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

PubMed

Guo, Xiao-Fang; Li, Sai-Sai; Zhu, Xiao-Fei; Dou, Qiao-Hua; Liu, Duan

2018-06-16

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.

Hot food and beverage consumption and the risk of esophageal squamous cell carcinoma: A case-control study in a northwest area in China.

PubMed

Tai, Wei-Ping; Nie, Guo-Ji; Chen, Meng-Jie; Yaz, Tajigul Yiminni; Guli, Arzi; Wuxur, Arzigul; Huang, Qing-Qing; Lin, Zhi-Gang; Wu, Jing

2017-12-01

This study was trying to investigate the association of hot food and beverage consumption and the risk of esophageal squamous cell carcinoma in Hotan, a northwest area of China with high risk of esophageal squmous cell carcinoma. A population-based case-control study was designed. For the study, 167 patients diagnosed with esophageal squamous cell carcinoma were selected from Hotan during 2014 to 2015, and 167 community-based controls were selected from the same area, matched with age and sex. Information involved of temperature of food and beverage intake was obtained by face-to-face interview. Logistic regression analyses were performed to investigate the association between temperature of food and beverage intake and the risk of esophageal squamous cell carcinoma. The temperature of the food and beverage consumed by the esophageal squamous cell carcinoma patients was significantly higher than the controls. High temperature of tea, water, and food intake significantly increased the risk of esophageal squamous cell carcinoma by more than 2-fold, with adjusted odds ratio 2.23 (1.45-2.90), 2.13 (1.53-2.66), and 2.98 (1.89-4.12). Intake of food and beverage with high temperature was positively associated with the incidence of esophageal squamous cell carcinoma in Northwestern China. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Management of Patients With Adenocarcinoma or Squamous Cancer of the Esophagus.

PubMed

Ilson, David H; van Hillegersberg, Richard

2018-01-01

Esophageal cancer is characterized by early and frequent metastasis. Surgery is the primary treatment for early-stage disease, whereas patients with patients with locally advanced disease receive perioperative chemotherapy or chemoradiotherapy. Squamous cancers can be treated with primary chemoradiotherapy without surgery, depending on their response to therapy and patient tolerance for subsequent surgery. Chemotherapy with a fluorinated pyrimidine and a platinum agent, followed by later treatment with taxanes and irinotecan, provides some benefit. Agents that inhibit the erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2), or vascular endothelial growth factor, including trastuzumab, ramucirumab, and apatinib, increase response and survival times. Esophageal adenocarcinomas have mutations in tumor protein p53 and mutations that activate receptor-associated tyrosine kinase, vascular endothelial growth factor, and cell cycle pathways, whereas esophageal squamous tumors have a distinct set of mutations. Esophageal cancers develop systems to evade anti-tumor immune responses, but studies are needed to determine how immune checkpoint modification contributes to esophageal tumor development. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Special AT-rich sequence binding protein 1 promotes tumor growth and metastasis of esophageal squamous cell carcinoma.

PubMed

Ma, Jun; Wu, Kaiming; Zhao, Zhenxian; Miao, Rong; Xu, Zhe

2017-03-01

Esophageal squamous cell carcinoma is one of the most aggressive malignancies worldwide. Special AT-rich sequence binding protein 1 is a nuclear matrix attachment region binding protein which participates in higher order chromatin organization and tissue-specific gene expression. However, the role of special AT-rich sequence binding protein 1 in esophageal squamous cell carcinoma remains unknown. In this study, western blot and quantitative real-time polymerase chain reaction analysis were performed to identify differentially expressed special AT-rich sequence binding protein 1 in a series of esophageal squamous cell carcinoma tissue samples. The effects of special AT-rich sequence binding protein 1 silencing by two short-hairpin RNAs on cell proliferation, migration, and invasion were assessed by the CCK-8 assay and transwell assays in esophageal squamous cell carcinoma in vitro. Special AT-rich sequence binding protein 1 was significantly upregulated in esophageal squamous cell carcinoma tissue samples and cell lines. Silencing of special AT-rich sequence binding protein 1 inhibited the proliferation of KYSE450 and EC9706 cells which have a relatively high level of special AT-rich sequence binding protein 1, and the ability of migration and invasion of KYSE450 and EC9706 cells was distinctly suppressed. Special AT-rich sequence binding protein 1 could be a potential target for the treatment of esophageal squamous cell carcinoma and inhibition of special AT-rich sequence binding protein 1 may provide a new strategy for the prevention of esophageal squamous cell carcinoma invasion and metastasis.

A Phase I Study of LJM716 in Squamous Cell Carcinoma of Head and Neck, or HER2+ Breast Cancer or Gastric Cancer

ClinicalTrials.gov

2014-04-21

HER2 + Breast Cancer, HER2 + Gastric Cancer, Squamous Cell Carcinoma of Head and Neck, Esophageal Squamous Cell Carcinoma; HER2 + Breast Cancer; HER2 + Gastric Cancer; Squamous Cell Carcinoma of Head and Neck; Esophageal Squamous Cell Carcinoma

Esophageal cancer

MedlinePlus

... old. There are two main types of esophageal cancer: squamous cell carcinoma and adenocarcinoma. These two types look different from each other under the microscope. Squamous cell esophageal cancer is linked to smoking and drinking too much ...

Overexpression of TRIM44 is related to invasive potential and malignant outcomes in esophageal squamous cell carcinoma.

PubMed

Kawaguchi, Tsutomu; Komatsu, Shuhei; Ichikawa, Daisuke; Hirajima, Shoji; Nishimura, Yukihisa; Konishi, Hirotaka; Shiozaki, Atsushi; Fujiwara, Hitoshi; Okamoto, Kazuma; Tsuda, Hitoshi; Otsuji, Eigo

2017-06-01

Recent studies have shown that some members of the tripartite motif-containing protein family function as important regulators for carcinogenesis. In this study, we investigated whether tripartite motif-containing protein 44 acts as a cancer-promoting gene through its overexpression in esophageal squamous cell carcinoma. We analyzed esophageal squamous cell carcinoma cell lines to evaluate malignant potential and also analyzed 68 primary tumors to evaluate clinical relevance of tripartite motif-containing protein 44 protein in esophageal squamous cell carcinoma patients. Expression of the tripartite motif-containing protein 44 protein was detected in esophageal squamous cell carcinoma cell lines (8/14 cell lines; 57%) and primary tumor samples of esophageal squamous cell carcinoma (39/68 cases; 57%). Knockdown of tripartite motif-containing protein 44 expression in esophageal squamous cell carcinoma cells using several specific small interfering RNAs inhibited cell migration and invasion, but not cell proliferation. Immunohistochemical analysis demonstrated that the overexpression of the tripartite motif-containing protein 44 protein in the tumor infiltrated region was associated with the status of lymph node metastasis ( p = 0.049), and the overall survival rates were significantly worse among patients with tripartite motif-containing protein 44-overexpressing tumors than those with non-expressing tumors ( p = 0.029). Moreover, multivariate Cox regression model identified that overexpression of the tripartite motif-containing protein 44 protein was an independent worse prognostic factor (hazard ratio = 2.815; p = 0.041), as well as lymphatic invasion (hazard ratio = 2.735; p = 0.037). These results suggest that tripartite motif-containing protein 44 protein could play a crucial role in tumor invasion through its overexpression and highlight its usefulness as a predictor and potential therapeutic target in esophageal squamous cell carcinoma.

Chemoradiotherapy for esophageal squamous cell cancer.

PubMed

Sasaki, Yusuke; Kato, Ken

2016-09-01

Chemoradiotherapy has been clinically indicated for patients with resectable esophageal squamous cell carcinoma who refuse surgical resection and in locally advanced unresectable esophageal squamous cell carcinoma patients. Concurrent chemoradiotherapy prolongs survival than radiation therapy alone when given as definitive treatment. Therefore, chemoradiotherapy is recognized as the standard non-invasive treatment for patients with localized esophageal cancer who opt for non-surgical treatment. JCOG9906 showed promising outcomes for stage II/III ESCC patients. But there are some problems about chemoradiotherapy for esophageal squamous cell carcinoma. Late toxicities are sometimes lethal for patients who achieved complete response even after years. Salvage treatment for residual or recurrent disease is unestablished. Modified Radiation Therapy Oncology Group regimen at the dose of 50.4 Gy reduced late toxicities without reducing efficacy. Optimal timings and procedure of salvage surgery and endoscopic therapy is evaluated in JCOG0909. Strategy including salvage therapy after chemoradiotherapy should be considered at the time of starting the treatment. Targeted therapy has not shown adding effect for chemoradiotherapy for esophageal squamous cell carcinoma yet. New agents, such as immune checkpoint inhibitors, are expected to show synergistic effect with chemoradiotherapy for esophageal squamous cell carcinoma. Further investigation is needed. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Molecular Mechanisms of Ethanol-associated Oro-esophageal Squamous Cell Carcinoma

PubMed Central

Liu, Yao; Chen, Hao; Sun, Zheng; Chen, Xiaoxin

2016-01-01

Alcohol drinking is a major etiological factor of oro-esophageal squamous cell carcinoma (OESCC). Both local and systemic effects of ethanol may promote carcinogenesis, especially among chronic alcoholics. However, molecular mechanisms of ethanol-associated OESCC are still not well understood. In this review, we summarize current understandings and propose three mechanisms of ethanol-associated OESCC: (1) Disturbance of systemic metabolism of nutrients: during ethanol metabolism in the liver, systemic metabolism of retinoids, zinc, iron and methyl groups is altered. These nutrients are known to be associated with the development of OESCC. (2) Disturbance of redox metabolism in squamous epithelial cells: when ethanol is metabolized in oro-esophageal squamous epithelial cells, reactive oxygen species are generated and produce oxidative damage. Meanwhile, ethanol may also disturb fatty-acid metabolism in these cells. (3) Disturbance of signaling pathways in squamous epithelial cells: due to its physico-chemical properties, ethanol changes cell membrane fluidity and shape, and may thus impact multiple signaling pathways. Advanced molecular techniques in genomics, epigenomics, metabolomics and microbiomics will help us elucidate how ethanol promotes OESCC. PMID:25766659

Clinical and biological significance of stem-like CD133(+)CXCR4(+) cells in esophageal squamous cell carcinoma.

PubMed

Lu, Chunlai; Xu, Fengkai; Gu, Jie; Yuan, Yunfeng; Zhao, Guangyin; Yu, Xiaofang; Ge, Di

2015-08-01

Esophageal squamous cell carcinoma is one of the most frequent malignant tumors. Cancer stem cells are considered to be responsible for tumor growth, metastasis, and recurrence. Cluster of differentiation 133 (CD133) and C-X-C chemokine receptor type 4 (CXCR4) are frequently applied markers for the identification and isolation of cancer stem cells. However, few studies have investigated the coexpression of CD133 and CXCR4 in esophageal squamous cell carcinoma. This study aims to explore the clinical and biological role of stem-like CD133(+)CXCR4(+) cells in esophageal squamous cell carcinoma. Immunohistochemical staining was performed to detect the expression of CD133 and CXCR4 in esophageal squamous cell carcinoma tissues of patients. Flow cytometry and fluorescence-activated cell sorting were applied to analyze and isolate each subgroup in esophageal squamous cell carcinoma cell line TE-1. The characteristic differences between each subgroup were assayed in vitro. The association between CD133/CXCR4 expression and patients' prognosis was analyzed by Kaplan-Meier and Cox regression. Among 154 patient tissues, concomitant high CD133-CXCR4 expression accounts for 20.78% (32/154). In vitro, CXCR4(+) cells (CD133(+)CXCR4(+) and CD133(-)CXCR4(+)) showed high invasive potential and CD133(+)CXCR4(+) cells showed high proliferative capacity. Clinically, patients with concomitant high CD133-CXCR4 expression had decreased disease-free survival and overall survival (P < .01). Esophageal squamous cell carcinoma cells coexpressing CD133 and CXCR4 possess the characteristics of cancer stem cells. The concomitant high CD133-CXCR4 expression might be a novel marker for predicting the poor prognosis of patients with esophageal squamous cell carcinoma, and CD133 and CXCR4 may serve as potential therapeutic targets. Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

PTK7 is a novel oncogenic target for esophageal squamous cell carcinoma.

PubMed

Liu, Kang; Song, Guiqin; Zhang, Xuqian; Li, Qiujiang; Zhao, Yunxia; Zhou, Yuchuan; Xiong, Rong; Hu, Xin; Tang, Zhirong; Feng, Gang

2017-05-25

Overexpression of PTK7 has been found in multiple cancers and has been proposed to serve as a prognostic marker for intrahepatic cholangiocarcinoma. Its role in esophageal cancer, however, remains to be clarified. We hypothesize that PTK7 positively regulates tumorigenesis of esophageal cancer. We examined PTK7 expression pattern in human esophageal squamous carcinoma by Oncomine expression analysis and by immunohistochemistry (IHC) staining. We knocked down PTK7 in two esophageal squamous cell carcinoma cell lines, TE-5, and TE-9, by siRNA, and evaluated cell proliferation, apoptosis, and migration ofPTK7-defective cells. Expressions of major apoptotic regulators and effectors were also determined by quantitative real-time PCR in PTK7-defective cells. We further overexpressed PTK7 in the cell to evaluate its effects on cell proliferation, apoptosis, and migration. Both Oncomine expression and IHC analyses showed that PTK7 is overexpressed in clinical esophageal squamous cell carcinoma tumors. PTK7 siRNA suppressed cell growth and promoted apoptosis of TE-5 and TE-9. PTK7-defective cells further displayed reduced cellular migration that was concomitant with upregulation of E-cadherin. Conversely, overexpression of PTK7 promotes cell proliferation and invasion, while apoptosis of the PTK7-overexpressing cells is repressed. Notably, major apoptotic regulators, such as p53 and caspases, are significantly upregulated in siPTK7 cells. PTK7 plays an oncogenic role in tumorigenesis and metastasis of esophageal squamous carcinoma. PTK7 achieves its oncogenic function in esophageal squamous cell carcinoma partially through the negative regulation of apoptosis.

The Prevalence of Human Papilloma Virus in Esophageal Squamous Cell Carcinoma

PubMed Central

Noori, Sadat; Monabati, Ahmad; Ghaderi, Abbasali

2012-01-01

Background: Carcinomas of esophagus, mostly squamous cell carcinomas, occur throughout the world. There are a number of suspected genetic or environmental etiologies. Human papilloma virus (HPV) is said to be a major etiology in areas with high incidence of esophageal carcinoma, while it is hardly detectable in low incidence regions. This study was designed to evaluate the prevalence of HPV in esophageal squamous cell carcinoma (ESCC) cases diagnosed in Pathology Department, Medical School, Shiraz University of Medical Sciences. Methods: DNA material for PCR amplification of HPV genome was extracted from formalin-fixed paraffin-embedded tissue blocks of 92 cases of ESCC, diagnosed during 20 years from 1982 to 2002. Polymerase chain reaction was performed for amplification and detection of common HPV and type specific HPV-16 and HPV-18 genomic sequences in the presence of positive control (HPV-18 and HPV positive biopsies of uterine exocervix) and additional internal controls i.e. beta-globin and cytotoxic T lymphocyte antigen 4 (CTLA4). Result: Good amplification of positive control and internal controls was observed. However, no amplification of HPV genome was observed. Conclusion: There is no association between HPV infection and the development of esophageal squamous cell carcinoma in the cases evaluated. PMID:23115442

Novel candidate genes may be possible predisposing factors revealed by whole exome sequencing in familial esophageal squamous cell carcinoma.

PubMed

Forouzanfar, Narjes; Baranova, Ancha; Milanizadeh, Saman; Heravi-Moussavi, Alireza; Jebelli, Amir; Abbaszadegan, Mohammad Reza

2017-05-01

Esophageal squamous cell carcinoma is one of the deadliest of all the cancers. Its metastatic properties portend poor prognosis and high rate of recurrence. A more advanced method to identify new molecular biomarkers predicting disease prognosis can be whole exome sequencing. Here, we report the most effective genetic variants of the Notch signaling pathway in esophageal squamous cell carcinoma susceptibility by whole exome sequencing. We analyzed nine probands in unrelated familial esophageal squamous cell carcinoma pedigrees to identify candidate genes. Genomic DNA was extracted and whole exome sequencing performed to generate information about genetic variants in the coding regions. Bioinformatics software applications were utilized to exploit statistical algorithms to demonstrate protein structure and variants conservation. Polymorphic regions were excluded by false-positive investigations. Gene-gene interactions were analyzed for Notch signaling pathway candidates. We identified novel and damaging variants of the Notch signaling pathway through extensive pathway-oriented filtering and functional predictions, which led to the study of 27 candidate novel mutations in all nine patients. Detection of the trinucleotide repeat containing 6B gene mutation (a slice site alteration) in five of the nine probands, but not in any of the healthy samples, suggested that it may be a susceptibility factor for familial esophageal squamous cell carcinoma. Noticeably, 8 of 27 novel candidate gene mutations (e.g. epidermal growth factor, signal transducer and activator of transcription 3, MET) act in a cascade leading to cell survival and proliferation. Our results suggest that the trinucleotide repeat containing 6B mutation may be a candidate predisposing gene in esophageal squamous cell carcinoma. In addition, some of the Notch signaling pathway genetic mutations may act as key contributors to esophageal squamous cell carcinoma.

Characterization of squamous esophageal cells resistant to bile acids at acidic pH: implication for Barrett's esophagus pathogenesis

PubMed Central

Goldman, Aaron; Chen, Hwu Dau Rw; Roesly, Heather B.; Hill, Kimberly A.; Tome, Margaret E.; Dvorak, Bohuslav; Bernstein, Harris

2011-01-01

Barrett's esophagus (BE) is a premalignant condition, where normal squamous epithelium is replaced by intestinal epithelium. BE is associated with an increased risk of developing esophageal adenocarcinoma (EAC). However, the BE cell of origin is not clear. We hypothesize that BE tissue originates from esophageal squamous cells, which can differentiate to columnar cells as a result of repeated exposure to gastric acid and bile acids, two components of refluxate implicated in BE pathology. To test this hypothesis, we repeatedly exposed squamous esophageal HET1A cells to 0.2 mM bile acid (BA) cocktail at pH 5.5 and developed an HET1AR-resistant cell line. These cells are able to survive and proliferate after repeated 2-h treatments with BA at pH 5.5. HET1AR cells are resistant to acidification and express markers of columnar differentiation, villin, CDX2, and cytokeratin 8/18. HET1AR cells have increased amounts of reactive oxygen species, concomitant with a decreased level and activity of manganese superoxide dismutase compared with parental cells. Furthermore, HET1AR cells express proteins and activate signaling pathways associated with inflammation, cell survival, and tumorigenesis that are thought to contribute to BE and EAC development. These include STAT3, NF-κB, epidermal growth factor receptor (EGFR), cyclooxygenase-2, interleukin-6, phosphorylated mammalian target of rapamycin (p-mTOR), and Mcl-1. The expression of prosurvival and inflammatory proteins and resistance to cell death could be partially modified by inhibition of STAT3 signaling. In summary, our study shows that long-term exposure of squamous cells to BA at acidic pH causes the cells to display the same characteristics and markers as BE. PMID:21127259

Oral Rigosertib for Squamous Cell Carcinoma

ClinicalTrials.gov

2017-06-22

Head and Neck Squamous Cell Carcinoma; Anal Squamous Cell Carcinoma; Lung Squamous Cell Carcinoma; Cervical Squamous Cell Carcinoma; Esophageal Squamous Cell Carcinoma; Skin Squamous Cell Carcinoma; Penile Squamous Cell Carcinoma

Esophageal achalasia: a risk factor for carcinoma. A systematic review and meta-analysis.

PubMed

Tustumi, F; Bernardo, W M; da Rocha, J R M; Szachnowicz, S; Seguro, F C; Bianchi, E T; Sallum, R A A; Cecconello, I

2017-10-01

Achalasia of the cardia is associated with an increased risk of esophageal carcinoma. The real burden of achalasia at the malignancy genesis is still a controversial issue. Therefore, there are no generally accepted recommendations on follow-up evaluation for achalasia patients. This study aims to estimate the risk of esophageal adenocarcinoma and squamous cell carcinoma in achalasia patients. We searched for association between carcinoma and esophageal achalasia in databases up to January 2017 to perform a systematic review and meta-analysis. A total of 1,046 studies were identified from search strategy, of which 40 were selected for meta-analysis. A cumulative number of 11,978 esophageal achalasia patients were evaluated. The incidence of squamous cell carcinoma was 312.4 (StDev 429.16) cases per 100,000 patient-years at risk. The incidence of adenocarcinoma was 21.23 (StDev 31.6) cases per 100,000 patient-years at risk. The prevalence for esophageal carcinoma was 28 carcinoma cases in 1,000 esophageal achalasia patients (CI 95% 2, 39). The prevalence for squamous cell carcinoma was 26 cases in 1,000 achalasia patients (CI 95% 18, 39) and for adenocarcinoma was 4 cases in 1,000 achalasia patients (CI 95% 3, 6).The absolute risk increase for squamous cell carcinoma was 308.1 and for adenocarcinoma was 18.03 cases per 100,000 patients per year. To the best of our knowledge, this is the first meta-analysis estimating the burden of achalasia as an esophageal cancer risk factor. The high increased risk rate for cancer in achalasia patients points to a strict endoscopic surveillance for these patients. Also, the increased risk for developing adenocarcinoma in achalasia patients suggests fundoplication after myotomy, to avoid esophageal reflux and Barret esophagus, a known risk factor for adenocarcinoma. © The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Inflammation-based prognostic score and number of lymph node metastases are independent prognostic factors in esophageal squamous cell carcinoma.

PubMed

Kobayashi, Takashi; Teruya, Masanori; Kishiki, Tomokazu; Kaneko, Susumu; Endo, Daisuke; Takenaka, Yoshiharu; Miki, Kenji; Kobayashi, Kaoru; Morita, Koji

2010-08-01

Few studies have investigated whether the Glasgow Prognostic Score (GPS), an inflammation-based prognostic score, is useful for postoperative prognosis of esophageal squamous cell carcinoma. GPS was calculated on the basis of admission data as follows: patients with elevated C-reactive protein level (>10 mg/l) and hypoalbuminemia (<35 g/l) were assigned to GPS2. Patients with one or no abnormal value were assigned to GPS1 or GPS0. A new scoring system was constructed using independent prognostic variables and was evaluated on whether it could be used to dictate the choice of clinical options. 65 patients with esophageal squamous cell carcinoma were enrolled. GPS and the number of lymph node metastases were found to be independent prognostic variables. The scoring system comprising GPS and the number of lymph node metastases was found to be effective in the prediction of a long-term outcome (p < 0.0001). Preoperative GPS may be useful for postoperative prognosis of patients with esophageal squamous cell carcinoma. GPS and the number of lymph node metastases could be used to identify a subgroup of patients with esophageal squamous cell carcinoma who are eligible for radical resection but show poor prognosis.

Pembrolizumab and Palliative Radiation Therapy in Treating Patients With Metastatic Esophagus, Stomach, or Gastroesophageal Junction Cancer

ClinicalTrials.gov

2017-12-07

Adenocarcinoma of the Gastroesophageal Junction; Gastric Adenocarcinoma; Gastric Squamous Cell Carcinoma; Metastatic Malignant Neoplasm in the Stomach; Stage IV Esophageal Adenocarcinoma; Stage IV Esophageal Squamous Cell Carcinoma

Morphofunctional analysis of experimental model of esophageal achalasia in rats.

PubMed

Sabirov, A G; Raginov, I S; Burmistrov, M V; Chelyshev, Y A; Khasanov, R Sh; Moroshek, A A; Grigoriev, P N; Zefirov, A L; Mukhamedyarov, M A

2010-10-01

We carried out a detailed analysis of rat model of esophageal achalasia previously developed by us. Manifest morphological and functional disorders were observed in experimental achalasia: hyperplasia of the squamous epithelium, reduced number of nerve fibers, excessive growth of fibrous connective tissue in the esophageal wall, high contractile activity of the lower esophageal sphincter, and reduced motility of the longitudinal muscle layer. Changes in rat esophagus observed in experimental achalasia largely correlate with those in esophageal achalasia in humans. Hence, our experimental model can be used for the development of new methods of disease treatment.

CD163 as a marker of M2 macrophage, contribute to predicte aggressiveness and prognosis of Kazakh esophageal squamous cell carcinoma.

PubMed

Hu, Jian Ming; Liu, Kai; Liu, Ji Hong; Jiang, Xian Li; Wang, Xue Li; Chen, Yun Zhao; Li, Shu Gang; Zou, Hong; Pang, Li Juan; Liu, Chun Xia; Cui, Xiao Bin; Yang, Lan; Zhao, Jin; Shen, Xi Hua; Jiang, Jin Fang; Liang, Wei Hua; Yuan, Xiang Lin; Li, Feng

2017-03-28

M2 macrophages was domesticated by tumor microenvironment to produce some angiogenic molecules and protease, facilitating angiogenesis and matrix breakdown, promoting tumor invasive and metastasis. However, The function of M2 macrophages to progression of eophageal carcinoma, especially Kazakh esophageal carcinoma is still dimness. This study aims to investigate M2 macrophages correlated with matrix metalloproteinase-9 (MMP9) and microvessel density, and the role in the progression of Kazakh esophageal squamous cell carcinoma. CD163 and CD34 as the marker of M2 macrophages and endothelial cells, were used to identify the M2 macrophages density and microvessel density, respectively. Immunohistochemistry staining was evaluated the expression of MMP9. The number of infiltrated CD163-positive M2 macrophages in tumor islets and stroma was significantly higher than in cancer adjacent normal tissues. The increased of M2 macrophages and microvessel density were significantly correlated with more malignant phenotypes including lymph node metastasis and clinical stage progression. Meanwhile, the expression of MMP9 showed much higher level in esophageal squamous cell carcinoma than that in cancer adjacent normal tissues, and high expression of MMP9 in Kazakh esophageal squamous cell carcinoma was significantly associated with age, depth of tumor invasion, lymph node metastasis, and tumor clinical stage. The quantity of M2 macrophages in tumor stroma was positively associated with microvessel density and the expression of MMP9, and as an independent poorly prognostic factor for overall survival time of Kazakh esophageal squamous cell carcinoma. These findings suggest the increased number of M2 macrophages correlated with high expression of MMP9 and high microvessel density may contribute to the tumor aggressiveness and angiogenesis, promoting the progression of Kazakh esophageal squamous cell carcinoma.

S-1 versus S-1 plus cisplatin concurrent intensity modulated radiation therapy in the treatment of esophageal squamous cell carcinoma: Study protocol for a randomized controlled phase II trial.

PubMed

Wen, Yixue; Zhao, Zhenhuan; Miao, Jidong; Yang, Qilin; Gui, Yan; Sun, Mingqiang; Tian, Honggang; Jia, Qiang; Liao, Dongbiao; Yang, Chen; Du, Xiaobo

2017-12-01

Chemotherapy regimens are often a 2-drug regimen in concurrent chemotherapy and radiotherapy for esophageal cancer (EC). However, some retrospective studies have suggested that for patients with EC receiving radiotherapy combined with 2-drug chemotherapy have the severe toxicity. And S-1 alone with the combination of radiotherapy treatment effect is good, and achieved good clinical remission rate. The purpose of this trial is compare the efficacy and toxicity of combining S-1 or S-1 plus cisplatin with radiotherapy for esophageal squamous cell carcinoma. The study is a randomized, controlled, multicenter trial, comparing S-1 versus S-1 plus cisplatin concurrent radiotherapy for patients with esophageal squamous cell carcinoma. Eighty-eight patients with unresectable or medically unfit for surgery esophageal squamous cell carcinoma (clinical stage I to III), will randomly assigned to receive four cycles (2 concomitant and 2 postradiotherapy) S-1 or S-1 plus cisplatin along with radiotherapy 60-66 Gy/30 to 33 fractions. The primary outcome is complete response rate of primary tumor which will be measured by endoscopy and computer screen at 3 months after the completion of treatment. Secondary outcomes include survival and toxicity. To our knowledge, this study protocol is the first to test the effect between S-1 versus S-1 plus cisplatin concurrent intensity modulated radiation therapy in the treatment of esophageal squamous cell carcinoma. If the result will be the same effect and fewer side effects and less costly in S-1 plus radiotherapy. It will supply more treatment selection for esophageal squamous cell carcinoma.

Oncogene GAEC1 regulates CAPN10 expression which predicts survival in esophageal squamous cell carcinoma

PubMed Central

Chan, Dessy; Tsoi, Miriam Yuen-Tung; Liu, Christina Di; Chan, Sau-Hing; Law, Simon Ying-Kit; Chan, Kwok-Wah; Chan, Yuen-Piu; Gopalan, Vinod; Lam, Alfred King-Yin; Tang, Johnny Cheuk-On

2013-01-01

AIM: To identify the downstream regulated genes of GAEC1 oncogene in esophageal squamous cell carcinoma and their clinicopathological significance. METHODS: The anti-proliferative effect of knocking down the expression of GAEC1 oncogene was studied by using the RNA interference (RNAi) approach through transfecting the GAEC1-overexpressed esophageal carcinoma cell line KYSE150 with the pSilencer vector cloned with a GAEC1-targeted sequence, followed by MTS cell proliferation assay and cell cycle analysis using flow cytometry. RNA was then extracted from the parental, pSilencer-GAEC1-targeted sequence transfected and pSilencer negative control vector transfected KYSE150 cells for further analysis of different patterns in gene expression. Genes differentially expressed with suppressed GAEC1 expression were then determined using Human Genome U133 Plus 2.0 cDNA microarray analysis by comparing with the parental cells and normalized with the pSilencer negative control vector transfected cells. The most prominently regulated genes were then studied by immunohistochemical staining using tissue microarrays to determine their clinicopathological correlations in esophageal squamous cell carcinoma by statistical analyses. RESULTS: The RNAi approach of knocking down gene expression showed the effective suppression of GAEC1 expression in esophageal squamous cell carcinoma cell line KYSE150 that resulted in the inhibition of cell proliferation and increase of apoptotic population. cDNA microarray analysis for identifying differentially expressed genes detected the greatest levels of downregulation of calpain 10 (CAPN10) and upregulation of trinucleotide repeat containing 6C (TNRC6C) transcripts when GAEC1 expression was suppressed. At the tissue level, the high level expression of calpain 10 protein was significantly associated with longer patient survival (month) of esophageal squamous cell carcinoma compared to the patients with low level of calpain 10 expression (37.73 ± 16.33 vs 12.62 ± 12.44, P = 0.032). No significant correction was observed among the TNRC6C protein expression level and the clinocopathologcial features of esophageal squamous cell carcinoma. CONCLUSION: GAEC1 regulates the expression of CAPN10 and TNRC6C downstream. Calpain 10 expression is a potential prognostic marker in patients with esophageal squamous cell carcinoma. PMID:23687414

Targeting CD47 Enhances the Efficacy of Anti-PD-1 and CTLA-4 in an Esophageal Squamous Cell Cancer Preclinical Model.

PubMed

Tao, Hua; Qian, Pudong; Wang, Feijiang; Yu, Hongliang; Guo, Yesong

2017-11-02

Esophageal squamous cell cancer is a highly aggressive cancer with a dismal 5-year survival rate. CD47 is a cell transmembrane protein that is involved in cell apoptosis, proliferation, adhesion, migration, and antigen presentation in the immune system. By interacting with signal regulatory protein-α expressed in antigen-presenting cells (APCs), CD47 acts as an antiphagocytic mechanism to inhibit APC-dependent antigen presentation. Overexpression of CD47 was found in various types of cancer. However, its role in esophageal squamous cell cancer is not yet clear. Anti-CD47 is an antagonist of CD47 signaling pathways by competing with its ligand. In the current study, we investigated the effects of anti-CD47 treatment on the antitumor immune response in an esophageal squamous cell cancer preclinical model. We found that anti-CD47 treatment enhanced proinflammatory responses and increased CD8+ T-cell infiltration in tumor tissue in the animal model. T cells in anti-CD47-treated tumors showed higher PD-1 and CTLA-4 expression, indicating T-cell activation and the rationale of combining anti-CD47 with anti-PD-1 and CLTA-4. The combinatory treatment showed the best antitumor response, implying a novel treatment strategy. The effects of anti-CD47 depended on dendritic cell function. In patient samples, expression of CD47 was negatively correlated with CD8+ T-cell infiltration in esophageal squamous cell cancer patients. Taken together, CD47 might be a novel target to enhance anti-PD-1 and CLTA-4 efficacy in esophageal squamous cell cancer.

