Invasive Esophageal Squamous Cell Carcinoma Research Articles

The seven-day cumulative post-esophagectomy inflammatory response predicts cancer recurrence

BackgroundThe relationship between postoperative cumulative systemic inflammation and cancer survival needs to be investigated. We developed an approach to the prognostication of postoperative esophageal cancer by establishing low and high cut-off values for the C-reactive protein (CRP) area under the curve (AUC) at 7 and 14 days after esophagectomy.MethodsOne hundred and twenty-five consecutive patients with biopsy-proven invasive esophageal squamous cell carcinoma (SCC) who underwent esophagectomies were evaluated. Postoperative CRP levels were analyzed for the first 14 days after surgery. The AUC on days 7 and 14 were calculated and compared with clinicopathological features and survival. The cut-off values for CRP at 7 days (CRP 7 d) and 14 days (CRP 14 d) were 599 mg/L and 1153 mg/L, respectively.ResultsThe patients in the low CRP 7 d group had significantly better recurrence-free survival (RFS) and overall survival (OS), not that in the low CRP 14d group. The OS rates in the high CRP groups at PODs 1, 3, 10, and 14 were significantly lower than those in the low CRP groups. Postoperative complications were more common in the high CRP groups on PODs 3, 10, and 14. Univariate analyses revealed that pTNM stage, depth of tumor invasion, tumor location, lymph node involvement, and CRP 7 d were significant prognostic factors for both OS and RFS. The Cox proportional hazards model identified pTNM, tumor location, and CRP 7d as independent prognostic factors for the RFS and OS.ConclusionsEarly prediction of patients with postoperative complications, and adequate management will suppress the elevation of CRP 7 d and further suppress the CRP value in the late postoperative period, which may improve the prognosis of esophageal cancer patients after esophagectomy.

Immunohistochemistry and oxygen saturation endoscopic imaging reveal hypoxia in submucosal invasive esophageal squamous cell carcinoma.

Hypoxic microenvironment is prominent in advanced esophageal squamous cell carcinoma (ESCC). However, it is unclear whether ESCC becomes hypoxic when it remains in the mucosal layer or as it invades the submucosal layer. We aimed to investigate whether intramucosal (Tis-T1a) or submucosal invasive (T1b) ESCC becomes hypoxic using endoscopic submucosal dissection samples. We evaluated the expression of hypoxia markers including hypoxia inducible factor 1α (HIF-1α), carbonic anhydrase IX (CAIX), and glucose transporter 1 (GLUT1) by H-score and vessel density by microvessel count (MVC) and microvessel density (MVD) for CD31 and α-smooth muscle actin (α-SMA) with immunohistochemical staining (n = 109). Further, we quantified oxygen saturation (StO2 ) with oxygen saturation endoscopic imaging (OXEI) (n = 16) and compared them to non-neoplasia controls, Tis-T1a, and T1b. In Tis-T1a, cccIX (13.0 vs. 0.290, p < 0.001) and GLUT1 (199 vs. 37.6, p < 0.001) were significantly increased. Similarly, median MVC (22.7/mm2 vs. 14.2/mm2 , p < 0.001) and MVD (0.991% vs. 0.478%, p < 0.001) were markedly augmented. Additionally, in T1b, the mean expression of HIF-1α (16.0 vs. 4.95, p < 0.001), CAIX (15.7 vs. 0.290, p < 0.001), and GLUT1 (177 vs. 37.6, p < 0.001) were significantly heightened, and median MVC (24.8/mm2 vs. 14.2/mm2 , p < 0.001) and MVD (1.51% vs. 0.478%, p < 0.001) were markedly higher. Furthermore, OXEI revealed that median StO2 was significantly lower in T1b than in non-neoplasia (54% vs. 61.5%, p = 0.00131) and tended to be lower in T1b than in Tis-T1a (54% vs. 62%, p = 0.0606). These results suggest that ESCC becomes hypoxic even at an early stage, and is especially prominent in T1b.

Genome-wide CRISPR/Cas9 screening identifies a targetable MEST-PURA interaction in cancer metastasis.

