophageal squamous cancer (ESCC) in Japan. We used propensity-matching analysis to clarify the safety and efficacy of NAC in daily clinical practice. We reviewed the medical records of 335 patients with clinical Stage II/III ESCC diagnosed between 2007 and 2012, including 191 who received preoperative NAC (NAC group) and 144 treated by upfront surgery (US group). After propensity score matching, there were 118 patients in each group. We compared the postoperative complications and long-term outcomes between the groups. Seven patients in the NAC group underwent replacement therapy. Complications occurred in 76 (68.5%) and 76 (64.4%) patients in NAC and US groups, respectively (p = 0.51), and severe complications occurred in 17 (22.4%) and 30 (39.5%) patients, respectively (p = 0.057). One (0.8%) and three patients (2.5%) from the US group died within 30days and 90days after surgery, respectively, but none of the patients from the NAC group died within the same period. The 5-year survival rate was 54.9% in the NAC group and 41.2% in the US group (p = 0.024). NAC is a safe and effective treatment to improve prognosis in the clinical setting.

RA02.02: RANDOMISED OESOPHAGECTOMY: MINIMALLY INVASIVE OR OPEN: THE ROMIO STUDY

Abstract Background Oesophagectomy is the mainstay of curative treatment for oesophageal cancer; however, surgery is followed by a reduction in health-related quality of life (HRQL). Whether minimally invasive approaches improve HRQL is unknown and limited comparative evidence available. The ROMIO study is a pragmatic multi-centre randomised controlled trial (RCT) aiming to establish the clinical and cost effectiveness of laparoscopically-assisted (LAO) versus open oesophagectomy (OO) in patients with oesophageal cancer in terms of HRQL, complications and survival. It includes an exploratory study of totally minimally invasive oesophagectomy (TMIO). Methods Adult participants referred for primary oesophagectomy or oesophagectomy following re-staging after neoadjuvant chemotherapy or chemoradiotherapy for oesophageal or oesophago-gastric adenocarcinoma or squamous cell cancer are eligible. Consenting patients are randomised 1:1 to receive OO or LAO except in two centres where participants are randomised to LAO, OO or TMIO (1:1:1). The primary outcome is the EORTC QLQ-C30 physical function scale, assessed at 3, 6 and 12 weeks after randomisation. Secondary outcomes include hospital stay, blinded assessment of pain, surgical complications, other aspects of HRQL and survival to 24 months. Quality assurance of surgery is assessed with, i) surgeon entry criteria based on provision of two operative videos, ii) 7 standard intra-operative photographs, and, iii) histopathological assessment of the specimen. A qualitative intervention is being used to train surgeons to recruit and communicate clinical equipoise. 406 patients are required to examine whether the minimum clinically important difference on the QLQ-C30 physical function scale is detected, allowing for 5% of patients allocated to LAO to undergo OO and a proportion to be inoperable or not followed up (90% power, 5% significance). This will also detect a clinically important reduction in length of stay. Results Seven UK centres involving 33 surgeons are recruiting. 288 patients have been screened, of which 206(73%) are eligible and 117(56%) eligible randomised. 21 surgeons have submitted at least two videos for assessment. Of the 102 patients operated on, 1058 photographs have been returned from 85 different patients. Follow up is currently at 79% for all time points. Conclusion This RCT will provide evidence to inform decision-making and informed consent for oesophagectomy. Disclosure All authors have declared no conflicts of interest.

Lapatinib in combination with paclitaxel plays synergistic antitumor effects on esophageal squamous cancer.

Paclitaxel-based chemoradiotherapy was proven to be efficacious in treating patients with advanced esophageal cancer. However, the toxicity and the development of resistance limited its anticancer efficiency. The present study was to evaluate the antitumor effects of lapatinib, a dual tyrosine inhibitor of both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), combined with paclitaxel on the esophageal squamous cancer. MTT assays were used to evaluate the effects of the combination of lapatinib and paclitaxel on the growth of esophageal squamous cancer cell lines (KYSE150, KYSE450, KYSE510 and TE-7). The activity of the combination of two agents on cell invasion, migration and apoptosis was measured by wound healing assay, transwell assay and Annexin V-FITC/PI stain assay. Western blot assay was used to analyze the effects of the two agents on the EGFR/HER2 signaling. The in vivo efficacy was evaluated in KYSE450 xenograft nude mouse model. The combination of lapatinib and paclitaxel was highly synergistic in inhibiting cell growth with a combination index of < 1, and suppressed significantly the invasion and migration capability of esophageal squamous cancer cells. Esophageal squamous cancer cells displayed increased rates of apoptosis after treatment with lapatinib plus paclitaxel. The phosphorylated EGFR and HER2 as well as the activation of downstream molecules MAPKs and AKT significantly decreased when exposed to lapatinib and paclitaxel. In vivo studies showed that the combination of two agents had greater antitumor efficacy than either agent alone. The combination of lapatinib with paclitaxel showed synergistic antitumor activity, suggesting their potential in treating patients with esophageal squamous cancer.