Histomorphologic changes of esophageal mucosa in experimental third degree stricture.

PubMed

Shaprynskyi, Volodymyr O; Shaprinskiy, Yevgeniy V; Karyi, Yaroslav V; Lysenko, Serhii A

Nowadays the level of early and late complications after the operations for esophageal corrosive strictures such as esophago-organ anastomotic leak, development of infections, pneumonia, pleural empyema, mediastinitis, peritonitis, postoperative corrosive stricture development etc. remains rather high. Besides, postoperative mortality rate is high as well - 3.5-30 %. For that reason, an experimental model of esophageal stricture was suggested and ultrastructural mucosal changes in the stricture itself were studied to elaborate the unified pathogenic approach in treatment of esophageal stricture and improvement of its results. The aim of our work was to study the dynamics of ultrastructural changes both in normal esophageal walls and in third degree esophageal stricture Materials and Methods: The experiment was carried out on white male rats weighting 250-300 grams, to whom the third degree esophageal stricture model was created. After layer-by-layer incision of anterior abdominal wall abdominal portion of the esophagus was completely ligated (10 rats). In the control group (6 rats) anterior abdominal wall was opened with its subsequent layered closure. The animals were withdrawn from the experiment on the third day by ketamine overdose, and the samples were taken for ultrastructural study. Electron microscopic study of submicroscopic organization of basal, prickle, superficial epithelial cells in stratified non-squamous epithelium, smooth myocytes of muscle plate and contractile elements in esophageal muscular layer was carried out. Nuclear membrane, membranes of mitochondria, endoplasmic reticulum and cytoplasmic Golgi complex were found to be subjected to focal lysis. The third degree esophageal stricture caused destructive lesions in ultrastructural architectonics of stratified non-squamous epithelium cells, smooth myocytes of muscle plate and contractile elements in esophageal muscular layer of rats. Thus, catabolic processes leading to organelle disintegration develop in esophageal cells of rats with third degree stricture.

InterSCOPE Study: Associations Between Esophageal Squamous Cell Carcinoma and Human Papillomavirus Serological Markers

PubMed Central

Egger, Sam; Urban, Margaret I.; Taylor, Philip R.; Abnet, Christian C.; Boffetta, Paolo; O’Connell, Dianne L.; Whiteman, David C.; Brennan, Paul; Malekzadeh, Reza; Pawlita, Michael; Dawsey, Sanford M.; Waterboer, Tim; Webb, Penelope M.; Green, Adèle C.; Hayward, Nicholas K.; Zaridze, David; Holcatova, Ivana; Mates, Dana; Szeszenia-Dabrowska, Neonila; Ferro, Gilles; Janout, Vladimir; Curado, Maria Paula; Menezes, Ana Maria; Koifman, Sergio; Islami, Farhad; Nasrollahzadeh, Dariush; Hu, Nan; Goldstein, Alisa M.; Gao, Ying; Ding, Ti; Kamangar, Farin

2012-01-01

Background The role of human papillomavirus (HPV) in the causation of esophageal squamous cell carcinoma is unclear. We examined the associations between esophageal squamous cell carcinoma and 28 centrally measured HPV serological markers in serum from six existing case–control studies conducted in regions with differing background risks of esophageal cancer. Methods We used centralized multiplex serology to test serum samples from 1561 case subjects and 2502 control subjects from six case–control studies for antibodies to the major HPV capsid protein (L1) and/or the early proteins E6 and/or E7 of eight high-risk, two low-risk, and four cutaneous HPV types. Study-specific odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using conditional logistic regression with adjustment for smoking, alcohol consumption, and other potential confounders. Pooled odds ratios and 95% confidence intervals were calculated using either a linear mixed-effects approach or a joint fixed-effects approach. All statistical tests were two-sided. Results We found statistically significant associations between esophageal squamous cell carcinoma and antibodies to E6 for HPV16 (OR = 1.89, 95% CI = 1.09 to 3.29, P = .023) and HPV6 (OR = 2.53, 95% CI = 1.51 to 4.25, P < .001) but not for other tested HPV types. There were no statistically significant associations between esophageal squamous cell carcinoma and antibodies to E7 for any of the tested HPV types. Simultaneous seropositivity for HPV16 E6 and E7 was rare (four case subjects, two control subjects; OR = 5.57, 95% CI = 0.90 to 34.35; P = .064). We also found statistically significant associations between esophageal squamous cell carcinoma and capsid antibodies for the high-risk mucosal type HPV33 L1 (OR = 1.30, 95% CI = 1.00 to 1.69; P = .047) and the low-risk mucosal types HPV6 (OR = 1.22, 95% CI = 1.05 to 1.42; P = .010) and HPV11 (OR = 1.30, 95% CI = 1.09 to 1.56, P = .0036). Conclusions We found limited serological evidence of an association between esophageal squamous cell carcinoma and HPV in the populations studied. Although HPV does not appear to be an important risk factor for esophageal squamous cell carcinoma, we cannot exclude the possibility that certain HPV types may be involved in a small subset of cancers. PMID:22228147

Coexistence of esophageal blue nevus, hair follicles and basaloid sqamous carcinoma: a case report.

PubMed

Wang, Dong-Guan; Li, Xin-Gong; Gao, Hong; Sun, Xi-Yin; Zhou, Xiao-Qiu

2008-07-14

We present the case of a 57-year-old man who underwent esophagectomy for esophageal carcinoma found at barium meal and gastroscopic examination. He was diagnosed as esophageal basaloid squamous carcinoma (BSC) and gastric stromal tumor, which were associated with focal proliferation of melanocytes/pigmentophages and hair follicles in esophageal mucosa. Melanocytic hyperplasia (melanocytosis) has previously been recognized as an occasional reactive lesion, which can accompany esophageal inflammation and invasive squamous carcinoma. The present case is unusual because of its hyperplasia of not only melanocytes but also hair follicles. To our knowledge, this is the first report of esophageal blue nevus and hair follicle coexisting with BSC.

Downregulated expression of the cyclase-associated protein 1 (CAP1) reduces migration in esophageal squamous cell carcinoma.

PubMed

Li, Mei; Yang, Xiaojing; Shi, Hui; Ren, Hanru; Chen, Xueyu; Zhang, Shu; Zhu, Junya; Zhang, Jianguo

2013-09-01

Overexpression of cyclase-associated proteins has been associated with poor prognosis in several human cancers. Cyclase-associated protein 1 is a member of the cyclase-associated proteins which contributes to tumor progression. The aim of the present study was to examine the expression of cyclase-associated protein 1 and to elucidate its clinicopathologic significance in a larger series of esophageal squamous cell carcinoma. Immunohistochemical and western blot analyses were performed in esophageal squamous cell carcinoma tissues. Survival analyses were performed by using the Kaplan-Meier method. The role of cyclase-associated protein 1 in migration was studied in esophageal squamous cell carcinoma cell lines of TE1 through knocking down cyclase-associated protein 1 with siRNA and overexpression of cyclase-associated protein 1. The regulation of cyclase-associated protein 1 on migration was determined by transwell and wound-healing assays. Immunohistochemical analysis showed that cyclase-associated protein 1 expression was negatively associated with E-cadherin and significantly associated with lymph node metastases. Survival analysis revealed that cyclase-associated protein 1 overexpression was significantly associated with overall survival (P = 0.011). Knock down of cyclase-associated protein 1 in TE1 cells resulted in decreased vimentin and F-actin levels and the capability for migration. In addition, overexpression of cyclase-associated protein 1 promoted the migration of TE1 cells. These findings suggest that cyclase-associated protein 1 is involved in the metastasis of esophageal squamous cell carcinoma, and that elevated levels of cyclase-associated protein 1 expression may indicate a poor prognosis for patients with esophageal squamous cell carcinoma.

Impacts of treatments on the quality of life among esophageal squamous cell carcinoma patients.

PubMed

Chen, C-Y; Hsieh, V C-R; Chang, C-H; Chen, P-R; Liang, W-M; Pan, S-C; Shieh, S-H

2017-10-01

This study aims to investigate the effects of treatments on the quality of life for patients with esophageal squamous cell carcinoma patients diagnosed at early and late stages. From a medical center in central Taiwan, patients who had been diagnosed with esophageal squamous cell carcinoma from February 2007 and March 2011 were recruited. Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Quality of Life Questionnaire Oesophageal 18 (QLQ-OES18), quality of life scores for 105 esophageal squamous cell carcinoma patients were obtained and assessed. Multivariate analysis was performed on the quality of life scores after stratification by cancer stage. Among early-stage esophageal squamous cell carcinoma patients, those received only surgery (S-only) performed better in physical and social functioning compared with patients who underwent surgery and concurrent chemoradiotherapy (S+CCRT) (β = 9.0, P = 0.03; β = 12.1, P = 0.04, respectively). For those that received only concurrent chemoradiotherapy (CCRT-only), they performed worse in role and emotional functioning relative to S+CCRT patients (β = -17.2, P = 0.02; β = -15.7, P = 0.05, respectively). Among late-stage patients, CCRT-only treatment gave insignificantly better global health status and functional scale scores and less severe symptoms compared to the S+CCRT option. Better functional scores and less aggravated symptoms are observed in early-stage esophageal squamous cell carcinoma patients who received surgery-only treatment relative to those that underwent both surgery and chemoradiotherapy. For late-stage esophageal cancer patients, the measured difference of quality of life is not significant between CCRT-only and S+CCRT treatments. © The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Three-dimensional conformal radiation therapy for squamous cell carcinoma of the esophagus: a prospective phase I/II study.

PubMed

Wu, Kai-Liang; Chen, Guei-Yuan; Xu, Zhi-Yong; Fu, Xiao-Long; Qian, Hao; Jiang, Guo-Liang

2009-12-01

A prospective phase I-II study was conducted to determine the tolerance and local control rate of three-dimensional conformal radiotherapy (3-DCRT) for esophageal squamous cell carcinoma (SCC). Thirty patients underwent 3-DCRT for thoracic esophageal SCC. PTV1 composed of a 1.2-1.5 cm margin lateral around GTV and 3.0 cm margin superior/inferior of GTV. PTV2 encompassed GTV with a margin of 0.5-0.7 cm. The dose for PTV1 was 50 Gy in 2 Gy daily fractions; PTV2 received a boost of 16 Gy in 2 Gy daily fractions to a total dose of 66 Gy. Median follow-up time was 18 months. The most common acute toxicity was esophagitis in 63% of patients with RTOG grades 1-2, and in 3% with grade 3. RTOG grades 1-2 radiation pneumonitis developed in 27% of patients. One patient developed pulmonary fibrosis RTOG grade 2 and another patient experienced grade 3 pulmonary fibrosis. Two patients developed mild esophageal stricture requiring dilatation. Two-year overall survival, local disease progression-free rate, and distant metastasis-free rate were 69%, 36% and 56%, respectively. Although 3-DCRT to 66 Gy for esophageal SCC was well tolerated, the local control was disappointing. The result supports the use of chemoradiation as the standard care for esophageal SCC.

Comparative Study of Esophageal Stent and Feeding Gastrostomy/Jejunostomy for Tracheoesophageal Fistula Caused by Esophageal Squamous Cell Carcinoma

PubMed Central

Chiu, Yi-Chun; Lu, Hung-I; Huang, Cheng-Hua; Rau, Kun-Ming; Liu, Chien-Ting

2012-01-01

Background A malignant tracheoesophageal/bronchoesophageal fistula (TEF) is a life-threatening complication of esophageal squamous cell carcinoma. A feeding gastrostomy/jejunostomy had been the most common treatment method for patients with TEF before the era of stenting. The aim of this retrospective study is to compare the prognosis of esophageal squamous cell carcinoma patients with TEF treated with an esophageal metallic stent to those treated with a feeding gastrostomy/jejunostomy. Methods We retrospectively reviewed a total of 1011 patients with esophageal squamous cell carcinoma between 1996 and 2011 at Kaohsiung Chang Gung Memorial Hospital, and 86 patients with TEF (8.5%) were identified. The overall survival and other clinical data were compared between 30 patients treated with an esophageal metallic stent and 35 patients treated with a feeding gastrostomy/jejunostomy. Results Among the 65 patients receiving either an esophageal metallic stent or a feeding gastrostomy/jejunostomy, univariate analysis showed that treatment modality with an esophageal metallic stent (P = 0.007) and radiotherapy treatment after fistula diagnosis (P = 0.04) were predictive of superior overall survival. In the multivariate comparison, treatment modality with an esophageal metallic stent (P = 0.026, odds ratio: 1.859) represented the independent predictive factor of superior overall survival. There were no significant differences between groups in mean decrease in serum albumin or mean body weight loss. Compared to the feeding gastrostomy/jejunostomy group, a significantly higher proportion of patients in the stenting group (53% versus 14%, P = 0.001) were able to receive chemotherapy within 30 days after fistula diagnosis, indicating better infection control in the stenting group. Conclusions Compared with a feeding gastrostomy/jejunostomy, an esophageal metallic stent significantly improves overall survival in patients with malignant TEF in our retrospective analysis. Esophageal metallic stent placement may be considered the first-line of treatment for patients with malignant TEF. PMID:22912737

Clinical significance of the correlation between PLCE 1 and PRKCA in esophageal inflammation and esophageal carcinoma

PubMed Central

Ma, Ming; Zhang, Shanshan; Zhang, Yongmeng; Yuan, Ming; Liu, Bing; Yang, Yiqiong; Cui, Wen; Ansong, Emmanuel; Dong, Huali; Macias, Virgilia; Yang, Wancai

2017-01-01

Esophagitis and Barrett's esophagus are linked to esophageal squamous cell carcinoma and adenocarcinoma, respectively. However, the underlying mechanisms are still unclear. This study analyzed the expression levels of and correlation between PLCE1 and PRKCA in human esophagitis, carcinogen NMBA-induced rat esophagus, PLCE1 genetic deficient mouse esophageal epithelial tissues and human esophageal cancer cell line, integrated with Online oncology data sets. We found that the expression levels of both PLCE1 and PRKCA were significantly elevated in human esophagitis, esophageal squamous cell carcinoma, Barrett's esophagus, esophageal adenocarcinoma and in NMBA-treated rat esophageal epithelia. However, PRKCA and cytokines were significantly downregulated in PLCE1-deficient mouse esophageal epithelia, and knockdown of PLCE1 in human esophageal cancer cells led to reduction of PRKCA and cytokines. Finally, high expression of both PLCE1 and PRKCA is significantly associated with poor outcomes of the patients with esophageal cancers. In conclusion, this study defined the initiation and progression of esophageal inflammation and malignant transformation, in which the positive correlation of PLCE1 and PRKCA exhibits critical clinical significance. PMID:28402280

Overexpression of Cks1 increases the radiotherapy resistance of esophageal squamous cell carcinoma.

PubMed

Wang, Xiao-Chun; Tian, Li-Li; Tian, Jin; Li, DeGuan; Wang, YueYing; Wu, HongYing; Zheng, Hang; Meng, Ai-Min

2012-01-01

The Cks1 protein is a member of the highly conserved family of Cks/Suc1 proteins, which interact with Cdks, and was found to be an essential cofactor for efficient Skp2-dependent ubiquitination of p27. The present study was undertaken to examine the expression status of Cks1 in esophageal squamous cell carcinoma and its significance. The expression of Cks1 in 140 esophageal squamous cell carcinoma patients was examined by immunohistochemistry. The correlations between Cks1 expression and tumor clinicopathologic features were analyzed. The effects of Cks1 expression on radiotherapy results were also examined. In the present study, we found that Cks1 is overexpressed in esophageal squamous cell carcinoma tissues. Elevated expression of Cks1 correlates significantly with tumor stage and positive lymph node metastasis (p < 0.05). Moreover, a significant negative correlation was found between Cks1 expression and the survival of patients who received radiotherapy (p < 0.05). At the molecular level, forced expression of Cks1 promotes the radio-resistance ability of EC9706 cells. Knockdown of Cks1 expression sensitizes cancer cells to radiation, and a wobble mutant of Cks1 that is resistant to Cks1 siRNA can rescue this effect. These results demonstrate for the first time that overexpression of Cks1 correlates with the increased radiotherapy resistance of esophageal squamous cell carcinoma.

Mitochondrial pyruvate carrier function is negatively linked to Warburg phenotype in vitro and malignant features in esophageal squamous cell carcinomas

PubMed Central

Li, Yaqing; Li, Xiaoran; Kan, Quancheng; Zhang, Mingzhi; Li, Xiaoli; Xu, Ruiping; Wang, Junsheng; Yu, Dandan; Goscinski, Mariusz Adam; Wen, Jian-Guo; Nesland, Jahn M.; Suo, Zhenhe

2017-01-01

Aerobic glycolysis is one of the emerging hallmarks of cancer cells. In this study, we investigated the relationship between blocking mitochondrial pyruvate carrier (MPC) with MPC blocker UK5099 and the metabolic alteration as well as aggressive features of esophageal squamous carcinoma. It was found that blocking pyruvate transportation into mitochondria attenuated mitochondrial oxidative phosphorylation (OXPHOS) and triggered aerobic glycolysis, a feature of Warburg effect. In addition, the HIF-1α expression and ROS production were also activated upon UK5099 application. It was further revealed that the UK5099-treated cells became significantly more resistant to chemotherapy and radiotherapy, and the UK5099-treated tumor cells also exhibited stronger invasive capacity compared to the parental cells. In contrast to esophageal squamous epithelium cells, decreased MPC protein expression was observed in a series of 157 human squamous cell carcinomas, and low/negative MPC1 expression predicted an unfavorable clinical outcome. All these results together revealed the potential connection of altered MPC expression/activity with the Warburg metabolic reprogramming and tumor aggressiveness in cell lines and clinical samples. Collectively, our findings highlighted a therapeutic strategy targeting Warburg reprogramming of human esophageal squamous cell carcinomas. PMID:27911865

Esophageal squamous cell carcinoma with dural and bone marrow metastases.

PubMed

Chen, Yen-Hao; Huang, Cheng-Hua

2014-09-21

Patients with esophageal squamous cell carcinoma generally present at an advanced stage at the time of diagnosis. The most common sites of visceral metastasis are the lung, liver and bone, but brain and bone marrow involvement is exceedingly rare. Herein, we report a 62-year-old man with a 4-wk history of progressive low back pain with radiation to bilateral lower legs, dysphagia and body weight loss. Esophageal squamous cell carcinoma with regional lymph node, liver and bone metastases was diagnosed. He underwent concurrent chemoradiotherapy and got a partial response. Four months later, he complained of headache, diplopia and severe hearing impairment in the left ear. There was no evidence for bacterial, fungal, tuberculous infection or neoplastic infiltration. Magnetic resonance imaging of the brain demonstrated thickening and enhancement of bilateral pachymeninges and multiple enhancing masses in bilateral skull. Dural metastasis was diagnosed and he received whole brain irradiation. In addition, laboratory examination revealed severe thrombocytopenia and leucopenia, and bone marrow study confirmed the diagnosis of metastatic squamous cell carcinoma. This is the first described case of esophageal squamous cell carcinoma with dural and bone marrow metastases. We also discuss the pathogenesis of unusual metastatic diseases and differential diagnosis of pachymeningeal thickening.

Numeric pathologic lymph node classification shows prognostic superiority to topographic pN classification in esophageal squamous cell carcinoma.

PubMed

Sugawara, Kotaro; Yamashita, Hiroharu; Uemura, Yukari; Mitsui, Takashi; Yagi, Koichi; Nishida, Masato; Aikou, Susumu; Mori, Kazuhiko; Nomura, Sachiyo; Seto, Yasuyuki

2017-10-01

The current eighth tumor node metastasis lymph node category pathologic lymph node staging system for esophageal squamous cell carcinoma is based solely on the number of metastatic nodes and does not consider anatomic distribution. We aimed to assess the prognostic capability of the eighth tumor node metastasis pathologic lymph node staging system (numeric-based) compared with the 11th Japan Esophageal Society (topography-based) pathologic lymph node staging system in patients with esophageal squamous cell carcinoma. We retrospectively reviewed the clinical records of 289 patients with esophageal squamous cell carcinoma who underwent esophagectomy with extended lymph node dissection during the period from January 2006 through June 2016. We compared discrimination abilities for overall survival, recurrence-free survival, and cancer-specific survival between these 2 staging systems using C-statistics. The median number of dissected and metastatic nodes was 61 (25% to 75% quartile range, 45 to 79) and 1 (25% to 75% quartile range, 0 to 3), respectively. The eighth tumor node metastasis pathologic lymph node staging system had a greater ability to accurately determine overall survival (C-statistics: tumor node metastasis classification, 0.69, 95% confidence interval, 0.62-0.76; Japan Esophageal Society classification; 0.65, 95% confidence interval, 0.58-0.71; P = .014) and cancer-specific survival (C-statistics: tumor node metastasis classification, 0.78, 95% confidence interval, 0.70-0.87; Japan Esophageal Society classification; 0.72, 95% confidence interval, 0.64-0.80; P = .018). Rates of total recurrence rose as the eighth tumor node metastasis pathologic lymph node stage increased, while stratification of patients according to the topography-based node classification system was not feasible. Numeric nodal staging is an essential tool for stratifying the oncologic outcomes of patients with esophageal squamous cell carcinoma even in the cohort in which adequate numbers of lymph nodes were harvested. Copyright © 2017 Elsevier Inc. All rights reserved.

Esophageal Cancer.

PubMed

Short, Matthew W; Burgers, Kristina G; Fry, Vincent T

2017-01-01

Esophageal cancer has a poor prognosis and high mortality rate, with an estimated 16,910 new cases and 15,910 deaths projected in 2016 in the United States. Squamous cell carcinoma and adenocarcinoma account for more than 95% of esophageal cancers. Squamous cell carcinoma is more common in nonindustrialized countries, and important risk factors include smoking, alcohol use, and achalasia. Adenocarcinoma is the predominant esophageal cancer in developed nations, and important risk factors include chronic gastroesophageal reflux disease, obesity, and smoking. Dysphagia alone or with unintentional weight loss is the most common presenting symptom, although esophageal cancer is often asymptomatic in early stages. Physicians should have a low threshold for evaluation with endoscopy if any symptoms are present. If cancer is confirmed, integrated positron emission tomography and computed tomography should be used for initial staging. If no distant metastases are found, endoscopic ultrasonography should be performed to determine tumor depth and evaluate for nodal involvement. Localized tumors can be treated with endoscopic mucosal resection, whereas regional tumors are treated with esophagectomy, neoadjuvant chemotherapy, chemoradiotherapy, or a combination of modalities. Nonresectable tumors or tumors with distant metastases are treated with palliative interventions. Specific prevention strategies have not been proven, and there are no recommendations for esophageal cancer screening.

A Study of LGK974 in Patients With Malignancies Dependent on Wnt Ligands

ClinicalTrials.gov

2018-05-16

Pancreatic Cancer; BRAF Mutant Colorectal Cancer; Melanoma; Triple Negative Breast Cancer; Head and Neck Squamous Cell Cancer; Cervical Squamous Cell Cancer; Esophageal Squamous Cell Cancer; Lung Squamous Cell Cancer

Identification of unique expression signatures and therapeutic targets in esophageal squamous cell carcinoma

PubMed Central

2012-01-01

Background Esophageal squamous cell carcinoma (ESCC), the predominant histological subtype of esophageal cancer, is characterized by high mortality. Previous work identified important mRNA expression differences between normal and tumor cells; however, to date there are limited ex vivo studies examining expression changes occurring during normal esophageal squamous cell differentiation versus those associated with tumorigenesis. In this study, we used a unique tissue microdissection strategy and microarrays to measure gene expression profiles associated with cell differentiation versus tumorigenesis in twelve cases of patient-matched normal basal squamous epithelial cells (NB), normal differentiated squamous epithelium (ND), and squamous cell cancer. Class comparison and pathway analysis were used to compare NB versus tumor in a search for unique therapeutic targets. Results As a first step towards this goal, gene expression profiles and pathways were evaluated. Overall, ND expression patterns were markedly different from NB and tumor; whereas, tumor and NB were more closely related. Tumor showed a general decrease in differentially expressed genes relative to NB as opposed to ND that exhibited the opposite trend. FSH and IgG networks were most highly dysregulated in normal differentiation and tumorigenesis, respectively. DNA repair pathways were generally elevated in NB and tumor relative to ND indicating involvement in both normal and pathological growth. PDGF signaling pathway and 12 individual genes unique to the tumor/NB comparison were identified as therapeutic targets, and 10 associated ESCC gene-drug pairs were identified. We further examined the protein expression level and the distribution patterns of four genes: ODC1, POSTN, ASPA and IGF2BP3. Ultimately, three genes (ODC1, POSTN, ASPA) were verified to be dysregulated in the same pattern at both the mRNA and protein levels. Conclusions These data reveal insight into genes and molecular pathways mediating ESCC development and provide information potentially useful in designing novel therapeutic interventions for this tumor type. PMID:22280838

Number of negative lymph nodes as a prognostic factor in esophageal squamous cell carcinoma.

PubMed

Ma, Mingquan; Tang, Peng; Jiang, Hongjing; Gong, Lei; Duan, Xiaofeng; Shang, Xiaobin; Yu, Zhentao

2017-10-01

The aim of this study is to investigate the number of negative lymph nodes (NLNs) as a prognostic factor for survival in patients with resected esophageal squamous cell carcinoma. A total of 381 esophageal squamous cell carcinoma patients who had underwent surgical resection as the primary treatment was enrolled into this retrospective study. The impact of number of NLNs on patient's overall survival was assessed and compared with the factors among the current tumor-nodes-metastasis (TNM) staging system. The number of NLNs was closely related to the overall survival, and the 5-year survival rate was 45.4% for number of NLNs of >20 (142 cases) and 26.4% for NLNs ≤ 20 (239 cases) (P = 0.001). In multivariate survival analysis, the number of NLNs remained an independent prognostic factor (P = 0.002) as did the other current TNM factors. For subgroup analysis, the predictive value of number of NLNs was significant in patients with T3 or T4 disease (P = 0.001) and patients with N1 and N2-3 disease (P = 0.025, 0.043), but not in patients with T1 or T2 disease or patients with N0 disease. The number of NLNs, which represents the extent of lymphadenectomy for esophageal squamous cell carcinoma, could impact the overall survival of patients with resected esophageal squamous cell carcinoma, especially among those with nodal-positive disease and advanced T-stage tumor. © 2016 John Wiley & Sons Australia, Ltd.

Expression of HIWI in human esophageal squamous cell carcinoma is significantly associated with poorer prognosis

PubMed Central

2009-01-01

Background HIWI, the human homologue of Piwi family, is present in CD34+ hematopoietic stem cells and germ cells, but not in well-differentiated cell populations, indicating that HIWI may play an impotent role in determining or maintaining stemness of these cells. That HIWI expression has been detected in several type tumours may suggest its association with clinical outcome in cancer patients. Methods With the methods of real-time PCR, western blot, immunocytochemistry and immunohistochemistry, the expression of HIWI in three esophageal squamous cancer cell lines KYSE70, KYSE140 and KYSE450 has been characterized. Then, we investigated HIWI expression in a series of 153 esophageal squamous cell carcinomas using immunohistochemistry and explored its association with clinicopathological features. Results The expression of HIWI was observed in tumour cell nuclei or/and cytoplasm in 137 (89.5%) cases, 16 (10.5%) cases were negative in both nuclei and cytoplasm. 86 (56.2%) were strongly positive in cytoplasm, while 49 (32.0%) were strongly positive in nuclei. The expression level of HIWI in cytoplasm of esophageal cancer cells was significantly associated with histological grade (P = 0.011), T stage (P = 0.035), and clinic outcome (P < 0.001), while there was no correlation between the nuclear HIWI expression and clinicopathological features. Conclusion The expression of HIWI in the cytoplasm of esophageal cancer cells is significantly associated with higher histological grade, clinical stage and poorer clinical outcome, indicating its possible involvement in cancer development. PMID:19995427

Endoscopic traversability in patients with locally advanced esophageal squamous cell carcinoma: Is it a significant prognostic factor?

PubMed

Shin, Hae Jin; Moon, Hee Seok; Kang, Sun Hyung; Sung, Jae Kyu; Jeong, Hyun Yong; Kim, Seok Hyun; Lee, Byung Seok; Kim, Ju Seok; Yun, Gee Young

2017-12-01

The purpose of this study was to evaluate the prognostic impact of endoscopic traversability in patients with locally advanced esophageal squamous cell carcinoma.This retrospective study was based on medical records from a single tertiary medical center. The records of 317 patients with esophageal squamous cell carcinoma treated with surgery or definitive chemoradiotherapy (CRT) between January 2009 and March 2016 were reviewed. Finally, we retrieved the data on 168 consecutive patients. These 168 patients were divided into 2 groups based on their endoscopic traversability findings: Group A (the endoscope traversable group), and Group B (the endoscope non-traversable group). We then retrospectively compared the clinical characteristics of these 2 groups.The endoscope non-traversable group (Group B) revealed an advanced clinical stage, a poor Eastern Cooperative Oncology Group (ECOG) score, a lower serum albumin level, a higher rate of requirement for esophageal stent insertion and definitive CRT as initial treatment than the endoscope traversable group (Group A). Patients with endoscope traversable cancer showed a significantly higher 3-year overall survival and 3-year relapse-free survival than patients who were endoscope non-traversable (53.8% vs 17.3%, P < .001 and 71.1% vs 45.3%, P = .003, respectively). Upon multivariate analysis of patients with locally advanced esophageal squamous cell carcinoma treated with definitive CRT, the serum albumin level <3.5 g/dL and endoscopic non-traversability were significant negative factors of survival.Endoscopic traversability in patients with locally advanced esophageal squamous cell carcinoma treated with definitive CRT is a significant prognostic factor. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Simultaneous fingerprint and high-wavenumber fiber-optic Raman spectroscopy improves in vivo diagnosis of esophageal squamous cell carcinoma at endoscopy

NASA Astrophysics Data System (ADS)

Wang, Jianfeng; Lin, Kan; Zheng, Wei; Yu Ho, Khek; Teh, Ming; Guan Yeoh, Khay; Huang, Zhiwei

2015-08-01

This work aims to evaluate clinical value of a fiber-optic Raman spectroscopy technique developed for in vivo diagnosis of esophageal squamous cell carcinoma (ESCC) during clinical endoscopy. We have developed a rapid fiber-optic Raman endoscopic system capable of simultaneously acquiring both fingerprint (FP)(800-1800 cm-1) and high-wavenumber (HW)(2800-3600 cm-1) Raman spectra from esophageal tissue in vivo. A total of 1172 in vivo FP/HW Raman spectra were acquired from 48 esophageal patients undergoing endoscopic examination. The total Raman dataset was split into two parts: 80% for training; while 20% for testing. Partial least squares-discriminant analysis (PLS-DA) and leave-one patient-out, cross validation (LOPCV) were implemented on training dataset to develop diagnostic algorithms for tissue classification. PLS-DA-LOPCV shows that simultaneous FP/HW Raman spectroscopy on training dataset provides a diagnostic sensitivity of 97.0% and specificity of 97.4% for ESCC classification. Further, the diagnostic algorithm applied to the independent testing dataset based on simultaneous FP/HW Raman technique gives a predictive diagnostic sensitivity of 92.7% and specificity of 93.6% for ESCC identification, which is superior to either FP or HW Raman technique alone. This work demonstrates that the simultaneous FP/HW fiber-optic Raman spectroscopy technique improves real-time in vivo diagnosis of esophageal neoplasia at endoscopy.

Red and processed meat consumption and the risk of esophageal and gastric cancer subtypes in The Netherlands Cohort Study.