Metastasis is one of the most lethal hallmarks of esophageal squamous cell carcinoma (ESCC), yet the mechanisms remain unclear due to a lack of reliable experimental models and systematic identification of key drivers. There is urgent need to develop useful therapies for this lethal disease. A genome-wide CRISPR/Cas9 screening, in combination with gene profiling of highly invasive and metastatic ESCC sublines, as well as PDX models, was performed to identify key regulators of cancer metastasis. The Gain- and loss-of-function experiments were taken to examine gene function. Protein interactome, RNA-seq, and whole genome methylation sequencing were used to investigate gene regulation and molecular mechanisms. Clinical significance was analyzed in tumor tissue microarray and TCGA databases. Homology modeling, modified ELISA, surface plasmon resonance and functional assays were performed to identify lead compound which targets MEST to suppress cancer metastasis. High MEST expression was associated with poor patient survival and promoted cancer invasion and metastasis in ESCC. Mechanistically, MEST activates SRCIN1/RASAL1-ERK-snail signaling by interacting with PURA. miR-449a was identified as a direct regulator of MEST, and hypermethylation of its promoter led to MEST upregulation, whereas systemically delivered miR-449a mimic could suppress tumor metastasis without overt toxicity. Furthermore, molecular docking and computational screening in a small-molecule library of 1,500,000 compounds and functional assays showed that G699-0288 targets the MEST-PURA interaction and significantly inhibits cancer metastasis. We identified the MEST-PURA-SRCIN1/RASAL1-ERK-snail signaling cascade as an important mechanism underlying cancer metastasis. Blockade of MEST-PURA interaction has therapeutic potential in management of cancer metastasis. This work was supported by National Key Research and Development Program of China (2021YFC2501000, 2021YFC2501900, 2017YFA0505100); National Natural Science Foundation of China (31961160727, 82073196, 81973339, 81803551); NSFC/RGC Joint Research Scheme (N_HKU727/19); Natural Science Foundation of Guangdong Province (2021A1515011158, 2021A0505030035); Key Laboratory of Guangdong Higher Education Institutes of China (2021KSYS009).

A comparative analysis of clinicopathological factors and survival between esophageal basaloid squamous cell carcinoma and conventional esophageal squamous cell carcinoma

IntroductionRecently, the number of diagnosed esophageal basaloid squamous cell carcinoma (EBSCC) has gradually increased. However, available data on EBSCC are limited to date. MethodsA total of 165 EBSCC (Cohort 1) and 515 conventional esophageal squamous cell carcinoma (ESCC) (Cohort 2) were retrospectively analyzed. ResultsIn Cohort 1, 70 cases only had invasive EBSCC component (42.4%, defined as Group 1), 73 cases had concomitant invasive ESCC component (44.2%, Group 2), and 22 had concomitant invasive poor-differentiated component (13.3%, Group 3). Lymph node metastasis rates of Group 3, Group 2 and Group 1 were ranked from high to low (P = 0.044). There were higher patient age (P = 0.047), smaller tumor size (P = 0.009), more nerve invasion (P < 0.001), and lower pTNM stage (P < 0.001) in EBSCC (Cohort 1), compared with ESCC (Cohort 2). In Cohort 1 and Cohort 2, pTNM stage was an independent prognostic factor for both DFS and OS. No significant survival difference was found between EBSCC (Cohort 1) and ESCC (Cohort 2) in pIA-B stage, pIIA-B stage, pIIIA-B stage and pIVA-B stage (P > 0.05). ConclusionOur analysis of the largest EBSCC series from a single institution to date with conventional ESCC demonstrated that EBSCC carried a similar prognosis with ESCC in pIA-B stage, pIIA-B stage, pIIIA-B stage and pIVA-B stage. And pure EBSCC, didn't have poorer survival than mixed EBSCC with concomitant ESCC or other components. Our findings may be valuable in the better understanding of EBSCC's biological behaviors, and the related molecular mechanism is needed to be explored in the future.