Prognostic value of metabolic tumor volume and total lesion glycolysis in esophageal carcinoma patients treated with definitive chemoradiotherapy.

The aim of this study was to evaluate the prognostic importance metabolic tumor volume (MTV), total lesion glycolysis (TLG), and standardized uptake value (SUV) in patients with esophageal cancer treated with definitive chemoradiotherapy. Seventy-two esophageal cancer patients treated with definitive chemoradiotherapy [57 (79%) patients] or definitive radiotherapy [15 (21%) patients] were retrospectively analyzed. The regions equal to or greater than SUV of 2.5 were selected to delineate MTV and TLG was calculated by multiplying the mean SUV by the MTV of the primary lesions. The overall survival (OS) and disease-free survival (DFS) were evaluated for all patients and also patients with squamous cell carcinoma. The median survival time was 13.4 months (range: 1.8-119.3 months) for all patients. Maximum SUV, mean SUV, MTV, and TLG values were significantly higher in patients with extensive T-stage (T3-T4) compared with patients with T1-T2 disease. Patients with regional lymph node metastasis had significantly higher MTV and TLG values compared with patients with no lymph node metastasis. On multivariate analysis, MTV, TLG, presence of lymph node metastasis, and lack of concurrent chemotherapy were negative significant prognostic factors for OS and DFS for the entire cohort and for patients with squamous cell carcinoma esophageal cancer. Metabolic volumes (MTV and TLG), regional lymph node metastasis, and concurrent chemotherapy are major prognostic factors for DFS and OS in patients with esophageal carcinoma. In addition, MTV and TLG are important in predicting nodal metastasis, and together with metabolic volumes, SUV are associated significantly with local tumor invasion.

Relationship between expression of PIK3CA protein and the clinicopathology of esophageal squamous cancer

Objective To analyze the expression and clinical significance of PIK3CA protein in squamous cell carcinoma of the esophagus. Methods Forty-five samples of surgical resection of esophageal squamous cell carcinoma were collected as the observation group, and 45 normal tissues adjacent to the carcinoma were selected as the control group.The expression of PIK3CA protein in the tissues of esophageal squamous cell carcinoma and the corresponding para cancerous tissue was detected by immunohistochemistry (IHC). Results The results of IHC showed that the positive expression rate of PIK3CA protein in esophageal squamous cell carcinoma was 53.33%, which in adjacent normal tissues was 0.00%, the difference was statistically significant (χ2=32.727, P<0.01). The positive expression rate of PIK3CA protein was correlated with lymph node metastasis, differentiation and clinical stage of esophageal squamous cell carcinoma (χ2=5.180, 8.201, 13.566, P=0.023, 0.017, 0.001), and was not correlated with the degree of tumor invasion(χ2=0.952, P=0.329). Conclusion The expression of PIK3CA protein is abnormal in esophageal squamous cell carcinoma, and the expression of PIK3CA protein plays a role in the occurrence and development of esophageal squamous cell carcinoma. Key words: Esophageal neoplasms; Phosphatidylinositol 3-kinase; Pathology, clinical

Gene expression profiling reveals the plausible mechanisms underlying the antitumor and antimetastasis effects of Andrographis paniculata in esophageal cancer.

Esophageal cancer (EC) is a seriously invasive malignancy with high mortality and poor prognosis. Metastasis of EC is the major cause of mortality. Our studies previously demonstrated that a herbal medicine Andrographis paniculata (AP) significantly suppressed EC growth and metastasis in vitro and in vivo. However, the underlying mechanisms responsible for these effects have not yet been systematically elucidated. In this context, gene expression profiling of AP-treated squamous EC cells (EC-109) was performed to reveal the regulatory mechanisms of AP in antitumor and antimetastasis signaling pathways using gene expression microarray analysis. Differentially expressed genes were identified by Affymetrix Gene Chip, followed by the real-time polymerase chain reaction validation. The results showed that the canonical pathways were significantly regulated by AP treatment, including multiple genes related to proliferation, apoptosis, intercellular adhesion, metastatic processes, and drug resistance, such as WNT, TGF-β, MAPK and ErbB signaling pathways, and ATP-binding cassette transporter subfamily members. This genomic study emerges candidate molecular targets and pathways to reveal the mechanisms involved in AP's effects, which provides scientific evidence to support the clinical application of AP in EC treatment.