PubMed

Keszei, A P; Schouten, L J; Goldbohm, R A; van den Brandt, P A

2012-09-01

Prospective data on red and processed meat in relation to risk of subtypes of esophageal and gastric cancer are scarce. We present analyses of association between red and processed meat and the risk of esophageal and gastric cancer subtypes within The Netherlands Cohort Study on Diet and Cancer. 120 852 individuals aged 55-69 years were recruited in 1986, and meat intake was assessed using a 150-item food frequency questionnaire. After 16.3 years of follow-up, 107 esophageal squamous cell carcinomas, 145 esophageal adenocarcinomas, 163 gastric cardia adenocarcinomas, 489 gastric non-cardia adenocarcinomas, and 3923 subcohort members were included in a case-cohort analysis. Processed as well as red meat intake was positively associated with esophageal squamous cell carcinoma in men. Hazard ratios for highest versus lowest quintile of processed and red meat were 3.47 [95% confidence intervals (CI): 1.21-9.94; P for trend: 0.04] and 2.66 (95% CI: 0.94-7.48; P for trend: 0.06), respectively. No association was seen for adenocarcinomas or gastric cancer subtypes or for any of the four subtypes among women. Our findings suggest that red and processed meat consumption is associated with increased risk of esophageal squamous cell carcinoma in men but not with cancers of other esophageal and gastric subtypes.

Adherence to Mediterranean-style dietary pattern and risk of esophageal squamous cell carcinoma: a case-control study in Iran

USDA-ARS?s Scientific Manuscript database

The benefit of adherence to a Mediterranean-style dietary pattern in relation to the risk of esophageal squamous cell carcinoma (ESCC) has not been investigated among non-Mediterranean high-risk populations. The objective of the present study was to examine the association of compliance with the Med...

The predictive role of E2-EPF ubiquitin carrier protein in esophageal squamous cell carcinoma.

PubMed

Chen, Miao-Fen; Lee, Kuan-Der; Lu, Ming-Shian; Chen, Chih-Cheng; Hsieh, Ming-Ju; Liu, Yun-Hen; Lin, Paul-Yang; Chen, Wen-Cheng

2009-03-01

The ubiquitin proteasome pathway has been implicated in carcinogenesis. However, the role of E2-EPF ubiquitin carrier protein (UCP) in esophageal cancer remains relatively unstudied. In the study, we examined the mRNA level of circulating tumor cells from 60 esophageal cancer patients by membrane arrays consisting of a panel of potential markers including UCP, compared to 40 normal populations. The predictive capacity of UCP was also assessed by immunohistochemical staining of a retrospective series of 84 biopsied esophageal squamous cell carcinomas in relation to clinical outcome. In addition, we studied in vitro biological changes including tumor growth, metastatic capacity, and the sensitivity to irradiation and cisplatin, after experimental manipulation of UCP expression in esophageal cancer cells. By the data of 25-gene membrane array analysis, UCP was the only factor significantly associated with the extent of tumor burden in esophageal cancer patients. Our immunochemistry findings further indicate that UCP positivity was linked to poor response to neoadjuvant therapy and worse survival. In cell culture, inhibited UCP significantly decrease tumor growth and the capacity for metastasis. The epithelial-mesenchymal transition (EMT) induced by VHL/HIF-1alpha-TGF-beta1 pathway might be the underlying mechanism responsible to the more aggressive tumor growth in UCP-positive esophageal cancer. Our results suggest that UCP was significantly associated with poor prognosis of esophageal cancer and may be a new molecular target for therapeutic intervention for esophageal squamous cell carcinoma.

Neoadjuvant paclitaxel poliglumex, cisplatin, and radiation for esophageal cancer: a phase 2 trial.

PubMed

Dipetrillo, Thomas; Suntharalingam, Mohan; Ng, Thomas; Fontaine, Jacques; Horiba, Naomi; Oldenburg, Nicklas; Perez, Kimberly; Birnbaum, Ari; Battafarano, Richard; Burrows, Whitney; Safran, Howard

2012-02-01

To evaluate the pathologic complete response (CR) rate and safety of paclitaxel poliglumex (PPX), cisplatin, and concurrent radiation for patients with esophageal cancer. Patients with adenocarcinoma or squamous cell carcinoma of the esophagus or gastroesophageal junction with no evidence of distant metastasis received PPX (50 mg/m(2)/wk) and cisplatin (25 mg/m(2)/wk) for 6 weeks with 50.4 Gy concurrent radiation. Six to eight weeks after completion of chemoradiotherapy, patients underwent surgical resection. Forty patients were enrolled, 37 patients with adenocarcinoma and 3 patients with squamous cell cancer. The treatment-related grade 3 nonhematologic toxicities included esophagitis (7%), nausea (7%), and fatigue (5%). Three patients with clinical endoscopic CR (2 with squamous cell cancer) refused surgery. Twelve of the remaining 37 patients (32%) had a pathologic CR. The 12 patients with pathologic CR all had adenocarcinoma. PPX, cisplatin, and concurrent radiation are well tolerated, easily administered regimen for esophageal cancer with a low incidence of significant esophagitis and a high pathologic CR rate consistent with the preclinical data of PPX and radiation.

Esophageal Xanthoma: Presence of M2 Macrophages Suggests Association with Late Inflammatory and Reparative Processes

PubMed Central

Uehara, Karina; Iwashita, Hidehiko; Tanabe, Yasuka; Kurima, Kiyoto; Oshiro, Mariko; Kina, Shinichiro; Ota, Atsuko; Iwashita, Akinori; Kinjo, Takao

2017-01-01

Abstract Esophageal xanthoma is a rare lesion which is an asymptomatic small yellowish polyp, and most of the reported cases were solitary lesion. Histologically, aggregations of foam cells are found under the papillary hypertrophic squamous epithelium and the foam cells express CD68. The etiology of esophageal xanthoma is unknown. The focal irritation of the esophageal mucosa and infiltrated inflammatory cells are presumed to contribute to its pathogenesis. Although the pathogenesis may be associated with inflammation, the type and nature of the macrophages remain unclear. Here we report a 46-year-old male with esophageal xanthoma, which was incidentally found by endoscopy. Histologically, acute inflammation was not noted, and immunohistochemistry revealed that the foam cells seen in this case of esophageal xanthoma expressed increased levels of M2 macrophage markers. These findings suggest that esophageal xanthoma is associated with late inflammatory and reparative processes long after the initial inflammation of esophageal squamous epithelium. PMID:29071304

BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis

PubMed Central

Jiang, Ming; Ku, Wei-Yao; Zhou, Zhongren; Dellon, Evan S.; Falk, Gary W.; Nakagawa, Hiroshi; Wang, Mei-Lun; Liu, Kuancan; Wang, Jun; Katzka, David A.; Peters, Jeffrey H.; Lan, Xiaopeng; Que, Jianwen

2015-01-01

Tissue homeostasis requires balanced self-renewal and differentiation of stem/progenitor cells, especially in tissues that are constantly replenished like the esophagus. Disruption of this balance is associated with pathological conditions, including eosinophilic esophagitis (EoE), in which basal progenitor cells become hyperplastic upon proinflammatory stimulation. However, how basal cells respond to the inflammatory environment at the molecular level remains undetermined. We previously reported that the bone morphogenetic protein (BMP) signaling pathway is critical for epithelial morphogenesis in the embryonic esophagus. Here, we address how this pathway regulates tissue homeostasis and EoE development in the adult esophagus. BMP signaling was specifically activated in differentiated squamous epithelium, but not in basal progenitor cells, which express the BMP antagonist follistatin. Previous reports indicate that increased BMP activity promotes Barrett’s intestinal differentiation; however, in mice, basal progenitor cell–specific expression of constitutively active BMP promoted squamous differentiation. Moreover, BMP activation increased intracellular ROS levels, initiating an NRF2-mediated oxidative response during basal progenitor cell differentiation. In both a mouse EoE model and human biopsies, reduced squamous differentiation was associated with high levels of follistatin and disrupted BMP/NRF2 pathways. We therefore propose a model in which normal squamous differentiation of basal progenitor cells is mediated by BMP-driven NRF2 activation and basal cell hyperplasia is promoted by disruption of BMP signaling in EoE. PMID:25774506

From blood to breath: New horizons for esophageal cancer biomarkers.

PubMed

Yazbeck, Roger; Jaenisch, Simone E; Watson, David I

2016-12-14

Esophageal cancer is a lethal cancer encompassing adenocarcinoma and squamous cell carcinoma sub-types. The global incidence of esophageal cancer is increasing world-wide, associated with the increased prevalence of associated risk factors. The asymptomatic nature of disease often leads to late diagnosis and five-year survival rates of less than 15%. Current diagnostic tools are restricted to invasive and costly endoscopy and biopsy for histopathology. Minimally and non-invasive biomarkers of esophageal cancer are needed to facilitate earlier detection and better clinical management of patients. This paper summarises recent insights into the development and clinical validation of esophageal cancer biomarkers, focussing on circulating markers in the blood, and the emerging area of breath and odorant biomarkers.

Neoadjuvant Therapy for Esophageal Cancer and Cardiopulmonary Physiology

ClinicalTrials.gov

2018-03-05

Esophageal Cancer; Radiation Pneumonitis; Pulmonary Fibrosis; Respiratory Failure; Pneumonia; Surgery; Chemotherapy Effect; Radiation Fibrosis; Radiation Toxicity; Adenocarcinoma; Squamous Cell Carcinoma

[Expression and significance of immunosuppressive acidic protein (IAP) in human esophageal squamous cell carcinoma].

PubMed

Guo, S Z; Shen, Q; Zhang, H B

1994-03-01

The expression of IAP in the esophageal tissues of 74 patients with esophageal squamous cell carcinoma and 12 normal controls were determined by using MI2, and anti-IAP monoclonal antibody, and ABC immunohistochemical staining. The results showed that there was no expression of IAP in normal esophageal epithelium of all control subjects, and the positive rate in specimens of the esophageal carcinomas was 90.3% (P < 0.001). The staining intensity of IAP was increasing with the decrease in degrees of cell differentiation of the tumors (P < 0.05). The expression of IAP in long survivors without lymph node metastasis were lower than that in cases with metastasis (P < 0.005) and short survivors (P < 0.001). The results suggest that IAP may play an important role in tumor cell differentiation, clinical course and prognosis of esophageal carcinoma, and may be used as a tumor marker for the diagnosis of this malignancy.

Telomerase antagonist imetelstat increases radiation sensitivity in esophageal squamous cell carcinoma

PubMed Central

Wu, Xuping; Zhang, Jing; Yang, Sijun; Kuang, Zhihui; Tan, Guolei; Yang, Gang; Wei, Qichun; Guo, Zhigang

2017-01-01

The morbidity and mortality of esophageal cancer is one of the highest around the world and the principal therapeutic method is radiation. Thus, searching for sensitizers with lower toxicity and higher efficiency to improve the efficacy of radiation therapy is critical essential. Our research group has previously reported that imetelstat, the thio-phosphoramidate oligonucleotide inhibitor of telomerase, can decrease cell proliferation and colony formation ability as well as increase DNA breaks induced by radiation in esophageal cancer cells. Further study in this project showed that imetelstat significantly sensitized esophageal cancer cells to radiation in vitro. Later study showed that imetelstat leads to increased cell apoptosis. We also measured the expression level of several DNA repair and apoptosis signaling proteins. pS345 CHK1, γ-H2AX, p53 and caspase3 expression were up-regulated in imetelstat treated cells, identifying these factors as molecular markers. Mouse in vivo model using imetelstat at clinically achievable concentrations and fractionated irradiation scheme yielded results demonstrating radiosensitization effect. Finally, TUNEL assay, caspase 3 and Ki67 staining in tumor tissue proved that imetelstat sensitized esophageal cancer to radiation in vivo through promoting cell apoptosis and inhibiting cell proliferation. Our study supported imetelstat increase radiation sensitivity of esophageal squamous cell carcinoma through inducing cell apoptosis and the specific inhibitor of telomerase might serve as a potential novel therapeutic tool for esophageal squamous cell carcinoma therapy. PMID:28099140

Telomerase antagonist imetelstat increases radiation sensitivity in esophageal squamous cell carcinoma.

PubMed

Wu, Xuping; Zhang, Jing; Yang, Sijun; Kuang, Zhihui; Tan, Guolei; Yang, Gang; Wei, Qichun; Guo, Zhigang

2017-02-21

The morbidity and mortality of esophageal cancer is one of the highest around the world and the principal therapeutic method is radiation. Thus, searching for sensitizers with lower toxicity and higher efficiency to improve the efficacy of radiation therapy is critical essential. Our research group has previously reported that imetelstat, the thio-phosphoramidate oligonucleotide inhibitor of telomerase, can decrease cell proliferation and colony formation ability as well as increase DNA breaks induced by radiation in esophageal cancer cells. Further study in this project showed that imetelstat significantly sensitized esophageal cancer cells to radiation in vitro. Later study showed that imetelstat leads to increased cell apoptosis. We also measured the expression level of several DNA repair and apoptosis signaling proteins. pS345 CHK1, γ-H2AX, p53 and caspase3 expression were up-regulated in imetelstat treated cells, identifying these factors as molecular markers. Mouse in vivo model using imetelstat at clinically achievable concentrations and fractionated irradiation scheme yielded results demonstrating radiosensitization effect. Finally, TUNEL assay, caspase 3 and Ki67 staining in tumor tissue proved that imetelstat sensitized esophageal cancer to radiation in vivo through promoting cell apoptosis and inhibiting cell proliferation. Our study supported imetelstat increase radiation sensitivity of esophageal squamous cell carcinoma through inducing cell apoptosis and the specific inhibitor of telomerase might serve as a potential novel therapeutic tool for esophageal squamous cell carcinoma therapy.

Esophageal luminal stenosis is an independent prognostic factor in esophageal squamous cell carcinoma.

PubMed

Yang, Yu-Shang; Hu, Wei-Peng; Ni, Peng-Zhi; Wang, Wen-Ping; Yuan, Yong; Chen, Long-Qi

2017-06-27

Predictive value of preoperative endoscopic characteristic of esophageal tumor has not been fully evaluated. The aim of this study is to investigate the impact of esophageal luminal stenosis on survival for patients with resectable esophageal squamous cell carcinoma (ESCC). The clinicopathologic characteristics of 623 ESCC patients who underwent curative resection as the primary treatment between January 2005 and April 2009 were retrospectively reviewed. The esophageal luminal stenosis measured by endoscopy was defined as a uniform measurement preoperatively. The impact of esophageal luminal stenosis on patients' overall survival (OS) and relation with other clinicopathological features were assessed. A Cox regression model was used to identify prognostic factors. The results showed that OS significantly decreased in patients with manifest stenotic tumor compared with patients without luminal obstruction (P<0.05). Considerable esophageal luminal stenosis was associated with a higher T stage, longer tumor length, and poorer differentiation (all P<0.05). In multivariate survival analysis, esophageal luminal stenosis remained as an independent prognostic factor for OS (P= 0.036). Esophageal luminal stenosis could have a significant impact on the OS in patients with resected ESCC and may provide additional prognostic value to the current staging system before any cancer-specific treatment.

Clinicopathologic Features of Submucosal Esophageal Squamous Cell Carcinoma.

PubMed

Emi, Manabu; Hihara, Jun; Hamai, Yoichi; Furukawa, Takaoki; Ibuki, Yuta; Okada, Morihito

2017-12-01

The prognoses of submucosal esophageal squamous cell carcinoma patients vary. Patients with favorable prognoses may receive less invasive or nonsurgical interventions, whereas patients with poor prognoses or advanced esophageal cancer may require aggressive treatments. We sought to identify prognostic factors for patients with submucosal esophageal squamous cell carcinoma, focusing on lymph node metastasis and recurrence. We included 137 submucosal esophageal squamous cell carcinoma patients who had undergone transthoracic esophagectomy with systematic extended lymph node dissection. Submucosal tumors were classified as SM1, SM2, and SM3 according to the depth of invasion. Prognostic factors were determined by univariable and multivariable analyses. Lymph node metastasis was observed in 18.8%, 30.5%, and 50.0% of SM1, SM2, and SM3 cases, respectively. The overall 5-year recurrence rate was 21.9%; the rates for SM1, SM2, and SM3 tumors were 9.4%, 18.6%, and 34.8%, respectively. The SM1 tumors all recurred locoregionally; distant metastasis occurred in SM2 and SM3 cases. The 5-year overall survival rates were 83%, 77%, and 59% for SM1, SM2, and SM3 cases, respectively. On univariable analysis, lymph node metastasis, depth of submucosal invasion (SM3 versus SM1/2), and tumor location (upper thoracic versus mid/lower thoracic) were poor prognostic factors for overall survival. Multivariable Cox regression analyses identified depth of submucosal invasion (hazard ratio 2.51, 95% confidence interval: 1.37 to 4.61) and tumor location (hazard ratio 2.43, 95% confidence interval: 1.18 to 4.63) as preoperative prognostic factors. Tumor location (upper thoracic) and infiltration (SM3) are the worse prognostic factors of submucosal esophageal squamous cell carcinoma, but lymph node metastasis is not a predictor of poorer prognosis. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Ultrasound-Guided Phrenic Nerve Block for Intractable Hiccups following Placement of Esophageal Stent for Esophageal Squamous Cell Carcinoma.

PubMed

Arsanious, David; Khoury, Spiro; Martinez, Edgar; Nawras, Ali; Filatoff, Gregory; Ajabnoor, Hossam; Darr, Umar; Atallah, Joseph

2016-05-01

Hiccups are actions consisting of sudden contractions of the diaphragm and intercostals followed by a sudden inspiration and transient closure of the vocal cords. They are generally short lived and benign; however, in extreme and rare cases, such as esophageal carcinoma, they can become persistent or intractable, up to and involving significant pain, dramatically impacting the patient's quality of life. This case involves a 60-year-old man with a known history of squamous cell carcinoma of the esophagus. He was considered to have high surgical risk, and therefore he received palliative care through the use of fully covered metallic esophageal self-expandable stents due to a spontaneous perforated esophagus, after which he developed intractable hiccups and associated mediastinal pain. Conservative treatment, including baclofen, chlorpromazine, metoclopramide, and omeprazole, provided no relief for his symptoms. The patient was referred to pain management from gastroenterology for consultation on pain control. He ultimately received an ultrasound-guided left phrenic nerve block with bupivacaine and depomedrol, and 3 days later underwent the identical procedure on the right phrenic nerve. This led to complete resolution of his hiccups and associated mediastinal pain. At follow-up, 2 and 4 weeks after the left phrenic nerve block, the patient was found to maintain complete alleviation of the hiccups. Esophageal dilatation and/or phrenic or vagal afferent fiber irritation can be suspected in cases of intractable hiccups secondary to esophageal stenting. Regional anesthesia of the phrenic nerve through ultrasound guidance offers a long-term therapeutic option for intractable hiccups and associated mediastinal pain in selected patients with esophageal carcinoma after stent placement. Esophageal stent, esophageal stenting, intractable hiccups, intractable singultus, phrenic nerve block, phrenic nerve, ultrasound, palliative care, esophageal carcinoma.

Paclitaxel and Carboplatin in Treating Patients With Metastatic or Recurrent Solid Tumors and HIV Infection

ClinicalTrials.gov

2017-12-19

HIV Infection; Recurrent Anal Cancer; Recurrent Breast Cancer; Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Salivary Gland Squamous Cell Carcinoma; Stage IV Anal Cancer; Stage IV Breast Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Unspecified Adult Solid Tumor, Protocol Specific

Barrett's esophagus: photodynamic therapy for ablation of dysplasia, reduction of specialized mucosa and treatment of superficial esophageal cancer

NASA Astrophysics Data System (ADS)

Overholt, Bergein F.; Panjehpour, Masoud

1995-03-01

Fifteen patients with Barrett's esophagus and dysplasia were treated with photodynamic therapy. Four patients also had early, superficial esophageal cancers and 5 had esophageal polyps. Light was delivered via a standard diffuser or a centering esophageal balloon. Eight patients maintained on omeprazole and followed for 6 - 54 months are the subject of this report. Photodynamic therapy ablated dysplastic or malignant mucosa in patients with superficial cancer. Healing and partial replacement of Barrett's mucosa with normal squamous epithelium occurred in all patients and complete replacement with squamous epithelium was found in two. Side effects included photosensitivity and mild-moderate chest pain and dysphagia for 5 - 7 days. In three patients with extensive circumferential mucosal ablation in the proximal esophagus, healing was associated with esophageal strictures which were treated successfully by esophageal dilation. Strictures were not found in the distal esophagus. Photodynamic therapy combined with long-term acid inhibition provides effective endoscopic therapy of Barrett's mucosal dysplasia and superficial (Tis-T1) esophageal cancer. The windowed centering balloon improves delivery of photodynamic therapy to diffusely abnormal esophageal mucosa.

Personalized targeted therapy for esophageal squamous cell carcinoma

PubMed Central

Kang, Xiaozheng; Chen, Keneng; Li, Yicheng; Li, Jianying; D'Amico, Thomas A; Chen, Xiaoxin

2015-01-01

Esophageal squamous cell carcinoma continues to heavily burden clinicians worldwide. Researchers have discovered the genomic landscape of esophageal squamous cell carcinoma, which holds promise for an era of personalized oncology care. One of the most pressing problems facing this issue is to improve the understanding of the newly available genomic data, and identify the driver-gene mutations, pathways, and networks. The emergence of a legion of novel targeted agents has generated much hope and hype regarding more potent treatment regimens, but the accuracy of drug selection is still arguable. Other problems, such as cancer heterogeneity, drug resistance, exceptional responders, and side effects, have to be surmounted. Evolving topics in personalized oncology, such as interpretation of genomics data, issues in targeted therapy, research approaches for targeted therapy, and future perspectives, will be discussed in this editorial. PMID:26167067

Evaluation of HPV, CMV, HSV and EBV in esophageal squamous cell carcinomas from a high-incidence area of China.

PubMed

Chang, F; Syrjänen, S; Shen, Q; Cintorino, M; Santopietro, R; Tosi, P; Syrjänen, K

2000-01-01

Certain viruses, notably human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV) and Epstein-Barr virus (EBV), are known to produce tumors in animals and cell transformation in vitro and they have been implicated in the pathogenesis of human cancers. All these viruses are also known to infect the esophagus. This study was aimed to determine whether these viruses play any causal role in the etiology of esophageal squamous cell carcinoma. A series of 103 esophageal squamous cell carcinomas derived from patients in the high-incidence area of northern China were analyzed by DNA in situ hybridization and polymerase chain reaction (PCR) for the presence of HPV DNA sequences and, using immunohistochemistry, for the demonstration of CMV, HSV and EBV infections. Six (5.8%) of the 103 tumors were found to contain HPV 16, 18 or 30 DNA sequences. HPV types 6, 11 and 53 were not detected in any of the cases. Amplified HPV DNA sequences were found in 17 out of 101 (16.8%) carcinoma specimens by PCR with L1 consensus primers. None of the 103 carcinomas tested was immunohistochemically positive for CMV, HSV or EBV. Our results confirmed the HPV involvement in esophageal carcinomas and provided further evidence to support a causal association of HPV infection with esophageal squamous cell carcinoma. However, the three herpesviruses, CMV, HSV and EBV, are highly unlikely to be involved in the pathogenesis of this malignancy in the high-incidence area of China.

From blood to breath: New horizons for esophageal cancer biomarkers

PubMed Central

Yazbeck, Roger; Jaenisch, Simone E; Watson, David I

2016-01-01

Esophageal cancer is a lethal cancer encompassing adenocarcinoma and squamous cell carcinoma sub-types. The global incidence of esophageal cancer is increasing world-wide, associated with the increased prevalence of associated risk factors. The asymptomatic nature of disease often leads to late diagnosis and five-year survival rates of less than 15%. Current diagnostic tools are restricted to invasive and costly endoscopy and biopsy for histopathology. Minimally and non-invasive biomarkers of esophageal cancer are needed to facilitate earlier detection and better clinical management of patients. This paper summarises recent insights into the development and clinical validation of esophageal cancer biomarkers, focussing on circulating markers in the blood, and the emerging area of breath and odorant biomarkers. PMID:28028355

Current treatment options for the management of esophageal cancer

PubMed Central

Mawhinney, Mark R; Glasgow, Robert E

2012-01-01

In recent years, esophageal cancer characteristics and management options have evolved significantly. There has been a sharp increase in the frequency of esophageal adenocarcinoma and a decline in the frequency of squamous cell carcinoma. A more comprehensive understanding of prognostic factors influencing outcome has also been developed. This has led to more management options for esophageal cancer at all stages than ever before. A multidisciplinary, team approach to management in a high volume center is the preferred approach. Each patient should be individually assessed based on type of cancer, local or regional involvement, and his or her own functional status to determine an appropriate treatment regimen. This review will discuss management of esophageal cancer relative to disease progression and patient functional status. PMID:23152702

African-American esophageal squamous cell carcinoma expression profile reveals dysregulation of stress response and detox networks.

PubMed

Erkizan, Hayriye Verda; Johnson, Kory; Ghimbovschi, Svetlana; Karkera, Deepa; Trachiotis, Gregory; Adib, Houtan; Hoffman, Eric P; Wadleigh, Robert G

2017-06-19

Esophageal carcinoma is the third most common gastrointestinal malignancy worldwide and is largely unresponsive to therapy. African-Americans have an increased risk for esophageal squamous cell carcinoma (ESCC), the subtype that shows marked variation in geographic frequency. The molecular architecture of African-American ESCC is still poorly understood. It is unclear why African-American ESCC is more aggressive and the survival rate in these patients is worse than those of other ethnic groups. To begin to define genetic alterations that occur in African-American ESCC we conducted microarray expression profiling in pairs of esophageal squamous cell tumors and matched control tissues. We found significant dysregulation of genes encoding drug-metabolizing enzymes and stress response components of the NRF2- mediated oxidative damage pathway, potentially representing key genes in African-American esophageal squamous carcinogenesis. Loss of activity of drug metabolizing enzymes would confer increased sensitivity of esophageal cells to xenobiotics, such as alcohol and tobacco smoke, and may account for the high incidence and aggressiveness of ESCC in this ethnic group. To determine whether certain genes are uniquely altered in African-American ESCC we performed a meta-analysis of ESCC expression profiles in our African-American samples and those of several Asian samples. Down-regulation of TP53 pathway components represented the most common feature in ESCC of all ethnic groups. Importantly, this analysis revealed a potential distinctive molecular underpinning of African-American ESCC, that is, a widespread and prominent involvement of the NRF2 pathway. Taken together, these findings highlight the remarkable interplay of genetic and environmental factors in the pathogenesis of African-American ESCC.

Comparison of manual and mechanical cervical esophagogastric anastomosis after esophageal resection for squamous cell carcinoma: a prospective randomized controlled trial.

PubMed

Hsu, Hsao-Hsun; Chen, Jin-Shing; Huang, Pei-Ming; Lee, Jang-Ming; Lee, Yung-Chie

2004-06-01

The use of a circular stapler in cervical esophagogastric anastomosis remains controversial. This study was to compare the postoperative and long-term results of manual and mechanical techniques for cervical esophagogastric anastomosis after resection for squamous cell carcinoma. A prospective randomized controlled trial was undertaken in 63 patients with curatively resectable squamous cell cancer of the thoracic esophagus between 1996 and 1999. Patients were randomized to receive either a hand-sewn (32 patients) or circular stapled (31 patients) cervical esophagogastric anastomosis. The mean operating time was longer when the hand-sewn method was used (524 vs. 447 min, P < 0.001). Anastomotic leakage was noted in seven patients (22%) in the hand-sewn group and eight patients (26%) in the stapler group (P = NS). Hospital mortality occurred in four patients (13%) of the hand-sewn group and in three patients (10%) of the stapler group (P = NS). After the operation, four patients (14%) in the hand-sewn group and five patients (18%) in the stapler group developed a benign esophageal stricture (P = NS). The mean follow-up time was 24 months, and the rates of freedom from benign stricture and survival were comparable in each group. Performing cervical esophagogastric anastomoses using a circular mechanical stapler had a shorter operating time and a comparable outcome to the hand-sewn method. The circular mechanical stapler could be used as an alternative for cervical esophagogastric anastomosis after resection for esophageal squamous cell cancer.

Endoscopic screening for synchronous esophageal neoplasia among patients with incident head and neck cancer: Prevalence, risk factors, and outcomes.

PubMed

Wang, Yao-Kuang; Chuang, Yun-Shiuan; Wu, Tzung-Shiun; Lee, Ka-Wo; Wu, Che-Wei; Wang, Hsiang-Chen; Kuo, Chie-Tong; Lee, Chien-Hung; Kuo, Wen-Rei; Chen, Chung-Ho; Wu, Deng-Chyang; Wu, I-Chen

2017-11-15

Esophageal squamous-cell neoplasia (ESCN) is a common second primary neoplasia found in patients with head-and-neck squamous-cell carcinoma (HNSCC). This study sought to identify the risk factors for synchronous ESCN and how they influence survival in HNSCC patient. Eight hundred and fifteen incident HNSCC patients were prospectively recruited for endoscopy screening for ESCN using white-light imaging, narrow-band imaging, Lugol chromoendoscopy, and pathological confirmation. Associated lifestyle and clinicopathological data were collected. The interquartile follow-up period cutoffs were 11.3, 20.5 and 34.9 months. 124 patients (15.2%) were diagnosed as having synchronous ESCN (66 low-grade dysplasia, 29 high-grade dysplasia, and 29 esophageal squamous-cell carcinoma). Consumption of alcohol, but not betel nut or cigarette, was significantly associated with the presence of synchronous ESCN (adjusted odds ratio [aOR] = 7.1 and 10.9 for former and current drinkers, respectively). There was an interaction between cumulative dose of alcohol consumption and alcohol flushing response on the development of ESCN. High-dose drinkers with flush response were 16.9 times more likely to have esophageal high-grade dysplasia/SCC than non-drinkers. Compared with oral cavity cancer patients, those with hypopharyngeal, laryngeal and oropharyngeal cancer were 6.8, 4.6 and 2.8 times more likely to have esophageal high-grade dysplasia/SCC. HNSCC patients with synchronous ESCN had lower overall survival than those without (p < 0.0001). In conclusion, surveillance of ESCN is strongly recommended for the high-risk subpopulation of HNSCC patients, especially drinkers who have a flush response to alcohol, and those with distant metastasis of index cancer and cancers in hypopharynx, oropharynx and larynx. © 2017 UICC.

Biomarkers Predict Prognosis of Esophageal Cancer Patients | Center for Cancer Research

Cancer.gov

New treatment strategies are needed to improve outcomes for patients with esophageal cancer. With five-year survival rates less than 25 percent, this is one of the deadliest forms of cancer. There are two main types of esophageal cancer—squamous cell carcinoma and adenocarcinoma. Esophageal adenocarcinoma is frequently preceded by Barrett’s esophagus, a chronic inflammatory

The role of PD-L1 in the radiation response and prognosis for esophageal squamous cell carcinoma related to IL-6 and T-cell immunosuppression.

PubMed

Chen, Miao-Fen; Chen, Ping-Tsung; Chen, Wen-Cheng; Lu, Ming-Shian; Lin, Paul-Yang; Lee, Kuan Der

2016-02-16

The aim of this study was to assess the significance of programmed cell death 1 ligand 1 (PD-L1) in esophageal squamous cell carcinoma (ESCC) and its association with IL-6 and radiation response. Weretrospectively enrolled 162 patients with ESCC, and examined the correlation between PD-L1 levels and clinical outcomes in esophageal cancer patients. Furthermore, the human esophageal SCC cell line CE81T and TE2 were selected for cellular experiments to investigate the role of PD-L1 in T cell functions and radiation response. Here we demonstrated that PD-L1 expression was significantly higher in esophageal cancer specimens than in non-malignant epithelium. In clinical outcome analysis, this staining of PD-L1 was positively linked to the clinical T4 stage (p=0.004), development of LN metastasis (p=0.012) and higher loco-regional failure rate (p=0.0001). In addition, the frequency of PD-L1 immunoreactivity was significantly higher in IL-6-positive esophageal cancer specimens. When IL-6 signaling was inhibited in vitro, the level of PD-L1 is significantly down-regulated. PD-L1 is a significant predictor for poor treatment response and shorter survival.As demonstrated through in vitro experiments, Irradiation increased PD-L1 expression in human esophageal cancer cells. The inhibition of T cell functions including proliferation and cytotoxicity against tumor cells might be the mechanisms responsible to the role of PD-L1 in radiation response. In conclusion, PD-L1 is important in determining the radiation response and could predict the prognosis of patients with esophageal SCC. Therefore, we suggest inhibition of PD-L1 as a potential strategy for the treatment of esophageal SCC.