S2846 Liquid Nitrogen Cryoablation Alone Is an Effective Palliative Treatment for Metastatic Esophageal Squamous Cell Carcinoma

Introduction: In 2012, Esophageal squamous cell carcinoma (ESCC) was reported as the most common type of esophageal cancer in the world. In patients with metastatic ESCC, the mainstay of palliative management includes radiation therapy and esophageal stenting. Endoscopic cryoablation has emerged as a minimally invasive treatment for malignant esophageal neoplasm. The administration of liquid nitrogen, achieving a temperature of -85°C, causes transient tissue ischemia and recruitment of immune cells resulting in localized tissue destruction. Most preliminary studies assessing cryoablation in esophageal cancer have demonstrated symptomatic improvement in esophageal adenocarcinoma. Few studies have assessed the use of cryoablation in ESCC. A prospective study conducted in China demonstrated cryoablation’s ability to achieve complete remission in patients with moderate to high grade ESC neoplasm. Here we present a case utilizing endoscopic liquid nitrogen cryoablation as palliative therapy in a symptomatic patient with metastatic ESCC. Case Description/Methods: 82-year-old male former smoker with daily alcohol use presented with dysphagia and weight loss. CT scan of the chest revealed a mid-esophageal mass concerning for malignancy. Upper endoscopy demonstrated a large, fungating esophageal mass with partial obstruction (Figure A). Pathology revealed invasive poorly-differentiated ESCC. PET scan confirmed metastatic disease involving the right lung and paraesophageal, mediastinal, supraclavicular and right thoracic inlet lymph nodes. A multidisciplinary team offered palliative chemotherapy and radiation, which he declined. Due to worsening dysphagia and a 35lbs weight loss, he agreed to cryoablation (Figure B). He underwent an additional three sessions at two-months, three-months, and five-months for small areas of mucosal abnormalities (Figure C). He is four months out from treatment with improved dysphagia and stable weight. Discussion: This case report provides further evidence for the use of cryoablation alone as a minimally invasive, palliative intervention in patients with ESCC. Previous studies have highlighted the effectiveness of cryoablation in improving dysphagia and quality of life in symptomatic patients. This case report provides endoscopic evidence of cryoablation’s ability to reduce tumor burden and achieve complete remission in ESCC. Cryoablation alone appears to be a safe and well tolerated palliative treatment for patients with metastatic ESCC.Figure 1.: Upper endoscopic liquid nitrogen cryoablation of esophageal neoplasm. A) Initial upper endoscopy demonstrating large fungating mass in mid-esophagus with partial obstruction. B) Following completion of cryoablation treatment. C) Following three additional cryoablation sessions for treatment of residual disease.

Anti-HIV Drug Elvitegravir Suppresses Cancer Metastasis via Increased Proteasomal Degradation of m6A Methyltransferase METTL3.

This study finds that METTL3 promotes cancer metastasis by activating EGR1/Snail signaling in an m6A-dependent manner, revealing vulnerability to METTL3 blockade in esophageal squamous cell carcinoma.

Feasibility of using P16 methylation as a cytologic marker for esophageal squamous cell carcinoma screening: A pilot study.

Early diagnosis and treatment of esophageal squamous cell dysplasia (ESCdys) and esophageal squamous cell carcinoma (ESCC) could significantly reduce the incidence and mortality of ESCC. This pilot study aimed to investigate whether P16/CDKN2A methylation could serve as a cytologic biomarker for early detection of ESCdys and ESCC. Paired esophageal biopsy and cytology specimens (exfoliated cells) were obtained from subjects at different stages of ESCC development. The methylation status of P16 gene in these two specimen types was determined using a 115-bp MethyLight assay. Categorical data were compared by the Chi-square test. Logistic regression was performed to assess adjusted odds ratios of P16 methylation associated with ESCC and ESCdys. Prediction models for identifying individuals at risk of ESCC and high-grade ESCdys (high-grade intraepithelial neoplasia, HGIN) were developed by multivariable logistic regression. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis. Internal validation of the prediction models was performed using the 1000-bootstrap resample. A total of 105 subjects with diagnoses ranging from normal mucosa through ESCC were included in this study. An increase in P16 methylation frequency was observed with increasing severity of esophageal lesions (p for trend <0.001). In the adjusted logistic regression models, P16 methylation in cytology specimens was positively associated with ESCC and ESCdys risk, whereas P16 methylation in biopsy specimens was only associated with a higher risk of developing ESCC. The predictive capacity of base model I (AUC, 0.816) for ESCC and HGIN was significantly increased by adding P16 methylation in cytology specimens (model III; AUC, 0.882; p=0.043), but not P16 methylation in biopsy specimens (model II; AUC, 0.850; p=0.225). Bootstrap validation showed optimism-corrected AUC of 0.789 for model I, 0.822 for model II, and 0.854 for model III. P16 methylation as a cytologic marker was associated with the ESCC development and has the potential for application in minimally invasive ESCC screening.