Involved field irradiation (IFI) versus elective nodal irradiation (ENI) in combination with concurrent chemotherapy for esophageal thoracic squamous cell cancer: a prospective, randomized, multicenter, controlled study

Objective This study was conducted to evaluate treatment-related toxicities, the patterns of failure, overall survival (OS) and progression-free survival (PFS) by comparing IFI with ENI in combination with chemotherapy. Methods Eligible patients were treated with concurrent chemoradiotherapy and randomized into either an IFI or ENI arm. The primary end points wereacute treatment-related toxicities. The secondary end points were patterns of failure, OS and PFS. Kaplan-Meier survival rate of the method for calculating the Logrank test difference method. Results Between April 2012 and October 2016, a total of 228 patients were enrolled from nine centers in china. Grade≥3, Grade≥2 radiation esophagitis and pneumonitis in the IFI arm were significantly lower than that of the ENI arm (P=0.018, 0.027). No significant differences were observed in overall failure rates, loco-regional failure, distant failure rates, in-field and out-field lymph node failure between the two arms (P=0.401, 0.561, 0.510, 0.561, 0.681). The 1-, 2-, 3-, 4-yearand median OS in the ENI arm and IFI arm were 84.1%, 57.3%, 39.4%, 31.6%, 28 months and 83.6%, 62.1%, 44.5%, 31.5%, 32 months (P=0.654), respectively. The 1-, 2-, 3-yearand median PFS in the ENI arm and IFI arm were 71.9%, 42.3%, 32.7%, 20 months and 70.1%, 45.0%, 35.9%, 22 months (P=0.885), respectively. Conclusions Compared to ENI, IFI resulted in decreased radiation pneumonitis and esophagitis without sacrificing loco-regional lymph nodal control, PFS and OS in thoracic ESCC. Clinical Trial Registry Chinese Clinical trail registry, registration number: NCT01551589. Key words: Esophageal neoplasms/radiotherapy; Elective nodal irradiation; Involved field irradiation; Toxicities; Patterns of failure

Chinese herb medicine matrine induce apoptosis in human esophageal squamous cancer KYSE-150 cells through increasing reactive oxygen species and inhibiting mitochondrial function

Matrine, as a natural alkaloid isolated from the traditional herb medicine sophora flavescens, has been proved to possess excellent biological activities, including anticancer effects. Now, this research aims to assess the anticancer activities and the mechanism of matrine against esophageal cancer cells, we investigated the proliferative inhibition, apoptosis induction, as well as the underlying mechanism of matrine on esophageal cancer KYSE-150 cells. It was found that matrine could suppress KYSE-150 cell proliferation and significantly mediate cell apoptosis in a dose-dependent relation by increasing intracellular reactive oxygen species level and triggering mitochondrial membrane potential disruption. More precise mechanism studies demonstrated that matrine could up-regulate the expression of Bax proteins and down-regulate the expression of Bcl-2 proteins, as well as the activation about caspase-3, 8 and 9 in KYSE-150 cells. The morphological analysis of KYSE-150 cells exhibited that matrine could destroy the F-actin and nuclei structures and induce morphological damage with increased surface height distribution and roughness of cell membrane. These results not only demonstrated the potential anticancer activity mechanism of matrine at nanoscale, but also provide preliminary guidance for the treatment of esophageal cancer using matrine.

P63 is a key regulator of iRHOM2 signalling in the keratinocyte stress response

Hyperproliferative keratinocytes induced by trauma, hyperkeratosis and/or inflammation display molecular signatures similar to those of palmoplantar epidermis. Inherited gain-of-function mutations in RHBDF2 (encoding iRHOM2) are associated with a hyperproliferative palmoplantar keratoderma and squamous oesophageal cancer syndrome (termed TOC). In contrast, genetic ablation of rhbdf2 in mice leads to a thinning of the mammalian footpad, and reduces keratinocyte hyperproliferation and migration. Here, we report that iRHOM2 is a novel target gene of p63 and that both p63 and iRHOM2 differentially regulate cellular stress-associated signalling pathways in normal and hyperproliferative keratinocytes. We demonstrate that p63–iRHOM2 regulates cell survival and response to oxidative stress via modulation of SURVIVIN and Cytoglobin, respectively. Furthermore, the antioxidant compound Sulforaphane downregulates p63–iRHOM2 expression, leading to reduced proliferation, inflammation, survival and ROS production. These findings elucidate a novel p63-associated pathway that identifies iRHOM2 modulation as a potential therapeutic target to treat hyperproliferative skin disease and neoplasia.