Breast mass as the initial presentation of esophageal carcinoma: a case report

PubMed Central

Norooz, Mohammad Tayefeh; Ahmadi, Hamed; Zavarei, Mansour Jamali; Daryaei, Parviz

2009-01-01

Introduction Esophageal cancer is considered as a fatal malignancy. It mostly metastasizes to lung, liver, and bone while breast metastasis has been rarely reported. This is the fifth report of metastatic breast cancer from esophageal cancer, which differs from previous reported cases in terms of initial presentation with metastatic breast mass and no metastatic involvement of other organs. Case presentation We present a 35-year-old Caucasian woman who initially complained of a painful breast mass. Squamous pearls on cytologic evaluation suggested a metastatic lesion. Two months history of dysphagia was extracted through detailed interview with patient and further investigation revealed a stage IV esophageal squamous cell carcinoma. Conclusion In this case, breast lesion as an unusual presentation of esophageal carcinoma emphasizes the great role of thorough medical history taking and cytologic study in evaluating an accidentally detected breast mass. The increasing reports of breast metastasis in patients with esophageal carcinoma necessitate the careful breast examination in visits after treatment of the primary tumor. PMID:19829901

[Esophageal papilloma: case report, molecular identification of human papillomavirus and literature review].

PubMed

Barbaglia, Yanina; Jiménez, Félix; Tedeschi, Fabián; Zalazar, Fabián

2013-09-01

sophageal squamous papilloma is an uncommon, usually asymptomatic, benign tumor of the squamous epithelium consisting of a raised, sessile, small and round (smooth or rough) lesion. The prevalence is between 0.01 and 0.45% of cases, with a male/female ratio of 3:1. The etiology and pathogenesis appear to be a mechanical or chemical irritation of the mucosa in addition to the presence of human papillomavirus (HPV), important agent in the evolution to a squamous carcinoma, especially HPV types 16 and 18. In this paper, we describe a case of esophageal papilloma whose diagnosis involved endoscopic images, pathological studies and detection of viral DNA by polymerase chain reaction. By using molecular techniques (PCR-RFLP) a profile consistent with HPV type 16 has been obtained. The patient underwent polypectomy and currently, after 3 years of diagnosis, he remains asymptomatic. This work is one of the first national reports of a patient with esophageal papilloma in which one of the most frequently HPV genotypes associated with esophageal carcinoma (HPV 16) has been detected.

New York esophageal squamous cell carcinoma-1 and cancer immunotherapy.

PubMed

Esfandiary, Ali; Ghafouri-Fard, Soudeh

2015-01-01

New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is a known cancer testis gene with exceptional immunogenicity and prevalent expression in many cancer types. These characteristics have made it an appropriate vaccine candidate with the potential application against various malignancies. This article reviews recent knowledge about the NY-ESO-1 biology, function, immunogenicity and expression in cancers as well as and the results of clinical trials with this antigen.

Polycyclic Aromatic Hydrocarbons and Esophageal Squamous Cell Carcinoma-A Review

PubMed Central

Roshandel, Gholamreza; Semnani, Shahryar; Malekzadeh, Reza; Dawsey, Sanford M.

2018-01-01

Esophageal cancer (EC) is the 8th most common cancer and the 6th most frequent cause of cancer mortality worldwide. Esophageal squamous cell carcinoma (ESCC) is the most common type of EC. Exposure to polycyclic aromatic hydrocarbons (PAHs) has been suggested as a risk factor for developing ESCC. In this paper we will review different aspects of the relationship between PAH exposure and ESCC. PAHs are a group of compounds that are formed by incomplete combustion of organic matter. Studies in humans have shown an association between PAH exposure and development of ESCC in many populations. The results of a recent case-control study in a high risk population in northeastern Iran showed a dramatic dose-response relationship between PAH content in non-tumor esophageal tissue (the target tissue for esophageal carcinogenesis) and ESCC case status, consistent with a causal role for PAH exposure in the pathogenesis of ESCC. Identifying the main sources of exposure to PAHs may be the first and most important step in designing appropriate PAH-reduction interventions for controlling ESCC, especially in high risk areas. Coal smoke and drinking mate have been suggested as important modifiable sources of PAH exposure in China and Brazil, respectively. But the primary source of exposure to PAHs in other high risk areas for ESCC, such as northeastern Iran, has not yet been identified. Thus, environmental studies to determining important sources of PAH exposure should be considered as a high priority in future research projects in these areas. PMID:23102250

Esophageal luminal stenosis is an independent prognostic factor in esophageal squamous cell carcinoma

PubMed Central

Yang, Yu-Shang; Hu, Wei-Peng; Ni, Peng-Zhi; Wang, Wen-Ping; Yuan, Yong; Chen, Long-Qi

2017-01-01

Background Predictive value of preoperative endoscopic characteristic of esophageal tumor has not been fully evaluated. The aim of this study is to investigate the impact of esophageal luminal stenosis on survival for patients with resectable esophageal squamous cell carcinoma (ESCC). Methods The clinicopathologic characteristics of 623 ESCC patients who underwent curative resection as the primary treatment between January 2005 and April 2009 were retrospectively reviewed. The esophageal luminal stenosis measured by endoscopy was defined as a uniform measurement preoperatively. The impact of esophageal luminal stenosis on patients’ overall survival (OS) and relation with other clinicopathological features were assessed. A Cox regression model was used to identify prognostic factors. Results The results showed that OS significantly decreased in patients with manifest stenotic tumor compared with patients without luminal obstruction (P<0.05). Considerable esophageal luminal stenosis was associated with a higher T stage, longer tumor length, and poorer differentiation (all P<0.05). In multivariate survival analysis, esophageal luminal stenosis remained as an independent prognostic factor for OS (P= 0.036). Conclusions Esophageal luminal stenosis could have a significant impact on the OS in patients with resected ESCC and may provide additional prognostic value to the current staging system before any cancer-specific treatment. PMID:28118615

Bevacizumab and Combination Chemotherapy Before Surgery in Treating Patients With Locally Advanced Esophageal or Stomach Cancer

ClinicalTrials.gov

2018-02-23

Adenocarcinoma of the Esophagus; Adenocarcinoma of the Gastroesophageal Junction; Diffuse Adenocarcinoma of the Stomach; Intestinal Adenocarcinoma of the Stomach; Mixed Adenocarcinoma of the Stomach; Squamous Cell Carcinoma of the Esophagus; Stage IA Esophageal Cancer; Stage IA Gastric Cancer; Stage IB Esophageal Cancer; Stage IB Gastric Cancer; Stage IIA Esophageal Cancer; Stage IIA Gastric Cancer; Stage IIB Esophageal Cancer; Stage IIB Gastric Cancer; Stage IIIA Esophageal Cancer; Stage IIIA Gastric Cancer; Stage IIIB Esophageal Cancer; Stage IIIB Gastric Cancer; Stage IIIC Esophageal Cancer; Stage IIIC Gastric Cancer

Photodynamic therapy in early esophageal squamous cell carcinoma

NASA Astrophysics Data System (ADS)

Spinelli, Pasquale; Dal Fante, Marco; Mancini, Andrea; Massetti, Renato; Meroni, Emmanuele

1995-03-01

From 1/1985 to 7/1993, 18 patients underwent endoscopic photodynamic therapy (PDT) for early stage esophageal squamous cell carcinoma -- as two patients had two synchronous esophageal cancers, 20 lesions were treated. Tumors were staged as Tis in 7 cases and T1 in 13. The average light energy delivered was 50 J/cm2 and 70 J/cm2 for the treatment of Tis and T1, respectively. To obtain a more uniform distribution of laser light in 12 cases the irradiation was performed through the wall of a transparent tube previously placed over the endoscope and advanced into the stomach. The overall results show a complete response in 14/20 (70%) tumors. Three patients developed a local recurrence, 6, 12, and 14 months after therapy. After a follow-up of 5 to 75 months, there was no evidence of disease in 10/18 patients (56%). The actuarial survival rate was 95%, 79%, and 26% at 1, 3, and 5 years, respectively. Complications were skin reaction in one patient and esophageal stenosis at the treatment site, that gradually responded to endoscopic bougienage, in 2 patients. Endoscopic PDT proved to be safe and effective in the treatment of superficial carcinoma of the esophagus.

Squamous cell carcinoma antigen (SCCA) is up-regulated during Barrett’s carcinogenesis and predicts esophageal adenocarcinoma resistance to neoadjuvant chemotherapy

PubMed Central

Fassan, Matteo; Realdon, Stefano; Vianello, Luca; Quarta, Santina; Ruol, Alberto; Castoro, Carlo; Scarpa, Marco; Zaninotto, Giovanni; Guzzardo, Vincenza; Sileni, Vanna Chiarion; Pontisso, Patrizia; Rugge, Massimo

2017-01-01

Squamous Cell Carcinoma Antigen (SCCA) is consistently overexpressed in many different solid tumors, and has been associated with both tumor aggressiveness and chemoresistance. No data, however, is currently available on SCCA expression during esophageal Barrett's carcinogenesis, nor on SCCA expression's role on esophageal adenocarcinoma chemoresistance. The SCCA immunohistochemical expression was assessed in a series of 100 biopsy samples covering the whole histological spectrum of Barrett's oncogenesis. Squamous native mucosa was characterized by a moderate to strong cytoplasmic and nuclear SCCA expression in suprabasal, medium, and superficial layers. On the other hand, almost half of the considered lesions did not express SCCA; the other half featured weak to moderate SCCA expression. The relationship between SCCA protein expression and tumor response to neoadjuvant chemotherapy was assessed in 90 esophageal adenocarcinoma specimens (40 biopsy and 50 surgery specimens), stratified according to Mandard tumor regression grade. As observed in other settings, the presence of SCCA expression clustered in the group of tumors characterized by a lower responsiveness to neoadjuvant treatments. The present results suggest an involvement of SCCA in a subset of Barrett-related tumors, and prompt to consider the SCCA-protein expression as response-predictive marker of neoadjuvant therapy in esophageal adenocarcinomas. PMID:28042960

Review of the gut microbiome and esophageal cancer: Pathogenesis and potential clinical implications.

PubMed

Baba, Yoshifumi; Iwatsuki, Masaaki; Yoshida, Naoya; Watanabe, Masayuki; Baba, Hideo

2017-06-01

Esophageal cancer ranks among the most aggressive malignant diseases. The limited improvements in treatment outcomes provided by conventional therapies have prompted us to seek innovative strategies for treating this cancer. More than 100 trillion microorganisms inhabit the human intestinal tract and play a crucial role in health and disease conditions, including cancer. The human intestinal microbiome is thought to influence tumor development and progression in the gastrointestinal tract by various mechanisms. For example, Fusobacterium nucleatum , which primarily inhabits the oral cavity and causes periodontal disease, might contribute to aggressive tumor behavior through activation of chemokines such as CCL20 in esophageal cancer tissue. Composition of the intestinal microbiota is influenced by diet, lifestyle, antibiotics, and pro- and prebiotics. Therefore, by better understanding how the bacterial microbiota contributes to esophageal carcinogenesis, we might develop novel cancer prevention and treatment strategies through targeting the gastrointestinal microflora. This review discusses the current knowledge, available data and information on the relationship of microbiota with esophagitis, Barrett's esophagus, esophageal adenocarcinoma and squamous cell carcinoma.

Is there a role of whole-body bone scan in patients with esophageal squamous cell carcinoma

PubMed Central

2012-01-01

Background Correct detection of bone metastases in patients with esophageal squamous cell carcinoma is pivotal for prognosis and selection of an appropriate treatment regimen. Whole-body bone scan for staging is not routinely recommended in patients with esophageal squamous cell carcinoma. The aim of this study was to investigate the role of bone scan in detecting bone metastases in patients with esophageal squamous cell carcinoma. Methods We retrospectively evaluated the radiographic and scintigraphic images of 360 esophageal squamous cell carcinoma patients between 1999 and 2008. Of these 360 patients, 288 patients received bone scan during pretreatment staging, and sensitivity, specificity, positive predictive value, and negative predictive value of bone scan were determined. Of these 360 patients, surgery was performed in 161 patients including 119 patients with preoperative bone scan and 42 patients without preoperative bone scan. Among these 161 patients receiving surgery, 133 patients had stages II + III disease, including 99 patients with preoperative bone scan and 34 patients without preoperative bone scan. Bone recurrence-free survival and overall survival were compared in all 161 patients and 133 stages II + III patients, respectively. Results The diagnostic performance for bone metastasis was as follows: sensitivity, 80%; specificity, 90.1%; positive predictive value, 43.5%; and negative predictive value, 97.9%. In all 161 patients receiving surgery, absence of preoperative bone scan was significantly associated with inferior bone recurrence-free survival (P = 0.009, univariately). In multivariate comparison, absence of preoperative bone scan (P = 0.012, odds ratio: 5.053) represented the independent adverse prognosticator for bone recurrence-free survival. In 133 stages II + III patients receiving surgery, absence of preoperative bone scan was significantly associated with inferior bone recurrence-free survival (P = 0.003, univariately) and overall survival (P = 0.037, univariately). In multivariate comparison, absence of preoperative bone scan was independently associated with inferior bone recurrence-free survival (P = 0.009, odds ratio: 5.832) and overall survival (P = 0.029, odds ratio: 1.603). Conclusions Absence of preoperative bone scan was significantly associated with inferior bone recurrence-free survival, suggesting that whole-body bone scan should be performed before esophagectomy in patients with esophageal squamous cell carcinoma, especially in patients with advanced stages. PMID:22853826

Meat consumption and risk of esophageal and gastric cancer in a large prospective study.

PubMed

Cross, Amanda J; Freedman, Neal D; Ren, Jiansong; Ward, Mary H; Hollenbeck, Albert R; Schatzkin, Arthur; Sinha, Rashmi; Abnet, Christian C

2011-03-01

Red and processed meats could increase cancer risk through several potential mechanisms involving iron, heterocyclic amines, polycyclic aromatic hydrocarbons, and N-nitroso compounds. Although there have been multiple studies of meat and colorectal cancer, other gastrointestinal malignancies are understudied. We estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between meat, meat components, and meat cooking by-products and risk of esophageal or gastric cancer in a large cohort study. During ∼10 years of follow-up, we accrued 215 esophageal squamous cell carcinomas, 630 esophageal adenocarcinomas, 454 gastric cardia adenocarcinomas, and 501 gastric non-cardia adenocarcinomas. Red meat intake was positively associated with esophageal squamous cell carcinoma (HR for the top versus bottom quintile=1.79, 95% CI: 1.07-3.01, P for trend=0.019). Individuals in the highest intake quintile of 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) had an increased risk for gastric cardia cancer (HR=1.44, 95% CI: 1.01-2.07, P for trend=0.104). Furthermore, those in the highest quintile of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), or heme iron intake had a suggestive increased risk for esophageal adenocarcinoma (HR=1.35, 95% CI: 0.97-1.89, P for trend=0.022; HR=1.45, 95% CI: 0.99-2.12, P for trend=0.463; or HR=1.47, 95% CI: 0.99-2.20, P for trend=0.063, respectively). Benzo[a]pyrene, nitrate, and nitrite were not associated with esophageal or gastric cancer. We found positive associations between red meat intake and esophageal squamous cell carcinoma, and between DiMeIQx intake and gastric cardia cancer.

Variety in vegetable and fruit consumption and the risk of gastric and esophageal cancer in the European Prospective Investigation into Cancer and Nutrition.

PubMed

Jeurnink, S M; Büchner, F L; Bueno-de-Mesquita, H B; Siersema, P D; Boshuizen, H C; Numans, M E; Dahm, C C; Overvad, K; Tjønneland, A; Roswall, N; Clavel-Chapelon, F; Boutron-Ruault, M C; Morois, S; Kaaks, R; Teucher, B; Boeing, H; Buijsse, B; Trichopoulou, A; Benetou, V; Zylis, D; Palli, D; Sieri, S; Vineis, P; Tumino, R; Panico, S; Ocké, M C; Peeters, P H M; Skeie, G; Brustad, M; Lund, E; Sánchez-Cantalejo, E; Navarro, C; Amiano, P; Ardanaz, E; Ramón Quirós, J; Hallmans, G; Johansson, I; Lindkvist, B; Regnér, S; Khaw, K T; Wareham, N; Key, T J; Slimani, N; Norat, T; Vergnaud, A C; Romaguera, D; Gonzalez, C A

2012-09-15

Diets high in vegetables and fruits have been suggested to be inversely associated with risk of gastric cancer. However, the evidence of the effect of variety of consumption is limited. We therefore investigated whether consumption of a variety of vegetables and fruit is associated with gastric and esophageal cancer in the European Prospective Investigation into Cancer and Nutrition study. Data on food consumption and follow-up on cancer incidence were available for 452,269 participants from 10 European countries. After a mean follow-up of 8.4 years, 475 cases of gastric and esophageal adenocarcinomas (180 noncardia, 185 cardia, gastric esophageal junction and esophagus, 110 not specified) and 98 esophageal squamous cell carcinomas were observed. Diet Diversity Scores were used to quantify the variety in vegetable and fruit consumption. We used multivariable Cox proportional hazard models to calculate risk ratios. Independent from quantity of consumption, variety in the consumption of vegetables and fruit combined and of fruit consumption alone were statistically significantly inversely associated with the risk of esophageal squamous cell carcinoma (continuous hazard ratio per 2 products increment 0.88; 95% CI 0.79-0.97 and 0.76; 95% CI 0.62-0.94, respectively) with the latter particularly seen in ever smokers. Variety in vegetable and/or fruit consumption was not associated with risk of gastric and esophageal adenocarcinomas. Independent from quantity of consumption, more variety in vegetable and fruit consumption combined and in fruit consumption alone may decrease the risk of esophageal squamous cell carcinoma. However, residual confounding by lifestyle factors cannot be excluded. Copyright © 2012 UICC.

Genomic and Epigenomic Aberrations in Esophageal Squamous Cell Carcinoma and Implications for Patients

PubMed Central

Lin, De-Chen; Wang, Ming-Rong; Koeffler, H. Phillip

2018-01-01

Esophageal squamous cell carcinoma (ESCC) is a common malignancy without effective therapy. The exomes of more than 600 ESCCs have been sequenced in the past 4 years, and numerous key aberrations have been identified. Recently, researchers reported both inter- and intratumor heterogeneity. Although these are interesting observations, their clinical implications are unclear due to the limited number of samples profiled. Epigenomic alterations, such as changes in DNA methylation, histone acetylation, and RNA editing, also have been observed in ESCCs. However, it is not clear what proportion of ESCC cells carry these epigenomic aberrations or how they contribute to tumor development. We review the genomic and epigenomic characteristics of ESCCs, with a focus on emerging themes. We discuss their clinical implications and future research directions. PMID:28757263

Safety and benefit of curative surgical resection for esophageal squamous cell cancer associated with multiple primary cancers.

PubMed

Otowa, Y; Nakamura, T; Takiguchi, G; Yamamoto, M; Kanaji, S; Imanishi, T; Oshikiri, T; Suzuki, S; Tanaka, K; Kakeji, Y

2016-03-01

Enhancements in surgical techniques have led to improved outcomes for esophageal cancer. Recent findings have showed that esophageal cancer is frequently associated with multiple primary cancers, and surgical resection is usually complicated in such cases. The aim of this study was to clarify the clinical significance of surgery for patients with esophageal squamous cell cancer associated with multiple primary cancers. The clinical outcomes of surgical resection for esophageal cancer were compared among 79 patients with antecedent and/or synchronous cancers (Multiple cancer group) and 194 patients without antecedent and/or synchronous cancers (Single cancer group). The most common site of multiple primary cancers was the pharynx (36 patients; 29.7%), followed by the stomach (24 patients; 19.8%). The reconstruction method was more complicated in the Multiple cancer group as a result of the prolonged surgery time and increased blood loss. However, postoperative morbidity and overall survival (OS) did not differ between the two groups. After esophagectomy, metachronous cancers were observed in 26 patients, with 30 regions in total, and 93.1% were found to be curable. Sex was the only independent risk factors for developing metachronous cancer after esophagectomy. The presence of antecedent and synchronous cancers complicates the surgical resection of esophageal cancer; however, no differences were found in the OS and postoperative morbidity between the two groups. Therefore, surgical intervention should be selected as a first-line treatment. Because second primary cancers are often observed in esophageal cancer, we recommend a close follow-up using esophagogastroduodenoscopy and contrast-enhanced computed tomography. Copyright © 2015 Elsevier Ltd. All rights reserved.

Longitudinal study of esophageal mucosal damage after esophagectomy and gastric interposition: relationship between reflux-related mucosal injury and Notch signaling

PubMed Central

Yuan, Yong; Tong, Tie-Jun; Zeng, Xiao-Xi; Yang, Yu-Shang; Wang, Zhi-Qiang; Wang, Yun-Cang; Gou, Jun-He

2017-01-01

Background Esophagectomy with gastric interposition could serve as a good human reflux model to study the molecular pathogenesis of esophageal mucosal damage induced by gastroesophageal reflux. This study was to investigate the role of Notch signaling in reflux injury of esophageal mucosa. Methods Patients undergoing Ivor-Lewis esophagectomy for early stage esophageal squamous cell carcinoma were included. Follow-ups were scheduled at 6, 18, 36 and 48 months postoperatively, including reflux symptom assessment, endoscopic and histological evaluation of esophageal mucosal damage. The expressions of Notch1 and its downstream target gene Hes1 were evaluated by real-time polymerase chain reaction (PCR) and immunohistochemistry (IHC). Results Forty-four out of 48 patients completed four follow-ups. Injuries of esophageal remnant confirmed by endoscopical and histological examinations were both more often with a longer postoperative period (P<0.05). The mRNA expression levels of Notch1 and Hes1 were decreased in a time-dependent manner after operation (P<0.001). Notch1 and Hes1 mRNA levels were significantly higher in normal squamous mucosa than in esophagitis, and higher in esophagitis than in metaplasia (P<0.05). Immunohistochemical study also demonstrated a similar protein expression pattern. Samples with endoscopic evidence of mucosal damage exhibited lower expression of Notch1 mRNA levels as compared to biopsies without visualized damage (P=0.035). Conclusions This is the first longitudinal study on Notch signaling in human esophagectomy model, our preliminary findings suggest decreased Notch signaling might be involved in the development of mucosa damage caused by gastroesophageal reflux. PMID:29312733

Decreased expression of GST pi is correlated with a poor prognosis in human esophageal squamous carcinoma

PubMed Central

2010-01-01

Background Glutathione S-transferase pi (GST pi) is a subgroup of GST family, which provides cellular protection against free radical and carcinogenic compounds due to its detoxifying function. Expression patterns of GST pi have been studied in several carcinomas and its down-regulation was implicated to be involved in malignant transformation in patients with Barrett's esophagus. However, neither the exact role of GST pi in the pathogenesis nor its prognostic impact in squamous esophageal carcinoma is fully characterized. Methods Immunohistochemistry was used to investigate GST pi expression on 153 archival squamous esophageal carcinoma specimens with a GST pi monoclonal antibody. Statistic analyses were performed to explore its association with clinicopathological factors and clinical outcome. Results The GST pi expression was greatly reduced in tissues of esophageal carcinomas compared to adjacent normal tissues and residual benign tissues. Absent of GST pi protein expression in cytoplasm, nuclear and cytoplasm/nucleus was found in 51%, 64.7% and 48% of all the carcinoma cases, respectively. GST pi deficiency in cytoplasm, nucleus and cytoplasm/nucleus was significantly correlated to poor differentiation (p < 0.001, p < 0.001 and p < 0.001, respectively). UICC stage and T stage were found significantly correlated to negative expression of GST pi in cytoplasm (p < 0.001 and p = 0.004, respectively) and cytoplasm/nucleus (p = 0.017 and p = 0.031, respectively). In univariate analysis, absent of GST pi protein expression in cytoplasm, nucleus and cytoplasm/nucleus was significantly associated with a shorter overall survival (p < 0.001, p < 0.001 and p < 0.001, respectively), whereas only GST pi cytoplasmic staining retained an independent prognostic significance (p < 0.001) in multivariate analysis. Conclusions Our results show that GST pi expression is down regulated in the squamous esophageal carcinoma, and that the lack of GST pi expression is associated with poor prognosis. Therefore, deficiency of GST pi protein expression may be an important mechanism involved in the carcinogenesis and progression of the squamous esophageal carcinoma, and the underlying mechanisms leading to decreased GST pi expression deserve further investigation. PMID:20602752

Differential role of microRNAs in the pathogenesis and treatment of Esophageal cancer.

PubMed

Hemmatzadeh, Maryam; Mohammadi, Hamed; Karimi, Mohammad; Musavishenas, Mohammad Hossein; Baradaran, Behzad

2016-08-01

Esophageal cancer (EC) is the most invasive disease associated with inclusive poor prognosis. EC usually is found as either adenocarcinoma (EAC) or squamous cell carcinomas (ESCC). ESCC forms in squamous cells and highly occurs in the upper third of the esophagus. EAC appears in glandular cells and ordinarily develops in the lower one third of the esophagus near the stomach. Barrett's esophagus (BE) is a metaplastic precursor of EAC. There is a persistent need for improving our understanding of the molecular basis of this disease. MicroRNAs (miRNAs) demonstrate an uncovered class of small, non-coding RNAs that can negatively regulate the protein coding gene, and are associated with approximately all known physiological and pathological processes, especially cancer. MiRNAs can affect cancer pathogenesis, playing a crucial role as either oncogenes or tumor suppressors. The recent emergence of observations on the role of miRNAs in cancer and their functions has induced many investigations to examine their relevance to esophageal cancer. In esophageal cancer, miRNA dysregulation plays a crucial role in cancer prognosis and in patients' responsiveness to neo-adjuvant and adjuvant therapies. In this review, the oncogenic, tumor suppressive, and drug resistance related roles of miRNAs, and their involvement in the pathogenesis and treatment of esophageal cancer were summarized. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Cross sectional study of serum selenium concentration and esophageal squamous dysplasia in western Kenya.

PubMed

Pritchett, Natalie R; Burgert, Stephen L; Murphy, Gwen A; Brockman, John D; White, Russell E; Lando, Justus; Chepkwony, Robert; Topazian, Mark D; Abnet, Christian C; Dawsey, Sanford M; Mwachiro, Michael M

2017-12-08

Low serum selenium status has been associated with increased risk of esophageal squamous cell carcinoma (ESCC). East Africa is a region of high ESCC incidence and is known to have low soil selenium levels, but this association has not previously been evaluated. In this study we assessed the association of serum selenium concentration and the prevalence of esophageal squamous dysplasia (ESD), the precursor lesion of ESCC, in a cross-sectional study of subjects from Bomet, Kenya. 294 asymptomatic adult residents of Bomet, Kenya completed questionnaires and underwent endoscopy with Lugol's iodine staining and biopsy for detection of ESD. Serum selenium concentrations were measured by instrumental neutron activation analysis. Odds ratios (OR) and confidence intervals (95% CI) for associations between serum selenium and ESD were calculated using unconditional logistic regression. The mean serum selenium concentration was 85.5 (±28.3) μg/L. Forty-two ESD cases were identified (14% of those screened), including 5 (12%) in selenium quartile 1 (Q1), 5 (12%) in Q2, 15 (36%) in Q3, and 17 (40%) in Q4. Higher serum selenium was associated with prevalence of ESD (Q4 vs Q1: OR: 3.03; 95% CI: 1.05-8.74) and this association remained after adjusting for potential confounders (Q4 vs Q1: OR: 3.87; 95% CI: 1.06-14.19). This is the first study to evaluate the association of serum selenium concentration and esophageal squamous dysplasia in an African population at high risk for ESCC. We found a positive association between higher serum selenium concentration and prevalence of ESD, an association contrary to our original hypothesis. Further work is needed to better understand the role of selenium in the etiology of ESCC in this region, and to develop effective ESCC prevention and control strategies.

Increased expression of c-Ski as a co-repressor in transforming growth factor-beta signaling correlates with progression of esophageal squamous cell carcinoma.

PubMed

Fukuchi, Minoru; Nakajima, Masanobu; Fukai, Yasuyuki; Miyazaki, Tatsuya; Masuda, Norihiro; Sohda, Makoto; Manda, Ryokuhei; Tsukada, Katsuhiko; Kato, Hiroyuki; Kuwano, Hiroyuki

2004-03-01

Transforming growth factor-beta (TGF-beta) regulates cell growth inhibition, and inactivation of the TGF-beta signaling pathway contributes to tumor development. In our previous study, altered expression of TGF-beta, TGF-beta-specific receptors and Smad4 was shown to correlate with tumor progression in esophageal squamous cell carcinoma (SCC). These components, however, were maintained normally in some patients with esophageal SCC. In our study, the mechanism by which aggressive esophageal SCC maintains these components was investigated, with particular emphasis on the participation of c-Ski and SnoN as transcriptional co-repressors in TGF-beta signaling. Immunohistochemistry for c-Ski and SnoN was carried out on surgical specimens obtained from 80 patients with esophageal SCC. The expression of c-Ski and SnoN was also studied in 6 established cell lines derived from esophageal SCC and compared to an immortalized human esophageal cell line by Western blotting. High levels of expression of c-Ski, detected immunohistologically, were found to correlate with depth of invasion (p = 0.0080) and pathologic stage (p = 0.0447). There was, however, no significant correlation between expression of SnoN and clinicopathologic characteristics. A significant correlation between c-Ski and TGF-beta expression was observed. Moreover, in patients with TGF-beta negative expression, the survival rates of patients with c-Ski positive expression were significantly lower than those of patients with c-Ski negative expression (p = 0.0486). c-Ski was expressed at a high level in 5 of 6 cell lines derived from esophageal SCC compared to immortalized esophageal keratinocytes. Furthermore, the cyclin-dependent kinase (CDK) inhibitor, p21 that was up-regulated by TGF-beta signaling was expressed at a low level in the 5 cell lines. The expression of c-Ski protein as a transcriptional co-repressor in TGF-beta signaling seems to be correlated with tumor progression of esophageal SCC. Copyright 2003 Wiley-Liss, Inc.