S3569 Case Report of Esophageal Squamous Cell Carcinoma Presenting as Gastroesophageal Reflux Disease: An Unusual Presentation

Introduction: Esophageal cancer ranks high among cancer-related mortality rates in the world with a 5-year survival rate of 20%. Though surveillance guidelines exist for esophageal adenocarcinoma (EA) in the Western world, guidelines for surveillance of esophageal squamous cell carcinoma (ESCC) are unclear, especially in the low-risk countries due to the low prevalence of the disease. We present a case of ESCC with an unusual presentation in the setting of gastroesophageal reflux disease (GERD). Case Description/Methods: A 47-year-old female with a history of GERD, gastritis with intestinal metaplasia and vulvar carcinoma status post resection and radiation therapy 12 year ago was being followed in Gastroenterology clinic. GERD was managed with a proton pump inhibitor and she underwent an EGD 17 months prior to the presentation which showed normal esophageal mucosa. The patient presented with 6 months of progressive dysphagia to solids followed by liquids and a 5-pound weight loss. She denied any other alarm symptoms such as change in bowel habits, blood in stool or hematemesis, but family history was notable for esophageal cancer in the patient's father, and gastric cancer in the paternal uncle. EGD revealed a large fungating mid esophageal mass partially obstructing the esophagus (Figure 1). It was confirmed to be stage III invasive ESCC on biopsy. Biopsy staining was negative for HPV. Patient was started on Cisplatin and 5-fluorouracil (5-FU) therapy and was noted to have symptom resolution. Discussion: Though the incidence of ESCC is trending down in the United States, it contributes to high cancer-related mortality burden. This case report showcases rapid progression and an unusual presentation of ESCC in a patient with GERD – a risk factor for EA, despite normal esophageal mucosa seen on EGD 17 months prior. The patient also had history of vulvar squamous cell carcinoma and a family history of esophageal malignancy in a first degree relative. Currently, the evidence linking HPV to esophageal cancer remains controversial. Similarly, data about genetic predisposition in the development of ESCC is also conflicting. This raises important questions regarding the association of vulvar cancer with esophageal cancers and magnitude of genetic risk among patients with family history of cancers of the digestive tract.Figure 1.: A Large Mid-esophageal Fungating Mass Partially Obstructing The Lumen

A RARE OCCURRENCE OF ESOPHAGEAL SPINOCELLULAR CARCINOMA IN A YOUNG ADULT

Esophageal squamous cell carcinoma is a relatively uncommon neoplasm that affects advanced age groups. Here we report a case of an invasive esophageal squamous cell carcinoma that affected a 17-year-old male patient with some evidence showing that the early stages of neoplastic development were throughout childhood. No risks factors were identified and the patient had an excellent long-term outcome.

&lt;p&gt;Wnt5a induces ROR1 and ROR2 to activate RhoA in esophageal squamous cell carcinoma cells&lt;/p&gt;