Single-cell Transcriptome Analyses Reveal Molecular Signals to Intrinsic and Acquired Paclitaxel Resistance in Esophageal Squamous Cancer Cells

Paclitaxel is widely used in the combination chemotherapy for many cancers including esophageal squamous cell carcinoma (ESCC). However, the paclitaxel resistance occurs frequently in treating ESCC and the mechanism is not fully understood yet. The heterogeneity of gene expression within the drug-resistant cancer cells may be one of the major factors contributing to its resistance. In the present study, we successfully induced paclitaxel resistance in ESCC cell line KYSE-30 through low dose and long-term treatment of paclitaxel. Gene expression profiles were measured utilizing population RNA-seq and single-cell RNA-seq (scRNA-seq). 37 single cells from KYSE-30 cells and 73 single cells from paclitaxel resistant KYSE-30 cells (Taxol-R) were subjected to scRNA-seq. Weighted gene co-expression network analysis (WGCNA) of scRNA-seq data revealed two major subpopulations in both KYSE-30 and Taxol-R cancer cells. Two subpopulations based on the KRT19 expression levels in KYSE-30 cells exhibited different paclitaxel sensitivity, suggesting the existence of an intrinsic paclitaxel resistance in KYSE-30 cells. In addition, the Taxol-R cells that acquired the resistance to paclitaxel through induction were characterized with higher expressions of proteasomes but a lower expression of HIF-1 signaling genes. Furthermore, we showed that carfilzomib (CFZ), a proteasome inhibitor, could attenuate the paclitaxel resistance in Taxol-R cancer cells through activating the HIF-1 signaling. Our new finding may pave a way leading to an improvement in the treatment on cancers including ESCC by combining CFZ with paclitaxel as a novel approach for cancer therapy.

A novel screening test for esophageal squamous cell carcinoma: sirtuin-3.

Human sirtuin-3, a protein involved in the mediation of tumors, has been shown to be present in malignancies. The goal of this study was to measure serum sirtuin-3 levels in esophageal squamous cancer cells and to determine whether sirtuin-3 may possess predictive value in advanced cases of esophageal squamous cell carcinoma (ESCC). A total of 130 ESCC patients and 50 healthy control subjects participated to the study. Serum sirtuin-3 levels for all 180 subjects were measured using enzyme-linked immunosorbent assay (ELISA). Median sirtuin-3 levels were significantly higher in patients with ESCC than in the control subjects. The presence of considerably elevated levels of sirtuin-3, could be a powerful mediator of advanced ESCC in ESCC patients, suggests that sirtuin-3 may be a useful indicator of the disease.

Lugol Chromoendoscopy Detects Esophageal Dysplasia With Low Levels of Sensitivity in a High-Risk Region of China

Chromoendoscopy with Lugol dye is used to screen for early-stage esophageal squamous dysplasia (ESD) and esophageal cancer. However, the sensitivity with which Lugol chromoendoscopy detects ESD or esophageal cancer has not been fully assessed in large populations in China. From 2012 to 2016, a total of 15,264 residents in rural Hua County, Henan Province, which is a high-incidence area of esophageal cancer in China, were screened by Lugol chromoendoscopy. Biopsies were collected from endoscopically visualized lesions, identified before and after Lugol chromoendoscopy, and analyzed histologically. Biopsies were also collected from standard sites in the esophagus (28 and 33 cm distal to the incisors) if no abnormalities were found. We calculated the sensitivity with which Lugol chromoendoscopy detects esophageal dysplasia and carcinoma, using findings from biopsy analysis as the reference standard. A total 586 participants were found by biopsy analysis to have ESD or more severe lesions. After endoscopy images were reviewed twice, Lugol chromoendoscopy sensitivity values for the detection of mild, moderate, and severe dysplasia, and esophageal cancer, were 45.9%, 55.3%, 87.0%, and 97.7%, respectively. ESDs were most frequently missed by Lugol chromoendoscopy in younger patients and men with moderate levels of dysplasia. In a screening analysis of a general population in China, we found Lugol chromoendoscopy to identify individuals with ESD with lower levels of sensitivity (46%-87%) than previously believed, although it identified patients with esophageal cancer with almost 98% sensitivity. Prospective studies are needed to evaluate the clinical significance of esophageal lesions that are not detected by endoscopy.