Pilot Trial of CRLX101 in Treatment of Patients With Advanced or Metastatic Stomach, Gastroesophageal, or Esophageal Cancer That Cannot be Removed by Surgery

ClinicalTrials.gov

2018-01-08

Adenocarcinoma of the Esophagus; Adenocarcinoma of the Gastroesophageal Junction; Diffuse Adenocarcinoma of the Stomach; Intestinal Adenocarcinoma of the Stomach; Mixed Adenocarcinoma of the Stomach; Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Squamous Cell Carcinoma of the Esophagus; Stage IIIB Esophageal Cancer; Stage IIIB Gastric Cancer; Stage IIIC Esophageal Cancer; Stage IIIC Gastric Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer

Esophageal adenosquamous carcinoma mimicking acantholytic squamous cell carcinoma

PubMed Central

Matsukuma, Susumu; Takahashi, Oh; Utsumi, Yoshitaka; Tsuda, Masaki; Miyai, Kosuke; Okada, Kenji; Takeo, Hiroaki

2017-01-01

Herein is described a unique case of esophageal cancer mimicking acantholytic squamous cell carcinoma (SCC). The patient succumbed to the disease within one month of diagnosis. Autopsy revealed a 10-cm esophageal tumor, characterized by prominent acantholysis-like areas composed of discohesive cancer cells, along with nested growth of SCC. These discohesive cancer cells focally exhibited pagetoid extension into adjacent esophageal epithelium, comprised ~60% of the esophageal tumor volume and had widely metastasized to the lungs, chest wall, liver, spleen, right adrenal gland, bones and lymph nodes. No metastases of SCC were observed. SCC cells were immunohistochemically positive for keratin 5/6 and E-cadherin and were negative for mucin and carcinoembryonic antigen (CEA). However, the discohesive cancer cells exhibited negativity for keratin 5/6, positivity for mucin and CEA, and diminished or no immunostaining for E-cadherin. Thus, these discohesive cells represented true adenocarcinomatous differentiation rather than acantholytic SCC cells. It was concluded that this tumor was an esophageal adenosquamous carcinoma with ‘pseudo’-acantholytic adenocarcinoma components, which should be considered as a rare but distinctive type of aggressive cancer. PMID:29085501

A Phase I/II Study of Oblimersen Plus Cisplatin and Fluorouracil in Gastric & Esophageal Junction Cancer

ClinicalTrials.gov

2015-06-10

Adenocarcinoma of the Esophagus; Adenocarcinoma of the Gastroesophageal Junction; Diffuse Adenocarcinoma of the Stomach; Intestinal Adenocarcinoma of the Stomach; Mixed Adenocarcinoma of the Stomach; Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Squamous Cell Carcinoma of the Esophagus; Stage III Esophageal Cancer; Stage IIIA Gastric Cancer; Stage IIIB Gastric Cancer; Stage IIIC Gastric Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer

The novel HDAC inhibitor OBP-801/YM753 enhances the effects of 5-fluorouracil with radiation on esophageal squamous carcinoma cells.

PubMed

Furutani, Akinobu; Sowa, Yoshihiro; Fujiwara, Hitoshi; Otsuji, Eigo; Sakai, Toshiyuki

2014-01-01

Histone deacetylase (HDAC) inhibitors have been shown to enhance the effects of 5-fluorouracil (5-FU) against various cancer cells; however, no report has shown that an HDAC inhibitor may enhance the effects of 5-FU with radiation. Therefore, we investigated whether the novel HDAC inhibitor OBP-801/YM753 could enhance the effects of 5-FU with radiation on esophageal squamous carcinoma KYSE170 cells. The inhibition of the cell growth was significantly stronger with the combination of OBP-801/YM753 with 5-FU than with the 5-FU treatment only. Furthermore, inhibition of the colony formation was the most effective with the combined treatment of OBP-801/YM753, 5-FU, and radiation. Western blot analysis showed that OBP-801/YM753 suppressed the expression of thymidylate synthase induced by 5-FU. Therefore, this three-combined therapy is promising for patients with esophageal squamous carcinoma.

[Determination of hyperregeneratory esophagopathy in dogs with clinical signs attributable to esophageal disease].

PubMed

Münster, M; Kook, P; Araujo, R; Hörauf, A; Vieth, M

2015-01-01

It was hypothesized that typical characteristics of hyperregeneratory esophagopathy (HRE) in humans such as basal cell hyperplasia and elongation of stromal papillae are also histologically detectable in canine esophageal epithelium, and that these changes are associated with clinical signs and endoscopic findings suggesting gastroesophageal reflux (GER). Sixty-five adult dogs with clinical signs attributable to esophageal disease underwent esophagoscopy and biopsy. Clinical signs suggesting GER (regurgitation, ptyalism, painful discomfort) were prospectively evaluated through a questionnaire. Endoscopic mucosal alterations suggesting GER such as minimal endoscopic changes and obvious mucosal defects were assessed via video endoscopy. Biopsy specimens obtained from the esophageal squamous epithelium were evaluated histologically. The squamous epithelium's substructures of esophageal biopsies were quantitatively assessed through microscopic morphometry. Esophageal squamous epithelium was considered normal in 48 dogs, and HRE was detected histologically in 17 dogs; both pathognomonic changes (basal cell hyperplasia, elongation of stromal papillae) were consistently present. Morphometrically assessed stromal papillary length and basal cell layer thickness was significantly (each, p < 0.0001) higher in the 17 dogs with HRE than in the 48 dogs without HRE, respectively. Overall, clinical signs suggesting GER were significantly (p = 0.02) more frequently encountered and regurgitation was significantly (p = 0.009) more common in the 17 dogs with HRE than in the 48 dogs without HRE. Similarly, endoscopic changes were significantly (p = 0.002) more frequently observed and minimal endoscopic changes suggesting GER were significantly (p = 0.004) more common in 17 dogs with HRE than in the 48 dogs without HRE. Typical characteristics of hyperregeneratory esophagopathy in humans are also histologically detectable in canine esophageal epithelium. Histological changes are associated with clinical signs and endoscopic findings suggesting GER.

Postoperative radiation therapy of pT2-3N0M0 esophageal carcinoma-a review.

PubMed

Luo, Yijun; Wang, Xiaoli; Yu, Jinming; Zhang, Bin; Li, Minghuan

2016-11-01

Esophageal cancer is one of the most malignant gastrointestinal cancers worldwide. Despite advances in surgical technique, 5-year survival in pathologic stage T2-3N0M0 esophageal squamous cell carcinoma patients who are treated with surgery alone is still poor. The addition of adjuvant radiotherapy may confer a benefit for these patients. However, not all patients could get a benefit from radiotherapy and patients with esophageal squamous cell carcinoma receiving radiotherapy seem to have a disparity in treatment response. Thus, identifying effective prognostic indicator to complement current clinical staging approaches is extremely important. Those prognostic factors could give rise to a novel prognostic stratification system, which serve as criteria for selecting patients for adjuvant therapy. Consequently, it may help to define the subgroups who are more likely to benefit from postoperative radiation therapy.

Preoperative serum lipids as prognostic predictors in esophageal squamous cell carcinoma patients with esophagectomy.

PubMed

Chen, Pengxiang; Han, Lihui; Wang, Cong; Jia, Yibin; Song, Qingxu; Wang, Jianbo; Guan, Shanghui; Tan, Bingxu; Liu, Bowen; Jia, Wenqiao; Cui, Jianfeng; Zhou, Wei; Cheng, Yufeng

2017-06-20

This study was to evaluate the prognostic significance of serum lipids in esophageal squamous cell carcinoma patients who underwent esophagectomy. Preoperative serum lipids were collected from 214 patients who were diagnosed with esophageal squamous cell carcinoma. All of the patients received esophagectomy in Qilu Hospital of Shandong University from January 2007 to December 2008. The records and data were analyzed retrospectively. We found that low total cholesterol (for T stage, p = 0.006; for TNM stage, p = 0.039) and low-density lipoprotein cholesterol (for T stage, p = 0.031; for TNM stage, p = 0.035) were associated with advanced T stage and TNM stage. Kaplan-Meier survival analysis indicated that low total cholesterol and low-density lipoprotein cholesterol were associated with shorter disease-free survival(for total cholesterol, p = 0.045; for low-density lipoprotein cholesterol, p < 0.001) and overall survival (for total cholesterol, p = 0.043; for low-density lipoprotein cholesterol, p < 0.001). Lower low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio (LHR) indicated poorer disease-free survival and overall survival (both p < 0.001). In the multivariate analysis, low-density lipoprotein cholesterol and LHR were independent prognostic factors for disease-free survival and overall survival. In conclusion, our study indicated that preoperative serum total cholesterol and low-density lipoprotein cholesterol are prognostic factors for esophageal squamous cell carcinoma patients who underwent esophagectomy. LHR can serve as a promising serum lipids-based prognostic indicator.

Rapid and sensitive detection of early esophageal squamous cell carcinoma with fluorescence probe targeting dipeptidylpeptidase IV

PubMed Central

Onoyama, Haruna; Kamiya, Mako; Kuriki, Yugo; Komatsu, Toru; Abe, Hiroyuki; Tsuji, Yosuke; Yagi, Koichi; Yamagata, Yukinori; Aikou, Susumu; Nishida, Masato; Mori, Kazuhiko; Yamashita, Hiroharu; Fujishiro, Mitsuhiro; Nomura, Sachiyo; Shimizu, Nobuyuki; Fukayama, Masashi; Koike, Kazuhiko; Urano, Yasuteru; Seto, Yasuyuki

2016-01-01

Early detection of esophageal squamous cell carcinoma (ESCC) is an important prognosticator, but is difficult to achieve by conventional endoscopy. Conventional lugol chromoendoscopy and equipment-based image-enhanced endoscopy, such as narrow-band imaging (NBI), have various practical limitations. Since fluorescence-based visualization is considered a promising approach, we aimed to develop an activatable fluorescence probe to visualize ESCCs. First, based on the fact that various aminopeptidase activities are elevated in cancer, we screened freshly resected specimens from patients with a series of aminopeptidase-activatable fluorescence probes. The results indicated that dipeptidylpeptidase IV (DPP-IV) is specifically activated in ESCCs, and would be a suitable molecular target for detection of esophageal cancer. Therefore, we designed, synthesized and characterized a series of DPP-IV-activatable fluorescence probes. When the selected probe was topically sprayed onto endoscopic submucosal dissection (ESD) or surgical specimens, tumors were visualized within 5 min, and when the probe was sprayed on biopsy samples, the sensitivity, specificity and accuracy reached 96.9%, 85.7% and 90.5%. We believe that DPP-IV-targeted activatable fluorescence probes are practically translatable as convenient tools for clinical application to enable rapid and accurate diagnosis of early esophageal cancer during endoscopic or surgical procedures. PMID:27245876

Current trends in multimodality treatment of esophageal and gastroesophageal junction cancer - Review article.

PubMed

Klevebro, Fredrik; Ekman, Simon; Nilsson, Magnus

2017-09-01

Multimodality treatment has now been widely introduced in the curatively intended treatment of esophageal and gastroesophageal junction cancer. We aim to give an overview of the scientific evidence for the available treatment strategies and to describe which trends that are currently developing. We conducted a review of the scientific evidence for the different curatively intended treatment strategies that are available today. Relevant articles of randomized controlled trials, cohort studies, and meta analyses were included. After a systematic search of relevant papers we have included 64 articles in the review. The results show that adenocarcinomas and squamous cell carcinomas of the esophagus and gastroesophageal junction are two separate entities and should be analysed and studied as two different diseases. Neoadjuvant treatment followed by surgical resection is the gold standard of the curatively intended treatment today. There is no scientific evidence to support the use of chemoradiotherapy over chemotherapy in the neoadjuvant setting for esophageal or junctional adenocarcinoma. There is reasonable evidence to support definitive chemoradiotherapy as a treatment option for squamous cell carcinoma of the esophagus. The evidence base for curatively intended treatments of esophageal and gastroesophageal junction cancer is not very strong. Several on-going trials have the potential to change the gold standard treatments of today. Copyright © 2017 Elsevier Ltd. All rights reserved.

Protective Effect of Dietary Calcium Intake on Esophageal Cancer Risk: A Meta-Analysis of Observational Studies.

PubMed

Li, Qianwen; Cui, Lingling; Tian, Yalan; Cui, Han; Li, Li; Dou, Weifeng; Li, Haixia; Wang, Ling

2017-05-18

Although several epidemiological studies have investigated the association between dietary calcium intake and the risk of esophageal cancer, the results are inconsistent. This study aimed to make a comprehensive evaluation regarding the association between calcium intake and risk of esophageal cancer through a meta-analysis approach. We searched for all relevant articles from the inception to April 2017, using PUBMED, EMBASE, and Web of Knowledge. The pooled odds ratio (ORs) with the 95% confidence interval (95% CI) for the highest versus the lowest categories of calcium intake was calculated using a Mantel-Haenszel fixed-effect model. In total, 15 articles reporting 17 studies including 3396 esophageal cancer cases and 346,815 controls were selected for the meta-analysis. By comparing the highest vs. the lowest levels of dietary calcium intake, we found that dietary calcium intake was inversely associated with the risk of esophageal cancer (OR = 0.80, 95% CI: 0.71-0.91, I ² = 33.6%). The subgroup analysis indicated that the protective function of dietary calcium intake were observed in esophageal squamous cell cancer, but not in esophageal adenocarcinoma in the studies conducted in Asia, but not those in Europe and America. In conclusion, our results suggest that higher dietary calcium intake is associated with a lower risk of esophageal cancer-especially esophageal squamous cell cancer-in Asian populations, though more data from prospective cohort studies are needed.

Analyzing esophageal squamous cell papillomas for the presence of human papilloma virüs.

PubMed

Tiftikçi, Arzu; Kutsal, Eser; Altıok, Ender; İnce, Ümit; Çicek, Bahattin; Saruç, Murat; Türkel, Nurten; Ersoy, Özdal; Yenmiş, Güven; Tözün, Nurdan

2017-05-01

Human Papilloma Virus (HPV) infection can be a predisposing condition for the development of squamous cell papilloma (SCP) of the esophagus, which can progress to dysplasia and to carcinoma as a result of chronic infection. The aim of the present study was to search for the presence of HPV in the esophageal SCP, and to genotype the detected HPV. Data from patients with definite diagnosis of SCP of the esophagus were identified from pathology records for two years period at different Hospitals. Slides from each patient were reviewed and samples with satisfactory papilloma tissues were submitted to molecular analysis. DNA has been isolated. DNA sequencing has been performed for genotyping HPV for all types. Our study group consisted of 21 women and 17 men (a total of 38 patients), mean age was 41 years (range 17-67 years). Most of the papillomas were located at mid-esophagus (68%). Eight out of 38 patients (21%) had associated erosive esophagitis, and fourteen patients (36.8%) had Helicobacter Pylori (H. pylori). Of the 38 SCP analyzed, seven (19%) were positive for HPV DNA. Three of them were of genotype 6, whereas four were of genotype 16, 18, 31, 81 that are known as highly oncogenic. There were no correlations between the presence of HPV and the patient's age, the presence of reflux esophagitis or H. pylori, smoking habit and the location of the papillomas. The presence of high-risk type HPV in esophageal SCP may implicate a role of the virus in the pathogenesis of the esophageal tumor.

Expression of thymidylate synthase and glutathione-s-transferase pi in patients with esophageal squamous cell carcinoma.

PubMed

Huang, Jun-Xing; Li, Feng-Yue; Xiao, Wei; Song, Zheng-Xiang; Qian, Rong-Yu; Chen, Ping; Salminen, Eeva

2009-09-14

To investigate the expression of thymidylate synthase (TS) and glutathione-s-transferase pi (GST-pi) in esophageal squamous cell carcinoma and their association with the clinicopathologic characteristics. Immunohistochemical methods were used to detect the expression of TS and GST-pi in surgically resected formalin-fixed, paraffin-embedded esophageal squamous cell carcinoma (ESCC) tissue sections from 102 patients (median age, 58 years) and in 28 normal esophageal mucosa (NEM) samples. The relationship between TS and GST-pi expression and clinicopathologic factors was examined. The expression of TS and GST-pi was not statistically significantly associated with age of the patients, tumor size, lymph node metastasis, depth of invasion or tumor stage. TS staining was positive in 17.86% of normal esophageal mucosa and in 42.16% of ESCC samples (P < 0.05). The expression level of TS was not only significantly lower in well-differentiated (21.88%) than in poorly-differentiated carcinomas (51.43%, P < 0.05), but was also significantly higher in samples from male patients (46.51%) than from female patients (18.75%, P < 0.05). GST-pi was positively stained in 78.57% of normal esophageal mucosa and in 53.92% of ESCC samples (P < 0.05). The expression level of GST-pi was also significantly higher in well-differentiated carcinomas (65.63%) than in poorly-differentiated carcinomas (35.00%, P < 0.05). The expression of TS and of GST-pi may be used as molecular markers for the characterization of ESCC. Poorly-differentiated cells showed increased expression of TS and reduced expression of GST-pi.

Erlotinib in Treating Patients With Solid Tumors and Liver or Kidney Dysfunction

ClinicalTrials.gov

2013-01-15

Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Myxopapillary Ependymoma; Adult Oligodendroglioma; Adult Pilocytic Astrocytoma; Adult Primary Hepatocellular Carcinoma; Adult Subependymoma; Advanced Adult Primary Liver Cancer; Advanced Malignant Mesothelioma; Male Breast Cancer; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adult Brain Tumor; Recurrent Adult Primary Liver Cancer; Recurrent Anal Cancer; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Bladder Cancer; Recurrent Breast Cancer; Recurrent Cervical Cancer; Recurrent Colon Cancer; Recurrent Esophageal Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Malignant Mesothelioma; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Pancreatic Cancer; Recurrent Prostate Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage II Esophageal Cancer; Stage II Pancreatic Cancer; Stage III Esophageal Cancer; Stage III Pancreatic Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Anal Cancer; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Bladder Cancer; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Esophageal Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Pancreatic Cancer; Stage IV Prostate Cancer; Stage IV Rectal Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Stage IVA Cervical Cancer; Stage IVB Cervical Cancer; Unspecified Adult Solid Tumor, Protocol Specific; Untreated Metastatic Squamous Neck Cancer With Occult Primary

EVALUATION OF LYMPHATIC SPREAD, VISCERAL METASTASIS AND TUMORAL LOCAL INVASION IN ESOPHAGEAL CARCINOMAS.

PubMed

Tustumi, Francisco; Kimura, Cintia Mayumi Sakurai; Takeda, Flavio Roberto; Sallum, Rubens Antônio Aissar; Ribeiro-Junior, Ulysses; Cecconello, Ivan

2016-01-01

Knowing esophageal tumors behavior in relationship to lymph node involvement, distant metastases and local tumor invasion is of paramount importance for the best esophageal tumors management. To describe lymph node involvement, distant metastases, and local tumor invasion in esophageal carcinoma, according to tumor topography and histology. A total of 444 patients with esophageal squamous cell carcinoma and 105 adenocarcinoma were retrospectively analyzed. They were divided into four groups: adenocarcinoma and squamous cell carcinoma in the three esophageal segments: cervical, middle, and distal. They were compared based on their CT scans at the time of the diagnosis. Nodal metastasis showed great relationship with of primary tumor site. Lymph nodes of hepatogastric, perigastric and peripancreatic ligaments were mainly affected in distal tumors. Periaortic, interaortocaval and portocaval nodes were more commonly found in distal squamous carcinoma; subcarinal, paratracheal and subaortic nodes in middle; neck chains were more affected in cervical squamous carcinoma. Adenocarcinoma had a higher frequency of peritoneal involvement (11.8%) and liver (24.5%) than squamous cell carcinoma. Considering the local tumor invasion, the more cranial neoplasia, more common squamous invasion of airways, reaching 64.7% in the incidence of cervical tumors. Middle esophageal tumors invade more often aorta (27.6%) and distal esophageal tumors, the pericardium and the right atrium (10.4%). Esophageal adenocarcinoma and squamous cell carcinoma in different topographies present peculiarities in lymph node involvement, distant metastasis and local tumor invasion. These differences must be taken into account in esophageal cancer patients' care. Conhecer o comportamento das neoplasias esofágicas em relação à disseminação linfonodal, distribuição de metástases e invasão local do tumor, pode auxiliar o manejo dos pacientes. Descrever o envolvimento linfonodal, disseminação metastática e invasão local dos carcinomas esofágicos, de acordo com a topografia e o tipo histológico do tumor. Pacientes com diagnóstico de carcinoma espinocelular de esôfago (n=444) e adenocarcinoma de esôfago (n=105) foram retrospectivamente analisados. Foram divididos em quatro grupos: adenocarcinoma e carcinoma espinocelular do segmento cervical, médio e distal. Tais grupos foram comparados baseando-se em tomografias computadorizadas realizadas no momento do diagnóstico. Disseminação linfonodal mostrou grande associação com topografia do tumor. Linfonodos do ligamento hepatogástrico, perigástricos e peripancreáticos foram acometidos principalmente por tumores de esôfago distal; linfonodos periaórticos, interaortocavais, portocavais no carcinoma espinocelular de esôfago distal; e linfonodos subcarinais, paratraqueais, subaórticos nos tumores de esôfago médio. Cadeias cervicais foram acometidas por espinocelulares cervicais. Adenocarcinoma teve maior frequência de acometimento peritoneal (11,8%) e hepático (24,5%) do que carcinoma espinocelular. Considerando invasão tumoral local, quanto mais cranial a neoplasia, mais comum a invasão do espinocelular em vias aéreas, chegando à incidência de 64,7% nos tumores cervicais. Tumores de esôfago médio invadem mais frequentemente aorta (27,6%) e tumores de esôfago distal, o pericárdio e átrio direito (10,4%). Adenocarcinoma e carcinoma espinocelular de esôfago em diferentes topografias apresentam peculiaridades na disseminação linfática, metástases à distância e invasão local do tumor. Tais diferenças devem ser consideradas no manejo do paciente com carcinoma esofágico.

The current status of neoadjuvant therapy for esophageal cancer.

PubMed

Lin, Daniel; Leichman, Lawrence

2014-01-01

Through the contribution of a very large number of single-arm phase II trials and many less randomized phase III trials, the standard of care for locally advanced esophageal cancer has evolved to either combination chemotherapy plus radiation or combination chemotherapy. In this review, we focus on the key findings of these studies and selected meta-analyses that have led to this evolution. We note differences in outcomes for adenocarcinomas of the esophagus when compared to squamous cell esophageal cancers. Despite progress in developing a consensus for therapy, the outcome for patients with locally advanced remains poor. We complete the review by noting newer areas of investigation seeking to provide targeted and more personalized therapy to patients with esophageal cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

Association Between Germline Mutation in VSIG10L and Familial Barrett Neoplasia.

PubMed

Fecteau, Ryan E; Kong, Jianping; Kresak, Adam; Brock, Wendy; Song, Yeunjoo; Fujioka, Hisashi; Elston, Robert; Willis, Joseph E; Lynch, John P; Markowitz, Sanford D; Guda, Kishore; Chak, Amitabh

2016-10-01

Esophageal adenocarcinoma and its precursor lesion Barrett esophagus have seen a dramatic increase in incidence over the past 4 decades yet marked genetic heterogeneity of this disease has precluded advances in understanding its pathogenesis and improving treatment. To identify novel disease susceptibility variants in a familial syndrome of esophageal adenocarcinoma and Barrett esophagus, termed familial Barrett esophagus, by using high-throughput sequencing in affected individuals from a large, multigenerational family. We performed whole exome sequencing (WES) from peripheral lymphocyte DNA on 4 distant relatives from our multiplex, multigenerational familial Barrett esophagus family to identify candidate disease susceptibility variants. Gene variants were filtered, verified, and segregation analysis performed to identify a single candidate variant. Gene expression analysis was done with both quantitative real-time polymerase chain reaction and in situ RNA hybridization. A 3-dimensional organotypic cell culture model of esophageal maturation was utilized to determine the phenotypic effects of our gene variant. We used electron microscopy on esophageal mucosa from an affected family member carrying the gene variant to assess ultrastructural changes. Identification of a novel, germline disease susceptibility variant in a previously uncharacterized gene. A multiplex, multigenerational family with 14 members affected (3 members with esophageal adenocarcinoma and 11 with Barrett esophagus) was identified, and whole-exome sequencing identified a germline mutation (S631G) at a highly conserved serine residue in the uncharacterized gene VSIG10L that segregated in affected members. Transfection of S631G variant into a 3-dimensional organotypic culture model of normal esophageal squamous cells dramatically inhibited epithelial maturation compared with the wild-type. VSIG10L exhibited high expression in normal squamous esophagus with marked loss of expression in Barrett-associated lesions. Electron microscopy of squamous esophageal mucosa harboring the S631G variant revealed dilated intercellular spaces and reduced desmosomes. This study presents VSIG10L as a candidate familial Barrett esophagus susceptibility gene, with a putative role in maintaining normal esophageal homeostasis. Further research assessing VSIG10L function may reveal pathways important for esophageal maturation and the pathogenesis of Barrett esophagus and esophageal adenocarcinoma.

Association Between Germline Mutation in VSIG10L and Familial Barrett Neoplasia

PubMed Central

Fecteau, Ryan E.; Kong, Jianping; Kresak, Adam; Brock, Wendy; Song, Yeunjoo; Fujioka, Hisashi; Elston, Robert; Willis, Joseph E.; Lynch, John P.; Markowitz, Sanford D.; Guda, Kishore; Chak, Amitabh

2016-01-01

IMPORTANCE Esophageal adenocarcinoma and its precursor lesion Barrett esophagus have seen a dramatic increase in incidence over the past 4 decades yet marked genetic heterogeneity of this disease has precluded advances in understanding its pathogenesis and improving treatment. OBJECTIVE To identify novel disease susceptibility variants in a familial syndrome of esophageal adenocarcinoma and Barrett esophagus, termed familial Barrett esophagus, by using high-throughput sequencing in affected individuals from a large, multigenerational family. DESIGN, SETTING, AND PARTICIPANTS We performed whole exome sequencing (WES) from peripheral lymphocyte DNA on 4 distant relatives from our multiplex, multigenerational familial Barrett esophagus family to identify candidate disease susceptibility variants. Gene variants were filtered, verified, and segregation analysis performed to identify a single candidate variant. Gene expression analysis was done with both quantitative real-time polymerase chain reaction and in situ RNA hybridization. A 3-dimensional organotypic cell culture model of esophageal maturation was utilized to determine the phenotypic effects of our gene variant. We used electron microscopy on esophageal mucosa from an affected family member carrying the gene variant to assess ultrastructural changes. MAIN OUTCOMES AND MEASURES Identification of a novel, germline disease susceptibility variant in a previously uncharacterized gene. RESULTS A multiplex, multigenerational family with 14 members affected (3 members with esophageal adenocarcinoma and 11 with Barrett esophagus) was identified, and whole-exome sequencing identified a germline mutation (S631G) at a highly conserved serine residue in the uncharacterized gene VSIG10L that segregated in affected members. Transfection of S631G variant into a 3-dimensional organotypic culture model of normal esophageal squamous cells dramatically inhibited epithelial maturation compared with the wild-type. VSIG10L exhibited high expression in normal squamous esophagus with marked loss of expression in Barrett-associated lesions. Electron microscopy of squamous esophageal mucosa harboring the S631G variant revealed dilated intercellular spaces and reduced desmosomes. CONCLUSIONS AND RELEVANCE This study presents VSIG10L as a candidate familial Barrett esophagus susceptibility gene, with a putative role in maintaining normal esophageal homeostasis. Further research assessing VSIG10L function may reveal pathways important for esophageal maturation and the pathogenesis of Barrett esophagus and esophageal adenocarcinoma. PMID:27467440

FGFR1 Amplification Is Often Homogeneous and Strongly Linked to the Squamous Cell Carcinoma Subtype in Esophageal Carcinoma

PubMed Central

Burkhardt, Lia; Simon, Ronald; Steurer, Stefan; Burdak-Rothkamm, Susanne; Jacobsen, Frank; Sauter, Guido; Krech, Till

2015-01-01

Background and Aims Amplification of the fibroblast growth factor receptor 1 (FGFR1) is believed to predict response to multi-kinase inhibitors targeting FGFR1. Esophageal cancer is an aggressive disease, for which novel targeted therapies are highly warranted. Methods This study was designed to investigate the prevalence and clinical significance of FGFR1 amplification in a tissue microarray containing 346 adenocarcinomas and 254 squamous cell carcinomas of the esophagus, using dual-labeling fluorescence in situ hybridization (FISH) analysis. Results FGFR1 amplification, defined as a ratio of FGFR1:centromere 8 copy numbers ≥ 2.0, was more frequently seen in squamous cell carcinoma (8.9% of 202 interpretable cases) than in adenocarcinoma (1.6% of 308; p<0.0001). There was no association between FGFR1 amplification and tumor phenotype or clinical outcome. To study potential heterogeneity of FGFR1 amplification, all available tumor blocks from 23 FGFR1 amplified tumors were analyzed on conventional large sections. This analysis revealed complete homogeneity of FGFR1 amplification in 20 (86.9%) primary tumors and in all available lymph node metastases. Remarkably, FGFR1 amplification was also seen in dysplasia adjacent to tumor in 6 of 9 patients with FGFR1 amplified primary cancers. Conclusions In conclusion, FGFR1 amplification occurs in a relevant subgroup of carcinomas of the esophagus and may play a particular role for development of squamous cell cancers. The high homogeneity of FGFR1 amplification suggests that patients with FGFR1 amplified esophageal cancers may particularly benefit from anti-FGFR1 therapies and prompt for clinical studies in this tumor type. PMID:26555375

Orthotopic Esophageal Cancers: Intraesophageal Hyperthermia-enhanced Direct Chemotherapy in Rats

PubMed Central

Shi, Yaoping; Zhang, Feng; Bai, Zhibin; Wang, Jianfeng; Qiu, Longhua; Li, Yonggang; Meng, Yanfeng; Valji, Karim

2017-01-01

Purpose To determine the feasibility of using intraesophageal radiofrequency (RF) hyperthermia to enhance local chemotherapy in a rat model with orthotopic esophageal squamous cancers. Materials and Methods The animal protocol was approved by the institutional animal care and use committee and the institutional review board. Human esophageal squamous cancer cells were transduced with luciferase lentiviral particles. Cancer cells, mice with subcutaneous cancer esophageal xenografts, and nude rats with orthotopic esophageal cancers in four study groups of six animals per group were treated with (a) combination therapy of magnetic resonance imaging heating guidewire–mediated RF hyperthermia (42°C) plus local chemotherapy (cisplatin and 5-fluorouracil), (b) chemotherapy alone, (c) RF hyperthermia alone, and (d) phosphate-buffered saline. Bioluminescent optical imaging and transcutaneous ultrasonographic imaging were used to observe bioluminescence signal and changes in tumor size among the groups over 2 weeks, which were correlated with subsequent histologic results. The nonparametric Mann-Whitney U test was used for comparisons of variables. Results Compared with chemotherapy alone, RF hyperthermia alone, and phosphate-buffered saline, combination therapy with RF hyperthermia and chemotherapy induced the lowest cell proliferation (relative absorbance of formazan: 23.4% ± 7, 44.6% ± 7.5, 95.8% ± 2, 100%, respectively; P < .0001), rendered the smallest relative tumor volume (0.65 mm3 ± 0.15, P < .0001) and relative bioluminescence optical imaging photon signal (0.57 × 107 photons per second per square millimeter ± 0.15, P < .001) of mice with esophageal cancer xenografts, as well as the smallest relative tumor volume (0.68 mm3 ± 0.13, P < .05) and relative photon signal (0.56 × 107 photons per second per square millimeter ± 0.11. P < .001) of rat orthotopic esophageal cancers. Conclusion Intraesophageal RF hyperthermia can enhance the effect of chemotherapy on esophageal squamous cell cancers. © RSNA, 2016 PMID:27404050

Durvalumab and Tremelimumab in Combination With First-Line Chemotherapy in Advanced Solid Tumors

ClinicalTrials.gov

2018-05-16

Small Cell Lung Carcinoma; Carcinoma, Squamous Cell of Head and Neck; Stomach Neoplasms; Triple Negative Breast Neoplasms; Ovarian Neoplasms; Fallopian Tube Neoplasms; Peritoneal Neoplasms; Esophagogastric Junction Neoplasms; Carcinoma, Pancreatic Ductal; Esophageal Squamous Cell Carcinoma

Zidovudine, abacavir and lamivudine increase the radiosensitivity of human esophageal squamous cancer cell lines.

PubMed

Chen, Xuan; Wang, Cong; Guan, Shanghui; Liu, Yuan; Han, Lihui; Cheng, Yufeng

2016-07-01

Telomerase is a type of reverse transcriptase that is overexpressed in almost all human tumor cells, but not in normal tissues, which provides an opportunity for radiosensitization targeting telomerase. Zidovudine, abacavir and lamivudine are reverse transcriptase inhibitors that have been applied in clinical practice for several years. We sought to explore the radiosensitization effect of these three drugs on human esophageal cancer cell lines. Eca109 and Eca9706 cells were treated with zidovudine, abacavir and lamivudine for 48 h before irradiation was administered. Samples were collected 1 h after irradiation. Clonal efficiency assay was used to evaluate the effect of the combination of these drugs with radiation doses of 2, 4, 6 and 8 Gy. DNA damage was measured by comet assay. Telomerase activity (TA) and relative telomere length (TL) were detected and evaluated by real-time PCR. Apoptosis rates were assessed by flow cytometric analysis. The results showed that all the drugs tested sensitized the esophageal squamous cell carcinoma (ESCC) cell lines to radiation through an increase in radiation-induced DNA damage and cell apoptosis, deregulation of TA and decreasing the shortened TL caused by radiation. Each of the drugs investigated (zidovudine, abacavir and lamivudine) could be used for sensitizing human esophageal cancer cell lines to radiation. Consequently, the present study supports the potential of these three drugs as therapeutic agents for the radiosensitization of esophageal squamous cell cancer.