Background: Wnt5a is a nontransforming Wnt family member and identified as an oncogenic role on cell motility of breast cancer and glioblastoma. However, Wnt5a signaling in esophageal squamous cell carcinoma (ESCC) progression remains poorly defined.Materials and methods: Immunohistochemistry assays were used to measure the Wnt5a expression in ESCC sections. We evaluated the role of receptor tyrosine kinase-like orphan receptor (ROR)1/2 and RhoA on the invasion of ESCC cells by using cell invasion assay, immunoprecipitation, immunofluorescence, and Rho activation assay.Results: Wnt5a was highly expressed in invasive ESCC tissues compared with that in noninvasive and nonmalignant tissues. In vitro assay showed that sfrp2 (Wnt5a antagonist) largely blocked the invasion but not the colony formation of KYSE410 and KYSE520 ESCC cells. Anti-ROR1 mAb and ROR2-shRNA markedly inhibited the disheveled-associated activator of morphogenesis 1 (DAAM1) activity, RhoA activity, microfilament formation and the invasion of ESCC cells. Fluorescent phalloidin staining experiment showed ROR1/ROR2, receptors of Wnt5a signaling, and regulated the reassembly of actin filaments in ESCC cells. Further experiments showed that ROR1 was strongly associated with ROR2 in KYSE410 cells. The activation of RhoA, not Rac1 or Rac2, was involved in ROR1/ROR2 signaling pathway. By using DAAM1 shRNA, we found that RhoA was downstream of DAAM1, which could be rescued by the overexpression of wild-type DAAM1. This could be further proved by a RhoA inhibitor CCG-1423 which could inhibit the invasion of ESCC cells but not DAAM1 activity.Conclusions: Wnt5a promotes ESCC cell invasion via ROR1 and ROR2 receptors and DAAM1/RhoA signaling pathway.

Expression analysis of cyclooxygenase-2 in patients suffering from esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is one of the aggressive malignancies and mechanisms underlying its pathogenesis remain unclear. Cyclooxygenase-2 (COX-2) enzyme system plays a crucial role in many gastrointestinal malignancies and is an important regulator of cell growth, proliferation, apoptosis, differentiation and transformation. More precise outcome of COX-2 in ESCC is less investigated. In this study we investigated the risk factors of ESCC and expression of COX-2 in Carcinoma in situ (CIS) and ESCC compared to normal esophageal mucosa. ESCC relationship to clinico-pathological parameters using immunohistochemistry was also part of this investigation. Current study was conducted in the Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan. A total of 69 diagnosed patients of ESCC, both Pakistanis and Afghans were enrolled. Various risk factors associated with ESCC were recorded. Mean age at the time of diagnosis was 55 years. Out of 69 patients of ESCC 46 (67%) were users of dipping tobacco (Naswar). Expression of COX-2 was determined in normal esophageal mucosa, CIS and invasive ESCC using Immunohistochemistry (IHC). Differences of mean were computed using ANOVA followed by applying Post Hoc test. Patients were categorized as positive with high expression or negative with low to nil expression. ANOVA showed large differences in expression of COX-2 in normal healthy mucosa compared with CIS and ESCC with the mean difference of -9.529 and -7.370 respectively, p-value being <.05 at 95% confidence interval (CI). No significant difference was noticed in the expression of COX-2 in CIS compared with ESCC with p-value >.05 at 95% CI. Our complete cohort (23–85 years) showed statistically significant difference in the expression of COX-2 gene in ESCC and CIS tissue samples compared with normal healthy mucosa. Results of this study indicate that over-expression of COX-2 is positively associated with ESCC.

Abstract 3168: Serglycin promotes migration and invasion of esophageal cancer cells