Texture analysis of CT imaging for assessment of esophageal squamous cancer aggressiveness.

To explore the role of texture analysis of computed tomography (CT) images in preoperative assessment of esophageal squamous cell carcinoma (ESCC) aggressiveness. Seventy-three patients with pathologically confirmed ESCC underwent unenhanced and contrast enhanced CT imaging preoperatively. Texture analysis was performed on unenhanced and contrast enhanced CT images, respectively. Six CT texture parameters were obtained. One-way analysis of variance or independent-samples t-test (normality), independent-samples Kruskal-Wallis test or Mann-Whitney U test (non-normality), binary Logistic regression analysis (multivariable), Spearman correlation test, receiver operating characteristic (ROC) curve analysis and intraclass correlation coefficient (ICC) were used for statistical analyses. Kurtosis was an independent predictor for T stages (T1-2 vs. T3-4) as well as overall stages (I-II vs. III-IV) based on unenhanced CT images, while entropy was an independent predictor for T stages (T1-2 vs. T3-4), lymph node metastasis (N- vs. N+) and overall stages (I/II vs. III/IV). Skew and kurtosis based on unenhanced CT images showed significant differences among N stages (N0, N1, N2 and N3) as well as 90th percentile based on contrast enhanced CT images. In correlation with T stage of ESCC, kurtosis and entropy significantly correlated with T stage both on unenhanced and contrast enhanced CT images. Reversely, entropy and 90th percentile based on contrast enhanced CT images showed significant correlations with N stage (r: 0.526, 0.265; both P<0.05), as well as overall stage (r: 0.562, 0.315; both P<0.05). For identifying ESCC with different T stages (T1-2 vs. T3-4), lymph node metastasis (N- vs. N+) and overall stages (I/II vs. III/IV), entropy based on contrast enhanced CT images, showed good performance with area under ROC curve area under curve (AUC) of 0.637, 0.815 and 0.778, respectively. Texture analysis of CT images held great potential in differentiating different T, N and overall stages of ESCC preoperatively, while failed to assess the differentiation degrees.

Zenker’s diverticulum and squamous esophageal cancer: a case report

Zenker’s diverticulum represents a rare esophageal lesion developed especially in the elderly population due to herniation of esophageal mucosa above the cricopharyngeus muscle. The condition leads to food retention, regurgitation, aspiration, and dysphagia in affected patients. Progressive dysphagia also characterizes malignant diseases of the esophagus like squamous esophageal carcinoma that typically appears in male patients in the seventh decade of life, with a history of cigarette smoking and alcohol abuse. We report a case of a male patient who presented with dysphagia for both solids and liquids along with significant weight loss, and who was diagnosed with medium esophageal cancer associated with Zenker’s diverticulum.

Relationship between expression of genes associated with retinoid interferon induced mortality-19, signal transducer and activators of transcription 3, and myeloid cell leukemia-1 with proliferation and apoptosis of esophageal squamous carcinoma cells