SU-E-P-18: Intensity-Modulated Radiation Therapy for Cervical Esophageal Squamous Cell Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bai, W; Qiao, X; Zhou, Z

2015-06-15

Purpose: To retrospectively analyze the outcomes and prognostic factors of cervical esophageal squamous cell carcinoma (SCC) treated with intensity modulated radiation therapy (IMRT). Methods: Thirty-seven patients with cervical esophageal SCC treated with IMRT were analyzed retrospectively. They received 54–66 Gy in 27–32 fractions. Nineteen patients received concurrent (n=12) or sequential (n=7) platinum-based two drugs chemoradiotherapy. Overall survival (OS), local control rates (LCR) and prognostic factors were evaluated. Acute toxicities and patterns of first failures were observed. Results: The median follow-up was 46 months for alive patients. The l-, 3-, 4- and 5-year OS of the all patients were 83.8%, 59.1%,more » 47.5% and 32.6% respectively. The median survival time was 46 months. The l-, 3-,4- and 5-year LCR were 82.9%, 63.0%, 54.5% and 54.5%, respectively. Univariate and Multivariate analysis all showed that size of GTV was an independent prognostic factor (p=0.033, p=0.039). There were no patients with Grade 3 acute radiation esophagitis and Grade 2–4 acute pneumonitis. The local failure accounted for 70.0% of all treatment-related failures. Conclusion: IMRT is safe and effective in the treatment of cervical esophageal squamous cell carcinoma. Size of GTV is an independent prognostic factor. Local failure still remains the main reason of treatment failures. The authors declare no conflicts of interest in preparing this article.« less

l-Type Amino Acid Transporter-1 Overexpression and Melphalan Sensitivity in Barrett's Adenocarcinoma1

PubMed Central

Lin, Jules; Raoof, Duna A; Thomas, Dafydd G; Greenson, Joel K; Giordano, Thomas J; Robinson, Gregory S; Bourner, Maureen J; Bauer, Christopher T; Orringer, Mark B; Beer, David G

2004-01-01

Abstract The L-type amino acid transporter-1 (LAT-1) has been associated with tumor growth. Using cDNA microarrays, overexpression of LAT-1 was found in 87.5% (7/8) of esophageal adenocarcinomas relative to 12 Barrett's samples (33% metaplasia and 66% dysplasia) and was confirmed in 100% (28/28) of Barrett's adenocarcinomas by quantitative reverse transcription polymerase chain reaction. Immunohistochemistry revealed LAT-1 staining in 37.5% (24/64) of esophageal adenocarcinomas on tissue microarray. LAT-1 also transports the amino acid-related chemotherapeutic agent, melphalan. Two esophageal adenocarcinoma and one esophageal squamous cell line, expressing LAT-1 on Western blot analysis, were sensitive to therapeutic doses of melphalan (P < .001). Simultaneous treatment with the competitive inhibitor, BCH [2-aminobicyclo-(2,1,1)-heptane-2-carboxylic acid], decreased sensitivity to melphalan (P < .05). In addition, confluent esophageal squamous cultures were less sensitive to melphalan (P < .001) and had a decrease in LAT-1 protein expression. Tumors from two esophageal adenocarcinoma cell lines grown in nude mice retained LAT-1 mRNA expression. These results demonstrate that LAT-1 is highly expressed in a subset of esophageal adenocarcinomas and that Barrett's adenocarcinoma cell lines expressing LAT-1 are sensitive to melphalan. LAT-1 expression is also retained in cell lines grown in nude mice providing a model to evaluate melphalan as a chemotherapeutic agent against esophageal adenocarcinomas expressing LAT-1. PMID:15068672

Synthesis and biological evaluation of novel 2-oxo-1,2-dihydroquinoline-4-carboxamide derivatives for the treatment of esophageal squamous cell carcinoma.

PubMed

Shahin, Mai I; Roy, Joyeeta; Hanafi, Maha; Wang, Dongyao; Luesakul, Urarika; Chai, Yifeng; Muangsin, Nongnuj; Lasheen, Deena S; Abou El Ella, Dalal A; Abouzid, Khaled A; Neamati, Nouri

2018-05-29

No new and effective treatments have been approved for the treatment of esophageal squamous cell carcinoma (ESCC) in the past decade. Cisplatin and 5-fluoruracil are the most commonly used drugs for this disease. In order to develop a new class of drugs effective in our ESCC phenotypic screens, we began a systematic approach to generate novel compounds based on the 2-oxo-1,2-dihydroquinoline-4-carboxamide fragment. Herein, we report on the synthesis and initial assessment of 55 new analogues in two ESCC cell lines. Some of the active analogues with IC 50 values around 10 μM were tested in three additional cell lines. Our structure-activity relationships revealed remarkable alterations in the anti proliferative activities upon modest chemical modifications and autophagy modulation is a suggested mechanism of action. Copyright © 2018. Published by Elsevier Masson SAS.

Overall Survival of Patients with Locally Advanced or Metastatic Esophageal Squamous Cell Carcinoma Treated with Nimotuzumab in the Real World.

PubMed

Saumell, Yaimarelis; Sanchez, Lizet; González, Sandra; Ortiz, Ramón; Medina, Edadny; Galán, Yaima; Lage, Agustin

2017-12-01

Despite improvements in surgical techniques and treatments introduced into clinical practice, the overall survival of patients with esophageal squamous cell carcinoma remains low. Several epidermal growth factor receptor inhibitors are being evaluated in the context of clinical trials, but there is little evidence of effectiveness in real-world conditions. This study aimed at assessing the effectiveness of nimotuzumab combined with onco-specific treatment in Cuban real-life patients with locally advanced or metastatic esophageal squamous cell carcinoma. A comparative and retrospective effectiveness study was performed. The 93 patients treated with nimotuzumab were matched, with use of propensity score matching, with patients who received a diagnosis of locally advanced or metastatic squamous cell carcinoma of the esophagus in three Cuban provinces reported between 2011 and 2015 to the National Cancer Registry. The Kaplan-Meier method was used to estimate event-time distributions. Log-rank statistics were used for comparisons of overall survival between groups. A two-component mixture model assuming a Weibull distribution was fitted to assess the effect of nimotuzumab on short-term and long-term survival populations. There was an increase in median overall survival in patients treated with nimotuzumab (11.9 months versus 6.5 months without treatment) and an increase in the 1-year survival rate (54.0% versus 21.9% without treatment). The 2-year survival rates were 21.1% for patients treated with nimotuzumab and 0% in the untreated cohort. There were statistically significant differences in survival between groups treated and not treated with nimotuzumab, both in the short-term survival population (6.0 months vs 4.0 months, p = 0.009) and in the long-term survival population (18.0 months vs 11.0 months, p = 0.001). Our study shows that nimotuzumab treatment concurrent with chemoradiotherapy increases the survival of real-world patients with locally advanced or metastatic esophageal squamous cell carcinoma. Further prospective studies are required to confirm the therapeutic effectiveness of nimotuzumab in esophageal cancer.

Prognostic significance of hyperfibrinogenemia in patients with esophageal squamous cell carcinoma.

PubMed

Suzuki, Takashi; Shimada, Hideaki; Nanami, Tatsuki; Oshima, Yoko; Yajima, Satoshi; Washizawa, Naohiro; Kaneko, Hironori

2017-06-01

Preoperative hyperfibrinogenemia is associated with inflammatory mediators and a poor prognosis in several types of cancer. However, there is no published information on the monitoring of patients with preoperative hyperfibrinogenemia after surgery. The aim of the study reported here was to assess the clinicopathological and prognostic significance of plasma fibrinogen levels in patients with esophageal squamous cell carcinoma before and after surgical treatment. Plasma fibrinogen levels were analyzed before surgical treatment (endoscopic submucosal dissection and surgery) in 82 patients with esophageal squamous cell carcinoma. The clinicopathological significance of plasma fibrinogen levels and the relationship of plasma fibrinogen levels with several biomarkers were evaluated. The cutoff value for hyperfibrinogenemia was 321 mg/dl. Univariate and multivariate analysis using the Cox proportional hazards model were performed to evaluate the prognostic significance of plasma fibrinogen levels. The changing patterns of plasma fibrinogen were monitored after surgical treatment to evaluate prognostic impact. Hyperfibrinogenemia was significantly associated with advanced pathological stage of cancer and high C-reactive protein levels. Plasma fibrinogen levels significantly decreased after surgical treatment in recurrence-free patients but did not decrease in patients with recurrence. The multivariate analysis indicated that preoperative hyperfibrinogenemia was an independent prognostic factor for poor survival (hazard ratio 1.005, 95% confidence interval 1.000-1.010; P = 0.039). Preoperative hyperfibrinogenemia was associated with inflammatory mediators, tumor progression, and poor survival in patients with esophageal squamous cell carcinoma. The absence of a decrease in plasma fibrinogen levels after surgical treatment may indicate the possibility of tumor recurrence.

Concurrent chemo-radiotherapy with S-1 as an alternative therapy for elderly Chinese patients with non-metastatic esophageal squamous cancer: evidence based on a systematic review and meta-analysis.

PubMed

Song, Guo-Min; Tian, Xu; Liu, Xiao-Ling; Chen, Hui; Zhou, Jian-Guo; Bian, Wei; Chen, Wei-Qing

2017-06-06

This systematic review and meta-analysis aims to systematically assess the effects of concurrent chemo-radiotherapy (CRT) compared with radiotherapy (RT) alone for elderly Chinese patients with non-metastatic esophageal squamous cancer. We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), China Biomedical Literature Database (CBM), and China National Knowledge Infrastructure (CNKI) databases. We retrieved randomized controlled trials on concurrent CRT with Gimeraciland Oteracil Porassium (S-1) compared with RT alone for aged Chinese patients with non-metastatic esophageal squamous cancer performed until August 2016. Eight eligible studies involving 536 patients were subjected to meta-analysis. As a response rate measure, a relative risk (RR) of 1.37 [95% confidence intervals (CIs): 1.24, 1.53; P = 0.00], which reached statistical significance, was estimated when concurrent CRT with S-1 was performed compared with RT alone. Sensitivity analysis on response rate confirmed the robustness of the pooled result. The RR values of 1.44 (95% CIs: 1.22, 1.70; P = 0.00) and 1.77 (95% CIs: 1.26, 2.48; P = 0.00) estimated for 1- and 2-year survival rate indices, respectively, were also statistically significant. The incidence of adverse events was similar in both groups. This review concluded that concurrent CRT with S-1 can improve the efficacy and prolong the survival period of elderly Chinese patients with non-metastatic esophageal squamous cancer and does not significantly increase the acute adverse effects of RT alone.

The expression of podoplanin protein is a diagnostic marker to distinguish the early infiltration of esophageal squamous cell carcinoma.

PubMed

Chen, Guangyong; Xu, Rui; Yue, Bing; Mei, Xue; Li, Peng; Zhou, Xiaoge; Huang, Shoufang; Gong, Liping; Zhang, Shutian

2017-03-21

The esophageal squamous cell carcinoma (ESCC) is usually develped from low-grade intraepithelial neoplasia (LGIEN) and high-grade intraepithelial neoplasia (HGIEN) to infiltrative squamous cell carcinoma. Till now, it remains hard to screen for infiltration at earlier stages, especially the differentiation between HGEIN and early infiltrative carcinoma. The purpose of this study is to determine a role of podoplanin in differentiating between HGEIN and early infiltrative squamous cell carcinoma. Totally 133 patients pathologically diagnosed with early ESCC and/or precancerous lesions were enrolled.The EnVision two-step IHC staining technique was applied using the monoclonal mouse anti-human Podoplanin antibody (clone number: D2-40). The expressions of PDPN protein on the basal layer of squamous epithelium lesions could be divided into three different patterns: complete type, incomplete (non-continuous) type, or missing type. A diagnosis of HGEIN can be made if the basal layer showed non-continuous or complete expression of PDPN and a diagnosis of early infiltration can be made if the expression of PDPN is completely missing. Our study confirmed that PDPN was a potential biomarker to identify the presence of early infiltrative squamous cell carcinoma.

The expression of podoplanin protein is a diagnostic marker to distinguish the early infiltration of esophageal squamous cell carcinoma

PubMed Central

Chen, Guangyong; Xu, Rui; Yue, Bing; Mei, Xue; Li, Peng; Zhou, Xiaoge; Huang, Shoufang; Gong, Liping; Zhang, Shutian

2017-01-01

The esophageal squamous cell carcinoma (ESCC) is usually develped from low-grade intraepithelial neoplasia (LGIEN) and high-grade intraepithelial neoplasia (HGIEN) to infiltrative squamous cell carcinoma. Till now, it remains hard to screen for infiltration at earlier stages, especially the differentiation between HGEIN and early infiltrative carcinoma. The purpose of this study is to determine a role of podoplanin in differentiating between HGEIN and early infiltrative squamous cell carcinoma. Totally 133 patients pathologically diagnosed with early ESCC and/or precancerous lesions were enrolled.The EnVision two-step IHC staining technique was applied using the monoclonal mouse anti-human Podoplanin antibody (clone number: D2-40). The expressions of PDPN protein on the basal layer of squamous epithelium lesions could be divided into three different patterns: complete type, incomplete (non-continuous) type, or missing type. A diagnosis of HGEIN can be made if the basal layer showed non-continuous or complete expression of PDPN and a diagnosis of early infiltration can be made if the expression of PDPN is completely missing. Our study confirmed that PDPN was a potential biomarker to identify the presence of early infiltrative squamous cell carcinoma. PMID:28086225

Bortezomib sensitizes esophageal squamous cancer cells to radiotherapy by suppressing the expression of HIF-1α and apoptosis proteins.

PubMed

Wang, Di; Qin, Qin; Jiang, Qin-Juan; Wang, Da-Fei

2016-04-13

Radiation therapy is a typical treatment for esophageal squamous cell carcinoma (ESCC), especially middle and upper segment esophagus, and inoperable patients. However, how to promote radiation sensitivity in radio-resistant cancer cells is a conundrum. Here, our study investigated the radiosensitizing effect of bortezomib, a specific and reversible dipeptide boronic acid analog, in ESCC cells. Human esophageal squamous carcinoma cell lines Eca109 and TE-13 were exposed to hypoxia and/or ionizing radiation (IR) with or without treatment of bortezomib. Cell proliferation assay was performed with CCK8. Cell apoptosis and cell cycle assay were performed with flow cytometry. The radiosensitization effect of was assessed by clonogenic survival and progression of tumor xenograft. The expression of HIF-1α, VEGF, and apoptosis proteins was evaluated by Western blot. Radiation-induced DNA double strand break and homologous recombination repair were assessed by immunofluorescence. Our results show that bortezomib efficiently radiosensitizes ESCC cells by decreasing the expression of HIF- 1α and VEGF, inducing apoptosis by activating caspase, and delaying DNA damage repair after radiation.

Alteration in gene expression profile and oncogenicity of esophageal squamous cell carcinoma by RIZ1 upregulation.

PubMed

Dong, Shang-Wen; Li, Dong; Xu, Cong; Sun, Pei; Wang, Yuan-Guo; Zhang, Peng

2013-10-07

To investigate the effect of retinoblastoma protein-interacting zinc finger gene 1 (RIZ1) upregulation in gene expression profile and oncogenicity of human esophageal squamous cell carcinoma (ESCC) cell line TE13. TE13 cells were transfected with pcDNA3.1(+)/RIZ1 and pcDNA3.1(+). Changes in gene expression profile were screened and the microarray results were confirmed by reverse transcription-polymerase chain reaction (RT-PCR). Nude mice were inoculated with TE13 cells to establish ESCC xenografts. After two weeks, the inoculated mice were randomly divided into three groups. Tumors were injected with normal saline, transfection reagent pcDNA3.1(+) and transfection reagent pcDNA3.1(+)/RIZ1, respectively. Tumor development was quantified, and changes in gene expression of RIZ1 transfected tumors were detected by RT-PCR and Western blotting. DNA microarray data showed that RIZ1 transfection induced widespread changes in gene expression profile of cell line TE13, with 960 genes upregulated and 1163 downregulated. Treatment of tumor xenografts with RIZ1 recombinant plasmid significantly inhibited tumor growth, decreased tumor size, and increased expression of RIZ1 mRNA compared to control groups. The changes in gene expression profile were also observed in vivo after RIZ1 transfection. Most of the differentially expressed genes were associated with cell development, supervision of viral replication, lymphocyte costimulatory and immune system development in esophageal cells. RIZ1 gene may be involved in multiple cancer pathways, such as cytokine receptor interaction and transforming growth factor beta signaling. The development and progression of esophageal cancer are related to the inactivation of RIZ1. Virus infection may also be an important factor.

Plummer-Vinson Syndrome with Proximal Esophageal Web.

PubMed

Changela, Kinesh; Haeri, Nami Safai; Krishnaiah, Mahesh; Reddy, Madhavi

2016-05-01

Plummer-Vinson Syndrome is a condition where iron deficiency is associated with difficulty swallowing due to the presence of an esophageal web. Deficiency of iron-dependent oxidative enzymes causes gradual degradation of the pharyngeal muscles which lead to mucosal atrophy and formation of webs. Although it is a very rare condition, an increased risk of esophageal squamous cell carcinoma makes its identification very important. Dilation of the esophageal web using a Savary dilator is a more effective and safer approach compared to conventional balloon dilation.

Influence of Ionizing Radiation on Stromal-Epithelial Communication in Esophageal Carcinogenesis

NASA Astrophysics Data System (ADS)

Huff, Janice; Patel, Zarana; Grugan, Katharine; Rustgi, Anil; Cucinotta, Francis A.

Esophageal cancer is the 6th leading cause of cancer death worldwide and is associated with a variety of risk factors including tobacco use, heavy alcohol consumption, human papilloma virus infection, and certain dietary factors such as trace mineral and vitamin deficiencies. A connection with ionizing radiation exposure is revealed by the high excess relative risk for esophageal squamous cell carcinoma observed in the survivors of the atomic bomb detonations in Japan. Esophageal carcinomas are also seen as secondary malignancies in patients who received radiotherapy for breast and thoracic cancers; additionally, patients with head/neck and oral squamous cell cancers are at increased risk for metachronous esophageal squamous cell cancers. This malignancy is rapidly fatal, mainly because it remains asymptomatic until late, advanced stages when the disease is rarely responsive to treatment. In normal epithelium, the stromal microenvironment is essential for the maintenance and modulation of cell growth and differentiation. Cross talk between the epithelial and stromal compartments can influence many aspects of malignant progression, including tumor cell proliferation, migration, invasion and recruitment of new blood vessels. To test the hypothesis that radiation exposure plays a role in esophageal carcinogenesis via non-targeted mechanisms involving stromal-epithelial cell communication, we are studying radiation effects on hTERT-immortalized human esophageal epithelial cells and genetic variants grown in co-culture with human esophageal stromal fibrob-lasts (Okawa et al., Genes Dev. 2007. 21: 2788-2803). We examined how irradiation of stromal fibroblasts affected epithelial migration and invasion, behaviors associated with cancer promotion and progression. These assays were conducted in modified Boyden chambers using conditioned media from irradiated fibroblasts. Our results using low LET gamma radiation showed a dose-dependent increase in migration of epithelial cells when exposed to conditioned media from irradiated vs. non-irradiated fibroblasts. We also observed enhanced invasion through a basement membrane matrix in similarly treated cells. Candidate factors that me-diate these effects were identified using antibody capture arrays, and their increased secretion in irradiated fibroblasts was confirmed using ELISAs. We are currently analyzing the effect of these individual factors on epithelial migration and invasion, as well as their influence on cell survival and DNA repair. Our current studies using high-LET radiation will elucidate radiation quality effects on these processes. These results should further our understanding of the mechanisms by which radiation impacts the tissue microenvironment and how it influences cancer development processes.

Eosinophilic esophageal myositis diagnosed by endoscopic ultrasound-guided fine-needle aspiration biopsy: a case report.

PubMed

Igarashi, Ryo; Irisawa, Atsushi; Shibukawa, Goro; Yamabe, Akane; Fujisawa, Mariko; Sato, Ai; Maki, Takumi; Arakawa, Noriyuki; Yoshida, Yoshitsugu; Yamamoto, Shogo; Ikeda, Tsunehiko

2016-10-01

Eosinophilic esophagitis (EoE) is diagnosed by microscopic findings of eosinophilic infiltration into the squamous epithelium. In contrast, another disease concept termed "eosinophilic esophageal myositis (EoEM)" has been proposed, whereby there is eosinophilic infiltration into the muscularis propria instead. A 60-year-old man was referred to our hospital for chest pain, dysphagia, and several episodes of esophageal food impaction. Although EoE was suspected based on clinical features, biopsy specimens showed no mucosal eosinophilic infiltration. Endoscopic ultrasound (EUS) showed thickening of the muscularis propria layer and subsequent EUS-guided fine-needle aspiration biopsy (EUS-FNA) revealed eosinophilic infiltration into the muscularis propria. Although the patient's symptoms gradually improved after steroid administration, complete remission was not achieved after 1 year of treatment. This case may reflect a disorder distinct from typical EoE based on eosinophilic infiltration of the muscularis propria but not the squamous epithelium, and we, therefore, diagnosed it as EoEM using the EUS-FNA findings as reference.

Alpha-Tocopherol prevents esophageal squamous cell carcinoma by modulating PPARγ-Akt signaling pathway at the early stage of carcinogenesis

PubMed Central

Zhang, Qiannan; Lu, Ping; Feng, Yongquan; Geng, Xue; Zhang, Lishi; Jia, Xudong

2017-01-01

The poor prognosis of esophageal squamous cell carcinoma (ESCC) emphasizes the urgent need to better understand the carcinogenesis and develop prevention strategies. Previous studies have highlighted the potential of using Vitamin E (tocopherols) for cancer chemoprevention, but the preventive activity of α-Tocopherol against ESCC remains to be elucidated. Our data showed that early-stage supplementation with α-Tocopherol significantly prevented esophageal carcinogenesis induced by N-nitrosomethylbenzylamine (NMBA) in ESCC rat model. In the Het-1A cell model, α-Tocopherol markedly suppressed cell proliferation, promoted cell cycle G2-phase arrest and increased apoptosis. Gene microarray and proteins array analysis indicated that Akt signaling was a potential target for α-Tocopherol. We further demonstrated that α-Tocopherol increased the expression of PPARγ and its downstream tumor suppressor PTEN. Knockdown of PPARγ activated Akt signaling transduction, whereas this process was attenuated by the presence of α-Tocopherol and PPARγ agonist Rosiglitazone. In contrast, the effect of α-Tocopherol on Akt inhibition was not observed in established tumors, neither in cancerous cell lines which constitutively expressed higher levels of PPARγ. These results were closely correlated with the ineffectiveness of α-Tocopherol in the late stage of ESCC carcinogenesis. Taken together, our study suggested that α-Tocopherol may serve as a PPARγ agonist for the chemoprevention of esophageal cancer. PMID:29221176

Prospective study of serum cysteine and cysteinylglycine and cancer of the head and neck, esophagus, and stomach in a cohort of male smokers.

PubMed

Miranti, Eugenia H; Freedman, Neal D; Weinstein, Stephanie J; Abnet, Christian C; Selhub, Jacob; Murphy, Gwen; Diaw, Lena; Männistö, Satu; Taylor, Philip R; Albanes, Demetrius; Stolzenberg-Solomon, Rachael Z

2016-09-01

The nonessential amino acid cysteine is known to be involved in many antioxidant and anticarcinogenic pathways. Cysteinylglycine is a pro-oxidant metabolite of glutathione and a precursor of cysteine. To examine the relation between serum cysteine and cysteinylglycine and risk of gastric adenocarcinomas, esophageal squamous cell carcinomas, and head and neck squamous cell carcinomas, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study of male Finnish smokers aged 50-69 y at baseline. In total, 170 gastric adenocarcinomas, 68 esophageal squamous cell carcinomas, and 270 head and neck squamous cell carcinomas (identified from the Finnish Cancer Registry) were matched one-to-one with cancer-free control subjects on age and the date of serum collection. We calculated ORs and 95% CIs with the use of a multivariate-adjusted conditional logistic regression. Cysteine had a U-shaped association with gastric adenocarcinomas; a model that included a linear and a squared term had a significant global P-test (P = 0.036). Serum cysteinylglycine was inversely associated with adenocarcinomas of the gastric cardia (OR for above the median compared with below the median: 0.07; 95% CI: 0.01, 0.70; n = 38 cases) but not for other sites. Both cysteine and cysteinylglycine were not associated with esophageal squamous cell carcinoma or head and neck squamous cell carcinoma. We observed associations between serum cysteine and cysteinylglycine with upper gastrointestinal cancer risk. Future studies are needed to replicate these findings. This trial was registered at clininicaltrials.gov as NCT00342992. © 2016 American Society for Nutrition.

Synchronous oral paracoccidioidomycosis and esophageal carcinoma.

PubMed

Tubino, Paulo Victor Alves; Sarmento, Bruno Jose de Queiroz; dos Santos, Vitorino Modesto; Borges, Estevão Ribeiro; da Silva, Lucas Evangelista Correia; Lima, Rodrigo de Souza

2012-08-01

Paracoccidioidomycosis is the most common deep mycosis in South America and is caused by Paracoccidioides brasiliensis (P. brasiliensis), a thermally dimorphic fungus. Infections usually occur by inhalation of conidia, which more often cause respiratory, mucocutaneous, and lymph nodal changes. Chronic features of this mycosis can mimic diverse infections and malignancies and constitute diagnosis challenges. Squamous cell carcinoma deserves special attention in this setting. We describe the case of a patient with synchronous diagnosis of oral paracoccidioidomycosis and esophageal squamous cell carcinoma. Concomitance of these conditions may be a casual event, but a not fully understood causal relationship can be involved.

Genetic variations in MTHFR and esophageal squamous cell carcinoma susceptibility in Chinese Han population.

PubMed

Tang, Weifeng; Zhang, Sheng; Qiu, Hao; Wang, Lixin; Sun, Bin; Yin, Jun; Gu, Haiyong

2014-05-01

Esophageal cancer is the sixth most common cancer worldwide. Esophageal squamous cell carcinoma (ESCC) is a fatal malignancy associated with low 5-year survival rate. The aim of this study was to assess the association between methylenetetrahydrofolate reductase (MTHFR) tagging single nucleotide polymorphisms (SNPs) rs1801133 C>T, rs3753584 A>G, rs4845882 G>A, rs4846048 A>G and rs9651118 T>C genotypes and ESCC susceptibility in a hospital-based case-control study. We conducted genotyping analyses for these five SNPs with 629 ESCC cases and 686 controls in a Chinese Han population. Ligation detection reaction method was used to identify genotypes of these MTHFR SNPs. Our results demonstrated that MTHFR rs1801133 C>T was associated with the risk of ESCC; however, MTHFR rs4845882 G>A and rs4846048 A>G SNPs were associated with the decreased risk of ESCC, and MTHFR rs3753584 A>G and rs9651118 T>C SNPs were not associated with ESCC risk. Our findings suggests that MTHFR rs1801133 C>T, rs4845882 G>A and rs4846048 A>G SNPs may be genetic modifiers for developing ESCC in Chinese Han population.

Role of AMPK signaling in mediating the anticancer effects of silibinin in esophageal squamous cell carcinoma.

PubMed

Li, Jin; Li, Bin; Xu, Wen Wen; Chan, Kwok Wah; Guan, Xin Yuan; Qin, Yan Ru; Lee, Nikki Pui Yue; Chan, Kin Tak; Law, Simon; Tsao, Sai Wah; Cheung, Annie Lm

2016-01-01

Emerging evidence suggests that activation of adenosine monophosphate-activated protein kinase (AMPK) may suppress cancer growth. Identification of novel AMPK activators is therefore crucial to exploit AMPK as a potential target for cancer prevention and treatment. We determined the expression status and role of AMPK in esophageal squamous cell carcinoma (ESCC) and investigated whether silibinin, a nontoxic natural product, could activate AMPK to inhibit ESCC development. Our results from 49 pairs of human ESCC and normal tissues showed that AMPK was constitutively inactive in the majority (69.4%) of ESCC. We found that silibinin induced apoptosis, and inhibited ESCC cell proliferation in vitro and tumorigenicity in vivo without any adverse effects. Silibinin also markedly suppressed the invasive potential of ESCC cells in vitro and their ability to form lung metastasis in nude mice. The anticancer effects of silibinin were abrogated by the presence of compound C or shRNA against AMPK. More importantly, silibinin enhanced the sensitivity of ESCC cells and tumors to the chemotherapeutic drugs, 5-fluorouracil and cisplatin. This preclinical study supports that AMPK is a valid therapeutic target and suggests that silibinin may be a potentially useful therapeutic agent and chemosensitizer for esophageal cancer.

Targeted imaging of esophageal neoplasia with a fluorescently labeled peptide: First in-human results

PubMed Central

Sturm, Matthew B.; Joshi, Bishnu P.; Lu, Shaoying; Piraka, Cyrus; Khondee, Supang; Elmunzer, B. Joseph; Kwon, Richard S.; Beer, David G.; Appelman, Henry; Turgeon, D. Kim; Wang, Thomas D.

2013-01-01

Esophageal adenocarcinoma is rising rapidly in incidence, and usually develops from Barrett’s esophagus, a precursor condition commonly found in patients with chronic acid reflux. Pre-malignant lesions are challenging to detect on conventional screening endoscopy because of their flat appearance. Molecular changes can be used to improve detection of early neoplasia. We have developed a peptide that binds specifically to high-grade dysplasia and adenocarcinoma. We first applied the peptide ex vivo to esophageal specimens from 17 patients to validate specific binding. Next, we performed confocal endomicroscopy in vivo in 25 human subjects after topical peptide administration and found 3.8-fold greater fluorescence intensity for esophageal neoplasia compared with Barrett’s esophagus and squamous epithelium with 75% sensitivity and 97% specificity. No toxicity was attributed to the peptide in either animal or patient studies. Therefore, our first-in-humans results show that this targeted imaging agent is safe, and may be useful for guiding tissue biopsy and for early detection of esophageal neoplasia and potentially other cancers of epithelial origin, such as bladder, colon, lung, pancreas, and stomach. PMID:23658246

Esophageal squamous cell carcinomas with DNA replication errors (RER+) are associated with p16/pRb loss and wild-type p53.

PubMed

Mathew, R; Arora, S; Mathur, M; Chattopadhyay, T K; Ralhan, R

2001-10-01

Microsatellite instability (MSI) as a determinant of propensity to esophageal squamous cell carcinoma (ESCC) at seven microsatellite markers at 2p (2p15-16), 3p (3p13, 3p14.1-3, 3p25, and 3p26) and 16q (16q12.1-3) was investigated to analyze their putative role as indicators of predisposition to esophageal malignancies. Seven microsatellite loci were amplified by polymerase chain reaction, from surgically resected tumor tissues from 30 ESCC patients from Indian population, to assess the loss of heterozygosity (LOH) and replication error repeats (RER) and to correlate these alterations with aberrations in major cell cycle regulatory proteins and histopathological parameters. LOH and RER analyses at these loci demonstrated moderate microsatellite alterations, suggesting the involvement of MSI in esophageal tumorigenesis in a subset of the Indian population. MSI, defined as RER in at least two or more of the loci studied, was observed in ten of 30 (33%) patients. Twenty-two of 30 patients (73%) showed LOH at one or more loci, while 17 of the 30 patients (60%) showed RER in at least one of the loci studied. RER-positive patients showed a trend towards better prognosis when compared to RER-negative patients. MSI demonstrated a significant association with concomitant loss of p16 and pRb (p16-/pRb- phenotype) (P=0.046). Interestingly, we observed an inverse correlation between MSI and p53 mutations (P=0.03) suggesting that MSI may provide a p53-independent pathway for esophageal tumorigenesis in RER+ patients. MSI showed a trend towards longer survival and absence of distant organ metastasis (P=0.06). The present study demonstrates the probable role of MSI in esophageal squamous cell carcinoma in the Indian population. Instability associated with the repetitive sequences--the revealing marks of loss of DNA replication fidelity may serve as an indicator of predisposition to esophageal cancer.