Abstract Esophageal cancer is the eighth most common cancer in the world and it ranks sixth in mortality rate among cancer diseases. While patients with early stage esophageal cancer without metastasis have a better chance of being cured by surgery, most patients present with locally advanced or metastatic disease. Unfortunately, some common cancer biomarkers such as carcinoembryonic antigen (CEA) and CA19-9 have low sensitivity and specificity in esophageal cancer. A better understanding of the molecular mechanisms underlying esophageal cancer progression is needed to identify novel diagnostic markers and therapeutic targets for intervention. We previously identified serglycin (SRGN) as the top upregulated gene in a highly invasive esophageal squamous cell carcinoma (ESCC) cell subline. Serglycin is a proteoglycan with a core protein and glycosaminoglycan (GAG) chains. Its significance in tumorigenesis is not well understood. The GAG chains have the ability of binding specific growth factors and ligands, which may play an important role in facilitating cancer cell migration and invasion. Immunohistochemical analysis showed that serglycin expression was higher in ESCC compared with normal esophageal epithelium, and in lymph node metastases compared with primary ESCC. Ectopic overexpression of serglycin in ESCC cells enhanced their migration and invasion potential in vitro. Knockdown of serglycin reduced ESCC cell migration and invasion. In invasion chamber assays, conditioned medium (CM) from SRGN-overexpressing ESCC cells stimulated the migration and invasion ability of less invasive ESCC cells. Conditioned medium from ESCC cells expressing serglycin that lacks the GAG attachment site had no such effects. Chemokine antibody array analysis showed that midkine (MDK), a heparin-binding growth factor, was the top upregulated protein in the CM of SRGN-overexpressing cells. Analysis of TCGA and GTEx datasets showed that MDK expression was higher in many cancer types such as breast cancer, colon adenocarcinoma, glioblastoma and lung cancer, than in corresponding normal tissues. Western blot analysis showed that forced expression of serglycin, but not serglycin without the GAG binding domain, led to increase of MDK in the CM of multiple ESCC cell lines. Forced expression of serglycin also increased the expression level of phosphorylated extracellular signal-regulated kinase (p-ERK) in ESCC cells. Taken together, serglycin may play an important role in the progression ESCC by promoting migration and invasion of cancer cells. These effects may be mediated through activation of the ERK signaling pathway. Whether MDK is involved in this regulatory mechanism warrants further investigation. [This study was supported by Research Grants Council of the Hong Kong SAR, China, GRF Project No. 17111016] Citation Format: Yun ZHU, Bin Li, Wenwen Xu, Aky Lam, Simon Law, ALM Cheung. Serglycin promotes migration and invasion of esophageal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3168.

Neoadjuvant chemoradiation radiation dose levels for surgically resectable esophageal cancer: predictors of use and outcomes.

Neoadjuvant chemoradiation (CRT) followed by surgical resection is the standard of care for resectable, locally advanced esophageal cancer. There are promising results using 41.4 Gy relative to historical controls using higher doses, but the utilization and efficacy of lower neoadjuvant radiation dosing is unclear. This study uses the National Cancer Database (NCDB) to explore patterns of care for neoadjuvant CRT dose levels and outcomes. The NCDB was queried for localized invasive esophageal adenocarcinoma (AC) or squamous cell carcinoma (SCC) receiving neoadjuvant CRT with doses from 40 to 54 Gy followed by surgical resection. Patients were divided into radiation levels: 40-41.4, 45, 50.4, and 54 Gy, respectively. Factors predicting use of 40-41.4 Gy vs. all other dose levels were compared using multivariable logistic regression. Factors affecting overall survival (OS) were compared using univariate and multivariate modeling. A total of 6,274 patients with AC (n=5,176) or SCC (n=1,098) receiving neoadjuvant CRT and definitive resection were identified. Hispanic race (OR 2.67 [95% CI 1.22-5.81]) and treatment at an academic center (OR 2.72 [95% CI 1.15-6.41]) predicted for use of low-dose CRT. Lower dose CRT increased from 3.9% in 2004 to 7.2% in 2013. There was no difference in OS when stratified according to radiation dose level (P=0.48). Multivariable analysis found private/government insurance, higher education, higher median income, and treatment at an academic center were associated with improved OS. Age, male gender, Charlson-Deyo comorbidity score, stage, tumor grade, and treatment in the South were associated with worse OS. Use of lower neoadjuvant CRT dose is more common at academic centers and shows possible increasing usage. Neoadjuvant radiation dose for esophageal cancer is not associated with differences in OS in this large database.

Submucosal Invasive Depth Predicts Lymph Node Metastasis and Poor Prognosis in Submucosal Invasive Esophageal Squamous Cell Carcinoma.

Lymph node metastasis (LNM) in submucosal invasive esophageal squamous cell carcinoma (SM-ESCC) is a prognostic factor. The aim of this study was to identify a histopathologic predictor of LNM in SM-ESCC. In total, 108 patients who underwent an esophagectomy and lymph node dissection without preoperative therapy and who were pathologically diagnosed with SM-ESCC were enrolled in this study. Relationships between several clinicopathologic factors and LNM were examined. A multivariate analysis revealed that a tumor size of 35 mm or more (P = .0025), submucosal invasive depth (SID) of 2,000 μm or more (P = .013), and lymphatic infiltration (P < .0001) were significant independent predictors of LNM. In addition, there were significant differences in recurrence-free survival curves between patients with SID less than 2,000 μm or not (P = .029) and tumor size less than 35 mm or not (P = .049). This study suggests that SID may predict not only LNM but also poor prognosis.