Objective To investigate the relationship between the expression of genes associated with retinoid interferon induced mortality-19 (GRIM-19), signal transducer and activators of transcription 3 (STAT3), and myeloid cell leukemia-1 (Mcl-1) with esophageal squamous carcinoma cells proliferation and apoptosis and the possible mechanism. Methods The protein expression of GRIM-19, STAT3, Mcl-1 and proliferation cell nuclear antigen (Ki-67) in 50 cases of esophageal squamous carcinoma tissues, 30 cases of atypical tissue adjacent to carcinoma and 50 cases of normal esophageal mucosa tissues was detected by immunohistochemical streptavidin avidin-peroxidase (SP) method. The mRNA expression of GRIM-19, STAT3, Mcl-1 and Ki-67 in 50 cases of esophageal squamous carcinoma tissues, 30 cases of atypical tissue adjacent to carcinoma and 50 cases of normal esophageal mucosa tissues was detected by in situ hybridization. TdT-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) method was applied to examine apoptosis of esophageal squamous carcinoma cells. Results The positive expression rate of GRIM-19 protein and mRNA in esophageal squamous carcinoma tissues was significantly lower than that in atypical hyperplasia tissue adjacent to carcinoma and normal esophageal mucosa (protein: χ2=12.130, P=0.000; mRNA: χ2=11.830, P=0.000). The positive expression rate of STAT3 and Mcl-1 protein and mRNA in esophageal squamous carcinoma tissues was significantly higher than that in atypical hyperplasia tissue adjacent to carcinoma and normal esophageal mucosa (STAT3 protein: χ2=4.910, P=0.000, STAT3 mRNA: χ2=5.410, P=0.000; Mcl-1 protein: χ2=4.970, P=0.000, Mcl-1 mRNA: χ2=5.370, P=0.000). The apoptosis of tumor cells in esophageal squamous carcinoma tissues was associated with the positive expression rate of GRIM-19, STAT3 and Mcl-1. The apoptosis index (AI) in the group of GRIM-19 positive expression was higher than that in the group of GRIM-19 negative expression (F=18.355, P=0.048). The AI in the group of STAT3 positive expression was lower than that in the group of STAT3 negative expression (F=19.003, P=0.036). The AI in the group of Mcl-1 positive expression was lower than that in the group of Mcl-1 negative expression (F=18.225, P=0.044). Conclusion The down-regulation of GRIM-19, and up-regulation of STAT3 and Mcl-1 may promote esophageal squamous cancer cell proliferation, and inhibit esophageal squamous cancer cell apoptosis. Key words: Genes associated with retinoid interferon induced mortality-19; Signal transducer and activators of transcription 3; Myeloid cell leukemia-1; Esophageal squamous carcinoma cells; Apoptosis

Concurrent chemoradiotherapy of capecitabine with or without oxaliplatin versus cisplatin with fluorouracil for treatment of squamous oesophageal cancer in Chinese patients (CRTCOESC): an interim report of a randomised, open-label, multicentre trial

BackgroundChemoradiotherapy with fluorouracil and cisplatin (PF) has shown greater clinical efficacy for local advanced oesophageal cancer but with high rate of acute toxicities. We designed the CRTCOESC study to evaluate the effect and safety of capecitabine with or without oxaliplatin versus PF with chemoradiotherapy in Chinese patients with oesophageal cancer. MethodsWe this randomised, open-label, multicentre trial in nine cancer centres in Henan province, China, in Chinese patients with biopsy-proven squamous oesophageal cancer (T2-4N0-2M0). We randomly assigned patients (1:1:1) to receive single capecitabine, capecitabine plus oxaliplatin, or PF, and every patient received daily radiation of 50 Gy in 2 Gy dose per fraction. Patients were stratified by different regimens cycles. Both grade 3–5 acute toxicities and 2-year overall survival were the primary endpoint, with a planned accrual of 249 patients to detect a decrease in grade 3–5 acute toxicities from 40% to 20%. Interim analysis of acute toxicities and overall response was planned for the first 120 patients. This study is registered with ClinicalTrials, number NCT02025036. FindingsBetween October, 2014, and December, 2016, we accrued 128 patients, of whom 118 were eligible. 86 patients finished at least 16 weeks' follow-up and were included in the interim report (n=24 capecitabine group, n=37 capecitabine plus oxaliplatin group, and n=25 PF group). Pretreatment characters (age, gender, weight, performance status, clinical stage, lymphonodus status, and pathology grade) did not differ between the groups. Incidence of grade 3–5 acute toxicities was 25% in the capecitabine group, 32% in the capecitabine plus oxaliplatin group, and 64% in the PF group (p=0·03); the incidence was significantly lower in the capectitabine groups than the PF group (capectitabine vs PF p=0·041; capecitabine plus oxaliplatin vs PF p=0·022) and did not differ between capectitabine and capecitabine plus oxaliplatin (p=0·738). 56 patients had finished 1-year follow-up (n=12 capecitabine group, n=26 capecitabine plus oxaliplatin group, and n=18 PF group). The 1-year overall survival was 75% in the capecitabine group, 92% in the capecitabine plus oxaliplatin group, and 76% in the PF group (p=0·166). Nine patients died in total: three patients in the capecitabine group, two patients in the capecitabine plus oxaliplatin group, and four patients in the PF group. InterpretationCompared with PF, chemoradiotherapy with single capecitabine with or without oxaliplatin showed lower incidence of acute toxicities and similar 1-year overall survival. FundingNational Natural Science Foundation of China.