Risk factors for esophageal stenosis after entire circumferential endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma.

PubMed

Miwata, Tomohiro; Oka, Shiro; Tanaka, Shinji; Kagemoto, Kenichi; Sanomura, Yoji; Urabe, Yuji; Hiyama, Toru; Chayama, Kazuaki

2016-09-01

Endoscopic submucosal dissection (ESD) is used to perform en block resection for esophageal squamous cell carcinoma, but it is strongly associated with postoperative stenosis, especially during entire circumferential resection. This study aimed to clarify the risk factors for refractory postoperative stenosis after entire circumferential esophageal ESD. Nineteen patients who underwent entire circumferential esophageal ESD from February 2006 to December 2013 at Hiroshima University Hospital were divided into two groups: refractory postoperative stenosis [≥6 endoscopic balloon dilation (EBD) procedures, 12 lesions in 12 patients] and non-refractory postoperative stenosis (≤5 EBD procedures, 7 lesions in 7 patients). We retrospectively examined the patient factors (age, sex, alcohol consumption, smoking index, and chemoradiation therapy history), tumor factors (location, macroscopic type, fibrosis, and depth), and treatment factors (mean procedure time, entire circumferential resection diameter, muscle layer damage, and steroid administration method) between the two groups. Muscle layer damage (p = 0.019) and ≥5 cm of longitudinal mucosal defect length after entire circumferential esophageal ESD (p = 0.010) were significant factors associated with the refractory group. Regarding the patient and tumor factors, there were no significant differences between the two groups. Our data suggest that refractory post-ESD stenosis occurs after entire circumferential esophageal ESD with muscle layer damage and ≥5 cm of longitudinal mucosal defect length.

Safety and efficacy of endoscopic submucosal dissection using IT knife nano with clip traction method for early esophageal squamous cell carcinoma.

PubMed

Kitagawa, Yoshiyasu; Suzuki, Takuto; Hara, Taro; Yamaguchi, Taketo

2018-01-01

Although endoscopic submucosal dissection (ESD) is an accepted and established treatment for early esophageal squamous cell carcinoma (EESCC), it is technically difficult, time consuming, and less safe than endoscopic mucosal resection. To perform ESD safely and more efficiently, we proposed a new technique of esophageal ESD using an IT knife nano with the clip traction method. This study aimed to evaluate the efficacy and safety of ESD using this new technique. We retrospectively reviewed all consecutive cases of esophageal ESD performed using an IT knife nano with the clip traction method at our hospital between March 2013 and January 2017. Therapeutic efficacy and safety were also assessed. A total of 103 patients underwent esophageal ESD using the IT knife nano with the clip traction method. In all cases, we performed en bloc resection. Complete resection was achieved in 100 cases (97.1%). The median operating time was 40 (range 13-230) min. No cases of perforation or delayed bleeding occurred. Although two cases (2.0%) of mediastinal emphysema occurred without visible perforation at endoscopy, all were successfully managed conservatively. The new technique of esophageal ESD using the IT knife nano with the clip traction method appears to be feasible, effective, and safe for EESCC treatment.

Transcriptional regulation of miR-146b by C/EBPβ LAP2 in esophageal cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Junxia; Shan, Fabo; Xiong, Gang

2014-03-28

Highlights: • MiR-146b promotes esophageal cancer cell proliferation. • MiR-146b inhibits esophageal cancer cell apoptosis. • C/EBPβ directly binds to miR-146b promoter conserved region. • MiR-146b is up-regulated by C/EBPβ LAP2 transcriptional activation. - Abstract: Recent clinical study indicated that up-regulation of miR-146b was associated with poor overall survival of patients in esophageal squamous cell carcinoma. However, the underlying mechanism of miR-146b dysregulation remains to be explored. Here we report that miR-146b promotes cell proliferation and inhibits cell apoptosis in esophageal cancer cell lines. Mechanismly, two C/EBPβ binding motifs are located in the miR-146b promoter conserved region. Among the threemore » isoforms of C/EBPβ, C/EBPβ LAP2 positively regulated miR-146b expression and increases miR-146b levels in a dose-dependent manner through transcription activation of miR-146b gene. Together, these results suggest a miR-146b regulatory mechanism involving C/EBPβ, which may contribute to the up-regulation of miR-146b in esophageal squamous cell carcinoma.« less

47-mG2a: A Mouse IgG2a-Type of PcMab-47 Useful for Detecting Podocalyxin in Esophageal Cancers by Immunohistochemistry.

PubMed

Kaneko, Mika K; Itai, Shunsuke; Yamada, Shinji; Kato, Yukinari

2018-04-09

Esophageal cancer is one of the highly malignant cancers. It comprises two of the most common histological tumor types: squamous cell carcinoma (SCC) and adenocarcinoma. SCC accounts for about 90% of esophageal cancers. Despite developments in treatment strategies, the prognosis and survival rate remain poor. Podocalyxin (PODXL) is a highly glycosylated type-I transmembrane protein. It is expressed in normal tissues such as kidney, heart, breast, and pancreas. Upregulation of PODXL correlates with tumor progression, invasion, and metastasis. Therefore, this glycoprotein could be a potential biomarker for predicting the prognosis of some cancers, for instance, brain, colorectal, oral, lung, bladder, prostate, and ovarian cancers. We previously developed a specific and sensitive anti-PODXL monoclonal antibody (mAb), PcMab-47 (mouse IgG 1 , kappa) and its mouse IgG 2a -type (47-mG 2a ). We showed their utility in immunohistochemical analysis of oral cancers. Herein, we demonstrate that PcMab-47 and 47-mG 2a can also be used to detect esophageal squamous cell carcinoma (ESCC) with this technique. These two antibodies, respectively, stained 123/130 (94.6%) and 127/130 (97.7%) ESCC cases, indicating that they can detect PODXL with high sensitivity in this carcinoma. Of more than 3+ cases, 47-mG 2a was more effective than PcMab-47, respectively, staining 56/127 (44.1%) and 41/123 (33.3%). Therefore, 47-mG 2a can be used for the detection of PODXL in ESCC using immunohistochemical analysis.

From reflux esophagitis to Barrett’s esophagus and esophageal adenocarcinoma

PubMed Central

Wang, Rui-Hua

2015-01-01

The occurrence of gastroesophageal reflux disease is common in the human population. Almost all cases of esophageal adenocarcinoma are derived from Barrett’s esophagus, which is a complication of esophageal adenocarcinoma precancerous lesions. Chronic exposure of the esophagus to gastroduodenal intestinal fluid is an important determinant factor in the development of Barrett’s esophagus. The replacement of normal squamous epithelium with specific columnar epithelium in the lower esophagus induced by the chronic exposure to gastroduodenal fluid could lead to intestinal metaplasia, which is closely associated with the development of esophageal adenocarcinoma. However, the exact mechanism of injury is not completely understood. Various animal models of the developmental mechanisms of disease, and theoretical and clinical effects of drug treatment have been widely used in research. Recently, animal models employed in studies on gastroesophageal reflux injury have allowed significant progress. The advantage of using animal models lies in the ability to accurately control the experimental conditions for better evaluation of results. In this article, various modeling methods are reviewed, with discussion of the major findings on the developmental mechanism of Barrett’s esophagus, which should help to develop better prevention and treatment strategies for Barrett’s esophagus. PMID:25954094

Evaluation of combined argon plasma coagulation and Savary Bougienage for the relief of anastomotic-stenosis after esophageal squamous cancer surgery.

PubMed

Jia, Ruinuo; Guo, Ruifeng; Liu, Gang; Yuan, Xiang; Dong, Caihong; Shan, Tanyou; Yuan, Xiaozhi; Zhang, Yi; Tai, Edmund Wing To; Feng, Xiaoshan; Gao, Shegan

2014-01-01

Several endoscopic dilation techniques have been reported for treatment of anastomotic-stenosis of esophageal cancer, but the high incidence of dysphagia has remained unchanged. The aim of this study was to compare the effect of Argon Plasma Coagulation (APC) combined with Savary Bougienage (SB) compared to APC alone or SB alone for anastomotic-stenosis after radical operation for squamous cell carcinoma of the esophagus. Patients with anastomotic-stenosis that was diagnosed for the first time following esophageal squamous cell carcinoma resection surgery were randomly assigned to undergo APC combined with SB, APC alone, or SB alone. Primary endpoints were the dysphagia-free survival (DFS defined as the time from first dilatation of effectively relieved dysphagia to dysphagia relapse expressed in days) after 6 months of follow up. A total of 90 patients from the Cancer Institute, First Affiliated Hospital of Henan University of Science and Technology were entered into the study (APC group, n = 30, SB group, n = 30, combination group [APC combined with SB], n = 30). Primary endpoints: 6 months after treatment, DFS of combination group (115.63 days; 95% CI, 105.31-125.95) was significantly longer than the APC alone group (39.53 days; 95% CI, 35.95-43.11, p = 0.000) and the SB alone group (16.93 days; 95% CI, 15.01-18.84, p = 0.000). No severe complications occurred within the three treatment groups. APC combined with SB was a safe and well-tolerated method for relieving dysphagia of esophageal squamous cell cancer patients with anastomotic-stenosis. (Registered with randomized controlled trials, ChiCRT, registration number ChiCTR-TRC-13003757.) © 2015 S. Karger AG, Basel.

[Comparison of the prognostic value of the seventh and eighth edition of The AJCC Esophageal Cancer Staging System for the patients with stage Ⅱ and Ⅲesophageal squamous cell carcinoma].

PubMed

Zhong, H; Ma, R; Gong, L; Chen, C G; Tang, P; Ren, P; Jiang, H J; Yu, Z T

2017-12-01

Objective: To compare and evaluate the prognostic value of the 7(th) and 8(th) edition of The AJCC Esophageal Cancer Staging System for patients with stage Ⅱ and Ⅲ esophageal squamous cell carcinoma. Methods: The clinical data of 328 esophageal cancer patients who received operation at Department of Esophageal Cancer, Tianjin Tumour Hospital from January 2006 to December 2010 were restrospectively analyzed. There were 63 female and 265 male patients. The mean age was 65 (range: 33 to 87) years. Univariate and multivariate analysis were performed to identify the prognosis factors. Results: The five years overall survival rates among patients with stage Ⅱ and Ⅲ were both significantly different (χ(2)=87.035, 84.730, all P =0.000) according to the 7(th) and 8(th) editions of the TNM staging systems. The five years overall survival rate among patients with stage ⅡB and ⅢA were significantly different (39.6% vs 23.4%, P =0.001) according to the 7(th) edition of the esophageal cancer staging systems.According to the 8(th) edition of the esophageal cancer staging system, the 5 years survival rate of patients with stage ⅡA and ⅡB, ⅢB and Ⅳ was statistically significant (58.5% vs . 35.5%, P =0.040; 18.9% vs . 0, P =0.000). In multivariate analysis, tumor size, T staging, N staging and tumor differentiation ( HR =1.592, 95% CI: 1.185 to 2.139, P =0.002; HR =1.519, 95% CI: 1.236 to 1.867, P =0.000; HR =1.647, 95% CI: 1.448 to 1.874, P =0.000; HR =1.404, 95% CI: 1.059 to 1.861, P =0.018) were the main independent prognosis factors affecting the prognosis of esophageal squamous cell carcinoma patients. Conclusions: Both the 7(th) and the 8(th) editions of TNM staging systems are able to reflect the clinical prognosis of patients receiving radical resection of esophageal cancer, and the factors of tumor size, differentiaton, invasion depth and lymph node metastases are the independent predictors of prognosis. The 8(th) edition provides a more detailed and more reasonable for the staging of stage Ⅱ and Ⅲ for esophageal cancer patients than the 7(th) edition, and it is more accurate for the prognosis of patients with esophageal cancer after surgery.

Influence of Ionizing Radiation on Stromal-Epithelial Intercellular Communication in Esophageal Carcinogenesis

NASA Technical Reports Server (NTRS)

Patel, Zarana S.; Kalabis, Jiri; Rustgi, Anil K.; Cucinotta, Francis A.; Huff, Janice L.

2010-01-01

Esophageal cancer is the 6th leading cause of cancer death worldwide. Its development is associated with a variety of risk factors including tobacco use, heavy alcohol consumption, human papilloma virus infection, and certain dietary factors such as trace mineral and vitamin deficiencies. An association with ionizing radiation exposure is revealed by the high excess relative risk for squamous cell carcinoma of the esophagus observed in the survivors of the atomic bomb detonations in Japan. It is also seen as a secondary malignancy in patients who received radiotherapy for breast and thoracic cancers; additionally, patients with head/neck and oral squamous cell cancers are at increased risk for metachronous esophageal squamous cell cancers. This malignancy is rapidly fatal, mainly because it remains asymptomatic until late, advanced stages when the disease is rarely curable. The stromal microenvironment plays an essential role in the maintenance and modulation of normal epithelial cell growth and differentiation and cross talk between the epithelial and stromal compartments can influence many aspects of malignant progression, including tumor cell proliferation, migration, invasion and recruitment of new blood vessels. To test the hypothesis that radiation exposure plays a role in esophageal carcinogenesis via non-targeted mechanisms involving stromal-epithelial cell communication, we are studying radiation effects on hTERT-immortalized human esophageal epithelial cells and genetic variants grown in co-culture with human esophageal stromal fibroblasts (Okawa et al., Genes & Dev. 2007. 21: 2788-2803). We examined how radiation treatment of stromal fibroblasts affected epithelial migration and invasion, behaviors associated with cancer promotion and progression. Chemotactic and haptotactic migration of epithelial cells stimulated by conditioned media from irradiated fibroblasts was measured using assays conducted in Transwell cell culture chambers. Our results using low LET radiation showed a dose-dependent increase in migration of epithelial cells when exposed to conditioned media from irradiated vs. non-irradiated fibroblasts. We also observed enhanced invasion through a basement membrane simulant. To identify chemotactic proteins secreted by irradiated stromal fibroblasts, we used antibody capture cytokine arrays and have identified several proteins as candidates. Increased secretion of these factors by irradiated fibroblasts was confirmed using ELISA. We are currently analyzing the contribution of these individual factors on epithelial migration and invasion, as well as their influence on cell survival and DNA repair. Studies using high-LET radiation will help determine radiation quality effects on these processes. These results should further our understanding of the mechanisms by which radiation impacts the tissue microenvironment and how it influences cancer development processes.

Marital status, education, and income in relation to the risk of esophageal and gastric cancer by histological type and site.

PubMed

Lagergren, Jesper; Andersson, Gunnar; Talbäck, Mats; Drefahl, Sven; Bihagen, Erik; Härkönen, Juho; Feychting, Maria; Ljung, Rickard

2016-01-15

Marital status, income, and education might influence the risk of esophageal and gastric cancer, but the literature is limited. A large study addressing subtypes of these tumors was used to clarify these associations. A nationwide, Swedish population-based cohort study from 1991 to 2010 included individuals who were 50 years old or older. Data on exposures, covariates, and outcomes were obtained from well-maintained registers. Four esophagogastric tumor subtypes were analyzed in combination and separately: esophageal adenocarcinoma, esophageal squamous cell carcinoma, cardia adenocarcinoma, and noncardia gastric adenocarcinoma. Poisson regression was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Analyses were stratified by sex and adjusted for confounders. Among 4,734,227 participants (60,634,007 person-years), 24,095 developed esophageal or gastric cancer. In comparison with individuals in a long marriage, increased IRRs were found among participants who were in a shorter marriage or were never married, remarried, divorced, or widowed. These associations were indicated for each tumor subtype but were generally stronger for esophageal squamous cell carcinoma. Higher education and income were associated with decreased IRRs in a seemingly dose-response manner and similarly for each subtype. In comparison with the completion of only primary school, higher tertiary education rendered an IRR of 0.64 (95% CI, 0.60-0.69) for men and an IRR of 0.68 (95% CI, 0.61-0.75) for women. Comparing participants in the highest and lowest income brackets (highest 20% vs lowest 20%) revealed an IRR of 0.74 (95% CI, 0.70-0.79) for men and an IRR of 0.83 (95% CI, 0.76-0.91) for women. Divorce, widowhood, living alone, low educational attainment, and low income increase the risk of each subtype of esophageal and gastric cancer. These associations require attention when high-risk individuals are being identified. Cancer 2016;122:207-212. © 2015 American Cancer Society. © 2015 American Cancer Society.

Is a Preoperative Gastrointestinal Endoscopy for Second Primary Cancer Detection in Head and Neck Cancer Necessary? Ten-year Registry Data.

PubMed

Heo, Gyeong Mi; Kim, Mi Hee; Kim, Jin Hwan; Rho, Young Soo; Shin, Woon Geon

2016-07-25

In head and neck squamous cell carcinoma, second primary gastrointestinal tumors are not uncommon. However, it is unclear whether a screening endoscopy is needed for detecting gastrointestinal neoplasm in patients with head and neck cancer. Therefore, we analyzed the prevalence and independent risk factors for second primary gastrointestinal neoplasm in head and neck squamous cell carcinoma. A consecutive series of 328 patients with primary head and neck squamous cell carcinoma that underwent esophagogastroduodenoscopy or colonoscopy were included using our registry. An age- and sex-matched group of 328 control subjects was enrolled. We assessed risk factors of synchronous gastrointestinal cancer. The prevalence of esophageal cancer with head and neck squamous cell carcinoma was significantly higher than that of the control group (1.5% vs. 0.0%, p=0.011). An age of 54 years or more (OR, 1.033; 95% CI, 1.008-1.059; p=0.009) and male gender (OR, 4.974; 95% CI, 1.648-15.013; p=0.004) were risk factors for concomitant colorectal cancer or adenomas in the head and neck squamous cell carcinoma patients. Preoperative colonoscopy can be recommended for detecting synchronous second primary colorectal lesions in head and neck squamous cell carcinoma patients with male sex regardless of age, and esophagogastroduodenoscopy is necessary in all head and neck squamous cell carcinoma patients for detecting esophageal cancer.

People’s Republic of China Scientific Abstracts, Number 171

DTIC Science & Technology

1977-07-07

Pathology of Paryngo- Esophageal Cancers in Domestic Fowls from Honan Migrant Communities and Native Inhabitants in Chung-hsiang County, Hupeh Province...survey on the mortality rate of esophageal cancers in Chung-hsiang county, Hupeh province, it is known that the communities of migrants from Honan...squamous cell carcinoma. In 5 out of the 12 cases of diseased fowls, the owners and their neighbors had also suffered from esophageal cancer. Results

Chronic inflammation-associated genomic instability paves the way for human esophageal carcinogenesis.

PubMed

Lin, Runhua; Zhang, Chong; Zheng, Jiaxuan; Tian, Dongping; Lei, Zhijin; Chen, Donglin; Xu, Zexin; Su, Min

2016-04-26

Chronic inflammation is associated with increased risk of cancer development, whereas the link between chronic inflammation and esophageal carcinogenesis is still obscure heretofore. This study aimed to investigate the relationship between chronic inflammation and DNA damage, as well as the possible role of DNA damage in esophageal carcinogenic process. Endoscopic esophageal biopsies from 109 individuals from Chaoshan littoral, a high-risk region for esophageal squamous cell carcinoma (ESCC), were examined to evaluate the association between chronic inflammation and histological severity, while additional 204 esophageal non-tumor samples from patients with ESCC were collected. Immunohistochemistry was performed to detect the oxidative DNA damage and DNA double-strand breaks (DSBs). Significantly positive correlation was observed between degree of chronic inflammation and esophageal precursor lesions (rs = 0.37, P < 0.01). Immunohistochemical analysis showed that oxidative DNA damage level was positively correlated with the degree of chronic inflammation (rs = 0.21, P < 0.05). Moreover, the level of oxidative DNA damage positively correlated with histological severity (rs = 0.49, P < 0.01). We found that the extent of DSBs was progressively increased with inflammation degree (P < 0.01) and the progression of precancerous lesions (P < 0.001). Collectively, these findings provide evidence linking chronic inflammation-associated genomic instability with esophageal carcinogenesis and suggest possibilities for early detection and intervention of esophageal carcinogenesis.

The initial establishment and epithelial morphogenesis of the esophagus: a new model of tracheal–esophageal separation and transition of simple columnar into stratified squamous epithelium in the developing esophagus

PubMed Central

Que, Jianwen

2016-01-01

The esophagus and trachea are tubular organs that initially share a single common lumen in the anterior foregut. Several models have been proposed to explain how this single-lumen developmental intermediate generates two tubular organs. However, new evidence suggests that these models are not comprehensive. I will first briefly review these models and then propose a novel ‘splitting and extension’ model based on our in vitro modeling of the foregut separation process. Signaling molecules (e.g., SHHs, WNTs, BMPs) and transcription factors (e.g., NKX2.1 and SOX2) are critical for the separation of the foregut. Intriguingly, some of these molecules continue to play essential roles during the transition of simple columnar into stratified squamous epithelium in the developing esophagus, and they are also closely involved in epithelial maintenance in the adults. Alterations in the levels of these molecules have been associated with the initiation and progression of several esophageal diseases and cancer in adults. PMID:25727889

Hyperinsulinemia Promotes Esophageal Cancer Development in a Surgically-Induced Duodeno-Esophageal Reflux Murine Model

PubMed Central

Dedja, Arben; Giacometti, Cinzia; Francia, Simona; Fabris, Federico; Zaramella, Alice; Gallagher, Emily J.; Cassaro, Mauro; Rugge, Massimo; LeRoith, Derek; Alberti, Alfredo; Realdon, Stefano

2018-01-01

Hyperinsulinemia could have a role in the growing incidence of esophageal adenocarcinoma (EAC) and its pre-cancerous lesion, Barrett’s Esophagus, a possible consequence of Gastro-Esophageal Reflux Disease. Obesity is known to mediate esophageal carcinogenesis through different mechanisms including insulin-resistance leading to hyperinsulinemia, which may mediate cancer progression via the insulin/insulin-like growth factor axis. We used the hyperinsulinemic non-obese FVB/N (Friend leukemia virus B strain) MKR (muscle (M)-IGF1R-lysine (K)-arginine (R) mouse model to evaluate the exclusive role of hyperinsulinemia in the pathogenesis of EAC related to duodeno-esophageal reflux. FVB/N wild-type (WT) and MKR mice underwent jejunum-esophageal anastomosis side—to end with the exclusion of the stomach. Thirty weeks after surgery, the esophagus was processed for histological, immunological and insulin/Insulin-like growth factor 1 (IGF1) signal transduction analyses. Most of the WT mice (63.1%) developed dysplasia, whereas most of the MKR mice (74.3%) developed squamous cell and adenosquamous carcinomas, both expressing Human Epidermal growth factor receptor 2 (HER2). Hyperinsulinemia significantly increased esophageal cancer incidence in the presence of duodenal-reflux. Insulin receptor (IR) and IGF1 receptor (IGF1R) were overexpressed in the hyperinsulinemic condition. IGF1R, through ERK1/2 mitogenic pattern activation, seems to be involved in cancer onset. Hyperinsulinemia-induced IGF1R and HER2 up-regulation could also increase the possibility of forming of IGF1R/HER2 heterodimers to support cell growth/proliferation/progression in esophageal carcinogenesis. PMID:29662006

Hyperinsulinemia Promotes Esophageal Cancer Development in a Surgically-Induced Duodeno-Esophageal Reflux Murine Model.

PubMed

Arcidiacono, Diletta; Dedja, Arben; Giacometti, Cinzia; Fassan, Matteo; Nucci, Daniele; Francia, Simona; Fabris, Federico; Zaramella, Alice; Gallagher, Emily J; Cassaro, Mauro; Rugge, Massimo; LeRoith, Derek; Alberti, Alfredo; Realdon, Stefano

2018-04-14

Hyperinsulinemia could have a role in the growing incidence of esophageal adenocarcinoma (EAC) and its pre-cancerous lesion, Barrett's Esophagus, a possible consequence of Gastro-Esophageal Reflux Disease. Obesity is known to mediate esophageal carcinogenesis through different mechanisms including insulin-resistance leading to hyperinsulinemia, which may mediate cancer progression via the insulin/insulin-like growth factor axis. We used the hyperinsulinemic non-obese FVB/N (Friend leukemia virus B strain) MKR (muscle (M)-IGF1R-lysine (K)-arginine (R) mouse model to evaluate the exclusive role of hyperinsulinemia in the pathogenesis of EAC related to duodeno-esophageal reflux. FVB/N wild-type (WT) and MKR mice underwent jejunum-esophageal anastomosis side-to end with the exclusion of the stomach. Thirty weeks after surgery, the esophagus was processed for histological, immunological and insulin/Insulin-like growth factor 1 (IGF1) signal transduction analyses. Most of the WT mice (63.1%) developed dysplasia, whereas most of the MKR mice (74.3%) developed squamous cell and adenosquamous carcinomas, both expressing Human Epidermal growth factor receptor 2 (HER2). Hyperinsulinemia significantly increased esophageal cancer incidence in the presence of duodenal-reflux. Insulin receptor (IR) and IGF1 receptor (IGF1R) were overexpressed in the hyperinsulinemic condition. IGF1R, through ERK1/2 mitogenic pattern activation, seems to be involved in cancer onset. Hyperinsulinemia-induced IGF1R and HER2 up-regulation could also increase the possibility of forming of IGF1R/HER2 heterodimers to support cell growth/proliferation/progression in esophageal carcinogenesis.

Comparison of the clinical efficacy between single-agent and dual-agent concurrent chemoradiotherapy in the treatment of unresectable esophageal squamous cell carcinoma: a multicenter retrospective analysis.

PubMed

Li, Jie; Gong, Youling; Diao, Peng; Huang, Qingmei; Wen, Yixue; Lin, Binwei; Cai, Hongwei; Tian, Honggang; He, Bing; Ji, Lanlan; Guo, Ping; Miao, Jidong; Du, Xiaobo

2018-01-22

Some Chinese patients with esophageal squamous cell carcinomaare often treated with single-agent concurrent chemoradiotherapy. However, no results have been reported from randomized controlled clinical trials comparing single-agent with double-agent concurrent chemoradiotherapy. It therefore remains unclear whether these regimens are equally clinically effective. In this study, we retrospectively analyzed and compared the therapeutic effects of single-agent and double-agent concurrent chemoradiotherapy in patients with unresectable esophageal squamous cell carcinoma. This study enrolled 168 patients who received definitive concurrent chemoradiotherapy for locally advanced unresectable esophageal squamous carcinoma at 10 hospitals between 2010 and 2015. We evaluated survival time and toxicity. The Kaplan-Meier method was used to estimate survival data. The log-rank test was used in univariate analysis A Cox proportional hazards regression model was used to conduct a multivariate analysis of the effects of prognostic factors on survival. In this study, 100 (59.5%) and 68 patients (40.5%) received single-agent and dual-agent combination chemoradiotherapy, respectively. The estimate 5-year progression-free survival (PFS) rate and overall survival (OS) rate of dual-agent therapy was higher than that of single-agent therapy (52.5% and 40.9%, 78.2% and 60.7%, respectively), but there were no significant differences (P = 0.367 and 0.161, respectively). Multivariate analysis showed that sex, age,and radiotherapy dose had no significant effects on OS or PFS. Only disease stage was associated with OS and PFS in the multivariable analysis (P = 0.006 and 0.003, respectively). In dual-agent group, the incidence of acute toxicity and the incidence of 3 and4 grade toxicity were higher than single-agent group. The 5-year PFS and OS rates of dual-agent therapy were higher than those of single-agent concurrent chemoradiotherapy for patients with unresectable esophageal squamous cell carcinoma; however, there were no significant differences in univariate analysis and multivariable analysis. Single-agent concurrent chemotherapy had less toxicity than a double-drug regimen. Therefore, we suggest that single therapis not inferior to dual therapy y. In the future, we aim to confirm our hypothesis through a prospective randomized study.

Long noncoding RNA, tissue differentiation-inducing nonprotein coding RNA is upregulated and promotes development of esophageal squamous cell carcinoma.

PubMed

Xu, Y; Qiu, M; Chen, Y; Wang, J; Xia, W; Mao, Q; Yang, L; Li, M; Jiang, F; Xu, L; Yin, R

2016-11-01

Esophageal squamous cell carcinoma (ESCC) is one of the major causes of cancer death worldwide, especially in Eastern Asia. Due to the poor prognosis, it is necessary to further dissect the underlying mechanisms and explore therapeutic targets of ESCC. Recently, studies show that long noncoding RNAs (lncRNAs) have critical roles in diverse biological processes, including tumorigenesis. Increasing evidence indicates that some lncRNAs are widely involved in the development and progression of ESCC, such as HOTAIR, SPRY4-IT1 and POU3F3. An emerging lncRNA, tissue differentiation-inducing nonprotein coding RNA (TINCR), has been studied in human cutaneous squamous cell carcinoma and has critical biological function, but its role in ESCC remains unknown. Here, we evaluated the expression profile of TINCR and its biological function in ESCC. In a cohort of 56 patients, TINCR was significantly overexpressed in ESCC tissues compared with paired adjacent normal tissues. Further, in vitro silencing TINCR via small interfering RNA (siRNA) inhibited the proliferation, migration and invasion of ESCC cells. Meantime, siRNA treatment induced apoptosis and blocked the progression of cell cycle. Taken together, our study suggests that TINCR promotes proliferation, migration and invasion of ESCC cells, acting as a potential oncogene of ESCC. © 2016 International Society for Diseases of the Esophagus.

Long non-coding RNA GAS5 is induced by interferons and plays an antitumor role in esophageal squamous cell carcinoma.

PubMed

Huang, Jianbing; Li, Yuan; Lu, Zhiliang; Che, Yun; Sun, Shouguo; Mao, Shuangshuang; Lei, Yuanyuan; Zang, Ruochuan; Li, Ning; Sun, Nan; He, Jie

2018-05-09

The long non-coding RNA GAS5 has been reported as a tumor suppressor in many cancers. However, its functions and mechanisms remain largely unknown in esophageal squamous cell carcinoma (ESCC). In this study, we found that GAS5 was over-expressed in ESCC tissue compared with that in normal esophageal tissue in a public database. Functional studies showed that GAS5 could inhibit ESCC cell proliferation, migration and invasion in vitro. Further analysis revealed that GAS5 was regulated by interferon (IFN) responses via the JAK-STAT pathway. Moreover, as an IFN-stimulated gene (ISG), GAS5 was a positive regulator of IFN responses. The feedback loop between GAS5 and the IFN signaling pathway plays an important antitumor role in ESCC, thus providing novel potential therapeutic targets. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Endoscopic Management of Early Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus: Screening, Diagnosis, and Therapy.