Significance of PI3K/AKT signaling pathway in metastasis of esophageal squamous cell carcinoma and its potential as a target for anti-metastasis therapy.

Metastasis is the most lethal hallmark of esophageal squamous cell carcinoma (ESCC). The aim of the study is to identify key signaling pathways that control metastasis in ESCC. Highly invasive ESCC sublines (designated I3 cells) were established through three rounds of selection of cancer cells invading through matrigel-coated chambers. Gene expression profile of one of the I3 sublines was compared with that of its parental cell line using cDNA microarray analysis. Gene ontology and pathway analyses of the differentially expressed genes (both upregulated and downregulated) indicated that genes associated with cellular movement and the AKT pathway were associated with increased cancer cell invasiveness. Western blot analysis confirmed increased phosphorylated AKT (p-AKT), N-cadherin and decreased E-cadherin expression in the I3 cells. Immunohistochemistry was used to evaluate the clinical significance of p-AKT expression in ESCC, and the results showed higher p-AKT nuclear expression in lymph node metastases when compared with primary carcinoma. Inactivation of the PI3K/AKT pathway with specific inhibitors, or with PTEN overexpression, resulted in reversed cadherin switching and inhibited cancer cell motility. Inhibition of the pathway by treatment with wortmannin markedly suppressed experimental metastasis in nude mice. Our data demonstrated the importance of the PI3K/AKT signaling pathway in ESCC metastasis and support PI3K/AKT as a valid therapeutic target in treatment of metastatic ESCC.

Clinical Outcomes of Endoscopic Submucosal Dissection for Early Esophageal Squamous Cell Neoplasms: A Retrospective Single-Center Study in China.

Aims. To retrospectively analyze the clinical outcomes for a large number of endoscopic submucosal dissections (ESDs) in early esophageal squamous cell neoplasms (ESCNs) at the First Affiliated Hospital of Nanjing Medical University. Patients and Methods. From January 2010 to February 2014, 296 patients (mean age 61.4 years, range 31–85 years; 202 men) with 307 early ESCNs (79 intramucosal invasive esophageal squamous cell carcinomas (ESCCs) and 228 high-grade intraepithelial neoplasia (HGIN) cases) were included from a total of 519 consecutive patients who were treated by esophageal ESD at our hospital. The primary end points of the study were rates of en bloc resection and complete resection. Secondary end points were complications, residual and recurrence rates, and mortality during follow-up. Results. The en bloc resection rate and complete resection rate were 93.5% and 78.2%, respectively. Complications included strictures (8.4%), perforations (1.0%), and bleedings (0.7%). Twenty-seven (9.1%) patients experienced residual and 18 (6.1%) patients experienced recurrence during a mean follow-up period of 30 months. Thirteen patients died from causes unrelated to ESCC, and no cancer-related death was observed. Conclusions. Our study showed that ESD is a successful and relatively safe treatment for intramucosal invasive ESCC and HGIN, fulfilling the criteria of lymph node negative tumors. This should encourage clinicians to select ESD performed by experienced operators as a potential or even preferred treatment option for lesions amenable to endoscopic treatment.

Transketolase Serves a Poor Prognosticator in Esophageal Cancer by Promoting Cell Invasion via Epithelial-Mesenchymal Transition.

Background: To characterize the potential function and clinical significance of Transketolase (TKT) in esophageal cancer.Methods: High invasive esophageal squamous cell carcinoma (ESCC) cell line CE48T/VGH was used. Cellular functions in response to TKT modulation were examined, including cell growth, migration and invasion. The underlying molecules involved in the TKT regulatory mechanism were determined by western blot and confocal microscopic analysis. Clinically, TKT expressions in 76 ESCC patients were assessed by immunohistochemical (IHC) method, and the association with treatment outcome was determined.Results: TKT silencing inhibited cell migration and invasion but had a minimal effect on cell growth. This TKT silencing also induced the reversion of epithelial-mesenchymal transition (EMT), as evidenced by the spindle to cuboidal morphological change, increased the expression of epithelial markers (γ-catenin), and decreased the levels of mesenchymal markers (fibronectin and N-cadherin). Mechanically, TKT was shown to modulate the EMT through the pERK-Slug/Snail-associated signaling pathway. Clinically, a high level of TKT in the cancer tissues of patients with esophageal squamous cell carcinoma was associated with poor survival (P = 0.042). In the multivariate analysis, a high TKT level was also shown to be an independent unfavorable prognostic factor (Odds ratio: 1.827, 95% confidence interval: 1.045-3.196, P = 0.035).Conclusions: TKT contributes to esophageal cancer by promoting cell invasion via meditating EMT process. Clinically, the over-expression of TKT in ESCC patients predicts poorer survival. TKT inhibition may be a useful strategy to intervene in cancer cell invasion and metastasis, which may lead to better prognosis for ESCC patients.

Tu1559 Safety of Same-Session Cryotherapy and Esophageal Stricture Dilation in the Treatment of Esophageal Neoplasia- a Multicenter Study

Tu1559 Safety of Same-Session Cryotherapy and Esophageal Stricture Dilation in the Treatment of Esophageal Neoplasia- a Multicenter Study

Photodynamic therapy downregulates the function of regulatory T cells in patients with esophageal squamous cell carcinoma

Photodynamic therapy (PDT) by selective photosensitization of cancer cells and subsequent laser application results in local tumor necrosis. However, the effects of PDT on immune function, which may depend on the type of immune response, are controversial. We investigated the immunological changes induced by PDT and the effect of PDT on level and function of regulatory T cells (Treg) in patients with invasive esophageal squamous cell carcinoma (ESCC). We analyzed patient's blood samples before and after PDT. Blood CD4+CD25+CD127-FoxP3+ Treg levels were quantified by FACS, and Treg function was evaluated by coculture proliferation assays with T effector (Teff) cells. We found that PDT abrogated the suppressive capacity of peripheral Treg (Days 7 and 14, p = 0.016) but had no effect on Treg levels. The effect of PDT on Treg function at Day 7 was accompanied by slight but statistically significant increases in peripheral neutrophil granulocytes (p = 0.035) and monocytes (p = 0.013) and a statistically significant increase (approximately 18-fold) in serum IL-6 levels (p = 0.008). In conclusion, PDT abolished Treg function, possibly due to increased IL-6 levels in treated ESCC patients. This may be crucial for an improved therapeutic outcome.

γ-Glutamylcyclotransferase as a novel immunohistochemical biomarker for the malignancy of esophageal squamous tumors

Recently, overexpression of γ-glutamylcyclotransferase (GGCT) has been reported in various cancer tissues suggesting that it has significant potential as a diagnostic marker. The aim of this study was to examine the suitability of GGCT for the detection of high-risk lesions at an early stage of esophageal squamous cell carcinoma (ESCC). A total of 200 lesions, including 120 invasive ESCC, 80 esophageal squamous intraepithelial neoplasia consisting of 40 low-grade intraepithelial neoplasia (LGIEN) and 40 high-grade intraepithelial neoplasia (HGIEN), as well as 20 confounding lesions, were examined by immunohistochemical (IHC) staining for GGCT. IHC staining for Ki-67 and p53 was also performed in esophageal squamous intraepithelial neoplasia to compare the diagnostic power of GGCT. Increased expression of GGCT was common in invasive ESCC and HGIEN (87.5% and 85.0%, respectively), but was much less frequently observed in LGIEN (17.5%). GGCT expression significantly correlated with the presence of lymph node metastasis and the degree of differentiation. In the differential diagnosis of LGIEN and HGIEN, GGCT possessed both high sensitivity and high specificity, while Ki-67 and p53 only possessed either high sensitivity or high specificity. Additionally, GGCT expression was higher in 7 out of 8 ESCC cell lines (KYSE series) than in a normal esophageal squamous cell line (Het-1A). The expression levels strongly correlated with enzymatic activity (r=.92; P<.001). These results indicate that overexpressed GGCT retains its enzymatic activity and can become a valuable biomarker for the diagnosis of HGIEN that is likely to progress to subepithelial invasion.