PubMed

di Pietro, Massimiliano; Canto, Marcia I; Fitzgerald, Rebecca C

2018-01-01

Because the esophagus is easily accessible with endoscopy, early diagnosis and curative treatment of esophageal cancer is possible. However, diagnosis is often delayed because symptoms are not specific during early stages of tumor development. The onset of dysphagia is associated with advanced disease, which has a survival at 5 years lower than 15%. Population screening by endoscopy is not cost-effective, but a number of alternative imaging and cell analysis technologies are under investigation. The ideal screening test should be inexpensive, well tolerated, and applicable to primary care. Over the past 10 years, significant progress has been made in endoscopic diagnosis and treatment of dysplasia (squamous and Barrett's), and early esophageal cancer using resection and ablation technologies supported by evidence from randomized controlled trials. We review the state-of-the-art technologies for early diagnosis and minimally invasive treatment, which together could reduce the burden of disease. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

High-dose-rate intraluminal brachytherapy prior to external radiochemotherapy in locally advanced esophageal cancer: preliminary results

PubMed Central

Safaei, Afsaneh Maddah; Ghalehtaki, Reza; Khanjani, Nezhat; Farazmand, Borna; Babaei, Mohammad

2017-01-01

Purpose Dysphagia is a common initial presentation in locally advanced esophageal cancer and negatively impacts patient quality of life and treatment compliance. To induce fast relief of dysphagia in patients with potentially operable esophageal cancer high-dose-rate (HDR) brachytherapy was applied prior to definitive radiochemotherapy. Material and methods In this single arm phase II clinical trial between 2013 to 2014 twenty patients with locally advanced esophageal cancer (17 squamous cell and 3 adenocarcinoma) were treated with upfront 10 Gy HDR brachytherapy, followed by 50.4 Gy external beam radiotherapy (EBRT) and concurrent chemotherapy with cisplatin/5-fluorouracil. Results Tumor response, as measured by endoscopy and/or computed tomography scan, revealed complete remission in 16 and partial response in 4 patients (overall response rate 100%). Improvement of dysphagia was induced by brachytherapy within a few days and maintained up to the end of treatment in 80% of patients. No differences in either response rate or dysphagia resolution were found between squamous cell and adenocarcinoma histology. The grade 2 and 3 acute pancytopenia or bicytopenia reported in 4 patients, while sub-acute adverse effects with painful ulceration was seen in five patients, occurring after a median of 2 months. A perforation developed in one patient during the procedure of brachytherapy that resolved successfully with immediate surgery. Conclusions Brachytherapy before EBRT was a safe and effective procedure to induce rapid and durable relief from dysphagia, especially when combined with EBRT. PMID:28344601

Oxaliplatin, Fluorouracil, Erlotinib Hydrochloride, and Radiation Therapy Before Surgery and Erlotinib Hydrochloride After Surgery in Treating Patients With Locally Advanced Cancer of the Esophagus or Gastroesophageal Junction

ClinicalTrials.gov

2017-04-17

Adenocarcinoma of the Esophagus; Adenocarcinoma of the Gastroesophageal Junction; Adenocarcinoma of the Stomach; Squamous Cell Carcinoma of the Esophagus; Stage II Esophageal Cancer; Stage II Gastric Cancer; Stage III Esophageal Cancer; Stage III Gastric Cancer

[Expression of SLP-2 protein in esophageal squamous cell carcinoma is associated with cancer invasion].

PubMed

Cao, Wen-feng; Zhang, Li-yong; Zhang, Bin; Wang, Yue-qi; Liu, Zhi-hua; Sun, Bao-cun

2010-11-01

To study the expression of stomatin-like protein-2 (SLP-2) in esophageal squamous cell carcinoma (ESCC), and analyze the correlation between SLP-2 expression and clinicopathological features. The expression of SLP-2 protein in ESCC tissues (18 and 220 cases respectively) was detected by Western blot and IHC. The association between SLP-2 expression and clinicopathological features was analyzed. Compared with normal epithelium, 13 cases of ESCC tissues showed a higher expression of SLP-2 on the protein level (72.2%, 13/18). IHC analysis on tissue microarray revealed that the expression rate of SLP-2 protein in ESCC was 54.1% and in normal esophageal mucosa was 3.6%, showing a significant difference (P < 0.001). SLP-2 high-level expression correlates with the extent of ESCC invasion (P = 0.033), but not with other clinicopathologic characteristics (P > 0.05). SLP-2 as a novel cancer-related gene may play an important role in tumorigenesis of ESCC. The overexpression of SLP-2 may be closely associated with the invasion of esophageal cancer.

Prognostic significance of phosphorylated RON in esophageal squamous cell carcinoma.

PubMed

Hui, Marco K C; Lai, Kenneth K Y; Chan, Kwok Wah; Luk, John M; Lee, Nikki P; Chung, Yvonne; Cheung, Leo C; Srivastava, Gopesh; Tsao, Sai Wah; Tang, Johnny C; Law, Simon

2012-09-01

Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer. RON is a transmembrane receptor overexpressed in various cancers; however, the clinical significance of its phosphorylated form (pRON) is not fully deciphered. This report is the first to investigate the expression and clinical significance of pRON in human ESCC. Quantitative polymerase chain reaction revealed an up-regulation of RON mRNA in 70% (7/10) of ESCC tissues when compared to the adjacent nontumor tissues. An overexpression of pRON protein was found in most of the ESCC cell lines studied (4/5) when compared to two non-neoplastic esophageal epithelial cells using immunoblot. In 64 ESCC tissues, pRON was localized at the cell membrane, cytoplasm and nucleus in 15 (23.4%), 63 (98.4%) and 61 (95.3%) cases using immunohistochemistry. Patients having high expression of cytoplasmic pRON significantly associated with shorter median survival when compared to those with low expression (25.41 months vs. 14.43 months), suggesting cytoplasmic pRON as a potential marker for poor prognosis in ESCC patients.

Endoscopic submucosal tunnel dissection for large superficial esophageal squamous cell neoplasms

PubMed Central

Zhai, Ya-Qi; Li, Hui-Kai; Linghu, En-Qiang

2016-01-01

Endoscopic submucosal dissection (ESD) is a well-established treatment for superficial esophageal squamous cell neoplasms (SESCNs) with no risk of lymphatic metastasis. However, for large SESCNs, especially when exceeding two-thirds of the esophageal circumference, conventional ESD is time-consuming and has an increased risk of adverse events. Based on the submucosal tunnel conception, endoscopic submucosal tunnel dissection (ESTD) was first introduced by us to remove large SESCNs, with excellent results. Studies from different centers also reported favorable results. Compared with conventional ESD, ESTD has a more rapid dissection speed and R0 resection rate. Currently in China, ESTD for large SESCNs is an important part of the digestive endoscopic tunnel technique, as is peroral endoscopic myotomy for achalasia and submucosal tunnel endoscopic resection for submucosal tumors of the muscularis propria. However, not all patients with SESCNs are candidates for ESTD, and postoperative esophageal strictures should also be taken into consideration, especially for lesions with a circumference greater than three-quarters. In this article, we describe our experience, review the literature of ESTD, and provide detailed information on indications, standard procedures, outcomes, and complications of ESTD. PMID:26755889

Chemoprevention of esophageal squamous cell carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stoner, Gary D.; Wang Lishu; Chen Tong

2007-11-01

Esophageal squamous cell carcinoma (SCC) is responsible for approximately one-sixth of all cancer-related mortality worldwide. This malignancy has a multifactorial etiology involving several environmental, dietary and genetic factors. Since esophageal cancer has often metastasized at the time of diagnosis, current treatment modalities offer poor survival and cure rates. Chemoprevention offers a viable alternative that could well be effective against the disease. Clinical investigations have shown that primary chemoprevention of this disease is feasible if potent inhibitory agents are identified. The Fischer 344 (F-344) rat model of esophageal SCC has been used extensively to investigate the biology of the disease, andmore » to identify chemopreventive agents that could be useful in human trials. Multiple compounds that inhibit tumor initiation by esophageal carcinogens have been identified using this model. These include several isothiocyanates, diallyl sulfide and polyphenolic compounds. These compounds influence the metabolic activation of esophageal carcinogens resulting in reduced genetic (DNA) damage. Recently, a few agents have been shown to inhibit the progression of preneoplastic lesions in the rat esophagus into tumors. These agents include inhibitors of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and c-Jun [a component of activator protein-1 (AP-1)]. Using a food-based approach to cancer prevention, we have shown that freeze-dried berry preparations inhibit both the initiation and promotion/progression stages of esophageal SCC in F-344 rats. These observations have led to a clinical trial in China to evaluate the ability of freeze-dried strawberries to influence the progression of esophageal dysplasia to SCC.« less

Signaling pathways in the molecular pathogenesis of adenocarcinomas of the esophagus and gastroesophageal junction

PubMed Central

Clemons, Nicholas J; Phillips, Wayne A; Lord, Reginald V

2013-01-01

Esophageal adenocarcinoma develops in response to severe gastroesophageal reflux disease through the precursor lesion Barrett esophagus, in which the normal squamous epithelium is replaced by a columnar lining. The incidence of esophageal adenocarcinoma in the United States has increased by over 600% in the past 40 years and the overall survival rate remains less than 20% in the community. This review highlights some of the signaling pathways for which there is some evidence of a role in the development of esophageal adenocarcinoma. An increasingly detailed understanding of the biology of this cancer has emerged recently, revealing that in addition to the well-recognized alterations in single genes such as p53, p16, APC, and telomerase, there are interactions between the components of the reflux fluid, the homeobox gene Cdx2, and the Wnt, Notch, and Hedgehog signaling pathways. PMID:23792587

Association of Kruppel-like factor 4 expression with the prognosis of esophageal squamous cell carcinoma patients

PubMed Central

Ma, Ming-Quan; Zhang, Hong-Dian; Tang, Peng; Jiang, Hong-Jing; Chen, Chuan-Gui

2014-01-01

Objective: To investigate the association of Kruppel-like factor 4 (KLF4) expressions with the prognosis of esophageal squamous cell carcinoma (SCC) patients. Methods: Ninety-eight cases of esophageal carcinoma patients were enrolled. The expression of KLF4 in the esophageal SCC and normal esophageal mucosa tissues were examined by immunohistochemistry. The correlations between the expression of KLF4 protein and patients’ clinical characteristics and prognosis were analyzed. Results: We observed higher expressed KLF4 in normal esophageal mucosa tissues than esophageal SCC tissues, with positive rate of 82.7% (81/98) and 43.8% (43/98) respectively. In patients with lymphatic metastasis, the positive rate of KLF4 was 24.4% (10/41), whereas it was 57.9% (33/57) in patients without lymphatic metastasis, and the difference was significant (x2 = 10.871, P = 0.001). The positive rates of KLF4 were 62.5% (5/8), 53.1% (26/49) and 29.3% (12/41) in stage I, II and III patients, respectively. There were no correlations between the expression of KLF4 and gender, age, tumor size, location, differentiation grade and infiltration depth. The 5-year survival rates and median survival times were 48.8% and 25.5%, and 55 and 26 months for the patients with KLF4 positive and negative expression, respectively. There were significant differences between the patients with KLF4 positive expression and negative expression in the 5-year survival rates and median survival times (x2 = 5.747 and 4.493, P = 0.017 and 0.034). Conclusion: KLF4 might act as a tumor suppressor in esophageal SCC and the expression status of KLF4 could be considered as a prognosis predictor for esophageal SCC patients. PMID:25400747

MiR-141-3p is upregulated in esophageal squamous cell carcinoma and targets pleckstrin homology domain leucine-rich repeat protein phosphatase-2, a negative regulator of the PI3K/AKT pathway.

PubMed

Ishibashi, Osamu; Akagi, Ichiro; Ogawa, Yota; Inui, Takashi

2018-05-11

The phosphatidylinositol-3-kinase (PI3K)/AKT pathway is frequently activated in various human cancers and plays essential roles in their development and progression. Accumulating evidence suggests that dysregulated expression of microRNAs (miRNAs) is closely associated with cancer progression and metastasis. Here, we focused on miRNAs that could regulate genes related to the PI3K/AKT pathway in esophageal squamous cell carcinoma (ESCC). To identify upregulated miRNAs and their possible target genes in ESCC, we performed microarray-based integrative analyses of miRNA and mRNA expression levels in three human ESCC cell lines and a normal esophageal epithelial cell line. The miRNA microarray analysis revealed that miR-31-5p, miR-141-3p, miR-200b-3p, miR-200c-3p, and miR-205-5p were expressed at higher levels in the ESCC cell lines than the normal esophageal epithelial cell line. Bioinformatical analyses of mRNA microarray data identified several AKT/PI3K pathway-related genes as candidate targets of these miRNAs, which include tumor suppressors such as DNA-damage-inducible transcript 4 and pleckstrin homology domain leucine-rich repeat protein phosphatase-2 (PHLPP2). To validate the targets of relevant miRNAs experimentally, synthetic mimics of the miRNAs were transfected into the esophageal epithelial cell line. Here, we report that miR-141-3p suppress the expression of PHLPP2, a negative regulators of the AKT/PI3K pathway, as a target in ESCC. Copyright © 2018 Elsevier Inc. All rights reserved.

Toll-like Receptor 2 Signalling and the Lysosomal Machinery in Barrett's Esophagus.

PubMed

Verbeek, Romy E; Siersema, Peter D; Vleggaar, Frank P; Ten Kate, Fiebo J; Posthuma, George; Souza, Rhonda F; de Haan, Judith; van Baal, Jantine W P M

2016-09-01

Inflammation plays an important role in the development of esophageal adenocarcinoma and its metaplastic precursor lesion, Barrett's esophagus. Toll-like receptor (TLR) 2 signalling and lysosomal function have been linked to inflammation-associated carcinogenesis. We examined the expression of TLR2 in the esophagus and the effect of long-term TLR2 activation on morphological changes and expression of factors involved in lysosomal function in a Barrett's esophagus epithelium cell line. TLR2 expression in normal squamous esophagus, reflux esophagitis, Barrett's esophagus and esophageal adenocarcinoma biopsies was assessed with Q-RT-PCR, in situ hybridization and immunohistochemistry. Barrett's esophagus epithelium cells (BAR-T) were incubated with acid and bile salts in the presence or absence of the TLR2 agonist Pam3CSK4 for a period up to 4 weeks. Morphological changes were assessed with electron microscopy, while Q-RT-PCR was used to determine the expression of lysosomal enzymes (Cathepsin B and C) and factors involved in endocytosis (LAMP-1 and M6PR) and autophagy (LC3 and Rab7). TLR2 was expressed in normal squamous esophagus, reflux esophagitis, Barrett's esophagus but was most prominent in esophageal adenocarcinoma. Long-term TLR2 activation in acid and bile salts exposed BAR-T cells resulted in more and larger lysosomes, more mitochondria and increased expression of LAMP-1, M6PR, Cathepsin B and C when compared to BAR-T cells incubated with acid and bile salts but no TLR2 agonist. Factors associated with autophagy (LC3 and Rab7) expression remained largely unchanged. Activation of TLR2 in acid and bile salts exposed Barrett epithelium cells resulted in an increased number of mitochondria and lysosomes and increased expression of lysosomal enzymes and factors involved in endocytosis.

Azoxystrobin Induces Apoptosis of Human Esophageal Squamous Cell Carcinoma KYSE-150 Cells through Triggering of the Mitochondrial Pathway.

PubMed

Shi, Xiao-Ke; Bian, Xiao-Bo; Huang, Tao; Wen, Bo; Zhao, Ling; Mu, Huai-Xue; Fatima, Sarwat; Fan, Bao-Min; Bian, Zhao-Xiang; Huang, Lin-Fang; Lin, Cheng-Yuan

2017-01-01

Recent studies indicate that mitochondrial pathways of apoptosis are potential chemotherapeutic target for the treatment of esophageal cancer. Azoxystrobin (AZOX), a methoxyacrylate derived from the naturally occurring strobilurins, is a known fungicide acting as a ubiquinol oxidation (Qo) inhibitor of mitochondrial respiratory complex III. In this study, the effects of AZOX on human esophageal squamous cell carcinoma KYSE-150 cells were examined and the underlying mechanisms were investigated. AZOX exhibited inhibitory effects on the proliferation of KYSE-150 cells with inhibitory concentration 50% (IC 50 ) of 2.42 μg/ml by 48 h treatment. Flow cytometry assessment revealed that the inhibitory effect of AZOX on KYSE-150 cell proliferation occurred with cell cycle arrest at S phase and increased cell apoptosis in time-dependent and dose-dependent manners. Cleaved poly ADP ribose polymerase (PARP), caspase-3 and caspase-9 were increased significantly by AZOX. It is worth noted that the Bcl-2/Bax ratios were decreased because of the down-regulated Bcl-2 and up-regulated Bax expression level. Meanwhile, the cytochrome c release was increased by AZOX in KYSE-150 cells. AZOX-induced cytochrome c expression and caspase-3 activation was significantly blocked by Bax Channel Blocker. Intragastric administration of AZOX effectively decreased the tumor size generated by subcutaneous inoculation of KYSE-150 cells in nude mice. Consistently, decreased Bcl-2 expression, increased cytochrome c and PARP level, and activated caspase-3 and caspase-9 were observed in the tumor samples. These results indicate that AZOX can effectively induce esophageal cancer cell apoptosis through the mitochondrial pathways of apoptosis, suggesting AZOX or its derivatives may be developed as potential chemotherapeutic agents for the treatment of esophageal cancer.

Azoxystrobin Induces Apoptosis of Human Esophageal Squamous Cell Carcinoma KYSE-150 Cells through Triggering of the Mitochondrial Pathway

PubMed Central

Shi, Xiao-ke; Bian, Xiao-bo; Huang, Tao; Wen, Bo; Zhao, Ling; Mu, Huai-xue; Fatima, Sarwat; Fan, Bao-min; Bian, Zhao-xiang; Huang, Lin-fang; Lin, Cheng-yuan

2017-01-01

Recent studies indicate that mitochondrial pathways of apoptosis are potential chemotherapeutic target for the treatment of esophageal cancer. Azoxystrobin (AZOX), a methoxyacrylate derived from the naturally occurring strobilurins, is a known fungicide acting as a ubiquinol oxidation (Qo) inhibitor of mitochondrial respiratory complex III. In this study, the effects of AZOX on human esophageal squamous cell carcinoma KYSE-150 cells were examined and the underlying mechanisms were investigated. AZOX exhibited inhibitory effects on the proliferation of KYSE-150 cells with inhibitory concentration 50% (IC50) of 2.42 μg/ml by 48 h treatment. Flow cytometry assessment revealed that the inhibitory effect of AZOX on KYSE-150 cell proliferation occurred with cell cycle arrest at S phase and increased cell apoptosis in time-dependent and dose-dependent manners. Cleaved poly ADP ribose polymerase (PARP), caspase-3 and caspase-9 were increased significantly by AZOX. It is worth noted that the Bcl-2/Bax ratios were decreased because of the down-regulated Bcl-2 and up-regulated Bax expression level. Meanwhile, the cytochrome c release was increased by AZOX in KYSE-150 cells. AZOX-induced cytochrome c expression and caspase-3 activation was significantly blocked by Bax Channel Blocker. Intragastric administration of AZOX effectively decreased the tumor size generated by subcutaneous inoculation of KYSE-150 cells in nude mice. Consistently, decreased Bcl-2 expression, increased cytochrome c and PARP level, and activated caspase-3 and caspase-9 were observed in the tumor samples. These results indicate that AZOX can effectively induce esophageal cancer cell apoptosis through the mitochondrial pathways of apoptosis, suggesting AZOX or its derivatives may be developed as potential chemotherapeutic agents for the treatment of esophageal cancer. PMID:28567017

Food intake and the occurrence of squamous cell carcinoma in different sections of the esophagus in Taiwanese men.

PubMed

Chen, Yu-Kuei; Lee, Chien-Hung; Wu, I-Chen; Liu, Jia-Sin; Wu, Deng-Chyang; Lee, Jang-Ming; Goan, Yih-Gang; Chou, Shah-Hwa; Huang, Chia-Tsuan; Lee, Chun-Ying; Hung, Hsin-Chia; Yang, Jeng-Fu; Wu, Ming-Tsang

2009-01-01

The main objective of this study was to further elucidate the effect of consuming various foods on the development of squamous cell carcinoma (SCC) in three different sections of the esophagus. A total of 343 patients with SCC of the esophagus and 755 cancer-free control subjects were recruited for this study from 1996 to 2005. We found that intake of vegetables, raw onions/garlic, and fruits are significantly protective against esophageal SSC risk, whereas intake of hot foods can significantly increase its risk. There was a significant inverse relation between the frequency of tea consumption and esophageal SCC risk (P for trend = 0.005), with a 0.5-fold lower risk associated with the intake of unfermented tea (green tea, oolong tea, or jasmine tea). The effects of dietary factors on esophageal SCC were similar in all subsites, with the exception of consumption of coffee. Coffee consumption was more pronounced in having a protective effect in the middle third section compared with the lower third section of the esophagus (adjusted odds ratio 0.4, 95% confidence interval 0.2-0.9), although this protective effect was marginally significant (adjusted odds ratio 0.6, 95% confidence interval 0.4-1.0) against esophageal SCC in all subsites. Our data also suggest that discomfort when eating hot foods may exert a carcinogenic effect by direct contact with the esophageal mucosa and tend to have more harmful effects in the upper than in the lower esophagus. In contrast, vegetables, fruits, and tea with components that are thought to inhibit carcinogenesis by absorbed components affected all subsites similarly. Our results add additional information that certain dietary components may affect carcinogenesis locally and systemically.

Integrative analyses of transcriptome sequencing identify novel functional lncRNAs in esophageal squamous cell carcinoma.

PubMed

Li, C-Q; Huang, G-W; Wu, Z-Y; Xu, Y-J; Li, X-C; Xue, Y-J; Zhu, Y; Zhao, J-M; Li, M; Zhang, J; Wu, J-Y; Lei, F; Wang, Q-Y; Li, S; Zheng, C-P; Ai, B; Tang, Z-D; Feng, C-C; Liao, L-D; Wang, S-H; Shen, J-H; Liu, Y-J; Bai, X-F; He, J-Z; Cao, H-H; Wu, B-L; Wang, M-R; Lin, D-C; Koeffler, H P; Wang, L-D; Li, X; Li, E-M; Xu, L-Y

2017-02-13

Long non-coding RNAs (lncRNAs) have a critical role in cancer initiation and progression, and thus may mediate oncogenic or tumor suppressing effects, as well as be a new class of cancer therapeutic targets. We performed high-throughput sequencing of RNA (RNA-seq) to investigate the expression level of lncRNAs and protein-coding genes in 30 esophageal samples, comprised of 15 esophageal squamous cell carcinoma (ESCC) samples and their 15 paired non-tumor tissues. We further developed an integrative bioinformatics method, denoted URW-LPE, to identify key functional lncRNAs that regulate expression of downstream protein-coding genes in ESCC. A number of known onco-lncRNA and many putative novel ones were effectively identified by URW-LPE. Importantly, we identified lncRNA625 as a novel regulator of ESCC cell proliferation, invasion and migration. ESCC patients with high lncRNA625 expression had significantly shorter survival time than those with low expression. LncRNA625 also showed specific prognostic value for patients with metastatic ESCC. Finally, we identified E1A-binding protein p300 (EP300) as a downstream executor of lncRNA625-induced transcriptional responses. These findings establish a catalog of novel cancer-associated functional lncRNAs, which will promote our understanding of lncRNA-mediated regulation in this malignancy.

Radical esophagectomy for a 92-year-old woman with granulocyte colony-stimulating factor-producing esophageal squamous cell carcinoma: a case report.

PubMed

Kitani, Mari; Yamagata, Yukinori; Tanabe, Asami; Yagi, Kouichi; Aikou, Susumu; Kiyokawa, Takashi; Nishida, Masato; Yamashita, Hiroharu; Mori, Kazuhiko; Nomura, Sachiyo; Seto, Yasuyuki

2016-10-13

Granulocyte colony-stimulating factor (G-CSF)-producing esophageal squamous cell carcinoma (ESCC) has been considered to have a poor prognosis. We successfully treated a case of G-CSF-producing ESCC in a 92-year-old woman. A 92-year-old woman was admitted to our hospital with the complaints of choking while swallowing and dysphagia. Esophagogastroduodenoscopy and contrast-enhanced computed tomography revealed a type 2 esophageal cancer located 26-35 cm from the dental arch, with no distant metastasis. The patient was diagnosed with G-CSF-producing ESCC based on remarkable leukocytosis and high G-CSF levels. The patient underwent radical subtotal esophagectomy. Subsequently, the level of neutrophils (from 23,500/μL to 5000/μL) and the level of G-CSF (from 131 to <19.5 pg/mL) decreased significantly. Immunohistochemistry analysis of the resected tissue specimen showed positive staining for G-CSF in the cytoplasm of the tumor cells. Although the patient developed aspiration pneumonitis, after antibiotic treatment, she promptly recovered and was discharged. Herein, we describe a case of successfully treated G-CSF-producing ESCC in a 92-year-old woman. Precise detection and safely performed immediate radical operation are considered essential to achieve a good clinical course.

Methylation of DACT2 accelerates esophageal cancer development by activating Wnt signaling

PubMed Central

Zhang, Meiying; Linghu, Enqiang; Zhan, Qimin; He, Tao; Cao, Baoping; Brock, Malcolm V.; Herman, James G.; Xiang, Rong; Guo, Mingzhou

2016-01-01

Esophageal cancer is one of the most common malignancies worldwide. DACT2 is frequently methylated in human lung, hepatic, gastric and thyroid cancers. The methylation status and function of DACT2 remain to be elucidated in human esophageal cancer. Ten esophageal cancer cell lines, 42 cases of dysplasia and 126 cases of primary esophageal cancer samples were analyzed in this study. The expression of DACT2 was detected in YES2 cells, while reduced DACT2 expression levels were found in TE8 and KYSE70 cells, and complete loss of DACT2 expression was found in KYSE30, KYSE140, KYSE150, KYSE410, KYSE450, TE3 and TE7 cells. Loss of expression or reduced expression of DACT2 correlated with promoter region hypermethylation in esophageal cancer cells. Restoration of DACT2 expression was induced by 5-aza-2′-deoxycytidine. In human primary esophageal squamous carcinoma, 69% (87/126) of samples were methylated. Methylation of DACT2 was significantly associated with tumor stage and metastasis (P < 0.01, P < 0.05). DACT2 suppressed colony formation, cell migration and invasion in esophageal cancer cells, and it also suppressed esophageal cancer cell xenograft growth. DACT2 inhibited Wnt signaling in human esophageal cancer cells. In conclusion, DACT2 is frequently methylated in human esophageal cancer and its expression is regulated by promoter region methylation. DACT2 suppresses esophageal cancer growth by inhibiting Wnt signaling. PMID:26919254

Molecular defense mechanisms of Barrett's metaplasia estimated by an integrative genomics.

PubMed

Ostrowski, Jerzy; Mikula, Michal; Karczmarski, Jakub; Rubel, Tymon; Wyrwicz, Lucjan S; Bragoszewski, Piotr; Gaj, Pawel; Dadlez, Michal; Butruk, Eugeniusz; Regula, Jaroslaw

2007-07-01

Barrett's esophagus is characterized by the replacement of squamous epithelium with specialized intestinal metaplastic mucosa. The exact mechanisms of initiation and development of Barrett's metaplasia remain unknown, but a hypothesis of "successful adaptation" against noxious reflux components has been proposed. To search for the repertoire of adaptation mechanisms of Barrett's metaplasia, we employed high-throughput functional genomic and proteomic methods that defined the molecular background of metaplastic mucosa resistance to reflux. Transcriptional profiling was established for 23 pairs of esophageal squamous epithelium and Barrett's metaplasia tissue samples using Affymetrix U133A 2.0 GeneChips and validated by quantitative real-time polymerase chain reaction. Differences in protein composition were assessed by electrophoretic and mass-spectrometry-based methods. Among 2,822 genes differentially expressed between Barrett's metaplasia and squamous epithelium, we observed significantly overexpressed metaplastic mucosa genes that encode cytokines and growth factors, constituents of extracellular matrix, basement membrane and tight junctions, and proteins involved in prostaglandin and phosphoinositol metabolism, nitric oxide production, and bioenergetics. Their expression likely reflects defense and repair responses of metaplastic mucosa, whereas overexpression of genes encoding heat shock proteins and several protein kinases in squamous epithelium may reflect lower resistance of normal esophageal epithelium than Barrett's metaplasia to reflux components. Despite the methodological and interpretative difficulties in data analyses discussed in this paper, our studies confirm that Barrett's metaplasia may be regarded as a specific microevolution allowing for accumulation of mucosal morphological and physiological changes that better protect against reflux injury.

Columnar metaplasia in a surgical mouse model of gastro-esophageal reflux disease is not derived from bone marrow-derived cell.

PubMed

Aikou, Susumu; Aida, Junko; Takubo, Kaiyo; Yamagata, Yukinori; Seto, Yasuyuki; Kaminishi, Michio; Nomura, Sachiyo

2013-09-01

The incidence of esophageal adenocarcinoma has increased in the last 25 years. Columnar metaplasia in Barrett's mucosa is assumed to be a precancerous lesion for esophageal adenocarcinoma. However, the induction process of Barrett's mucosa is still unknown. To analyze the induction of esophageal columnar metaplasia, we established a mouse gastro-esophageal reflux disease (GERD) model with associated development of columnar metaplasia in the esophagus. C57BL/6 mice received side-to-side anastomosis of the esophagogastric junction with the jejunum, and mice were killed 10, 20, and 40 weeks after operation. To analyze the contribution of bone marrow-derived cells to columnar metaplasia in this surgical GERD model, some mice were transplanted with GFP-marked bone marrow after the operation. Seventy-three percent of the mice (16/22) showed thickened mucosa in esophagus and 41% of mice (9/22) developed columnar metaplasia 40 weeks after the operation with a mortality rate of 4%. Bone marrow-derived cells were not detected in columnar metaplastic epithelia. However, scattered epithelial cells in the thickened squamous epithelia in regions of esophagitis did show bone marrow derivation. The results demonstrate that reflux induced by esophago-jejunostomy in mice leads to the development of columnar metaplasia in the esophagus. However, bone marrow-derived cells do not contribute directly to columnar metaplasia in this mouse model. © 2013 Japanese Cancer Association.

TGFβ loss activates ADAMTS-1-mediated EGF-dependent invasion in a model of esophageal cell invasion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Le Bras, Grégoire F.; Taylor, Chase; Koumangoye, Rainelli B.

2015-01-01

The TGFβ signaling pathway is essential to epithelial homeostasis and is often inhibited during progression of esophageal squamous cell carcinoma. Recently, an important role for TGFβ signaling has been described in the crosstalk between epithelial and stromal cells regulating squamous tumor cell invasion in mouse models of head-and-neck squamous cell carcinoma (HNSCC). Loss of TGFβ signaling, in either compartment, leads to HNSCC however, the mechanisms involved are not well understood. Using organotypic reconstruct cultures (OTC) to model the interaction between epithelial and stromal cells that occur in dysplastic lesions, we show that loss of TGFβ signaling promotes an invasive phenotypemore » in both fibroblast and epithelial compartments. Employing immortalized esophageal keratinocytes established to reproduce common mutations of esophageal squamous cell carcinoma, we show that treatment of OTC with inhibitors of TGFβ signaling (A83-01 or SB431542) enhances invasion of epithelial cells into a fibroblast-embedded Matrigel/collagen I matrix. Invasion induced by A83-01 is independent of proliferation but relies on protease activity and expression of ADAMTS-1 and can be altered by matrix density. This invasion was associated with increased expression of pro-inflammatory cytokines, IL1 and EGFR ligands HB-EGF and TGFα. Altering EGF signaling prevented or induced epithelial cell invasion in this model. Loss of expression of the TGFβ target gene ROBO1 suggested that chemorepulsion may regulate keratinocyte invasion. Taken together, our data show increased invasion through inhibition of TGFβ signaling altered epithelial-fibroblasts interactions, repressing markers of activated fibroblasts, and altering integrin-fibronectin interactions. These results suggest that inhibition of TGFβ signaling modulates an array of pathways that combined promote multiple aspects of tumor invasion. - Highlights: • Chemical inhibition of TGFβ signaling advances collective invasion of esophageal keratinocytes. • Collective cell invasion is protease dependent and ADAMTS-1 is upregulated. • Inhibition of TGFβ signaling promotes EGF-mediated invasion. • Loss of TGFβ signaling promotes collagen binding and induces alterations in integrin expression. • The TGFβ target ROBO1 is downregulated in cell invasion implying mechanisms of chemorepulsion.« less

Biomarkers Predict Prognosis of Esophageal Cancer Patients | Center for Cancer Research

Cancer.gov

New treatment strategies are needed to improve outcomes for patients with esophageal cancer. With five-year survival rates less than 25 percent, this is one of the deadliest forms of cancer. There are two main types of esophageal cancer—squamous cell carcinoma and adenocarcinoma. Esophageal adenocarcinoma is frequently preceded by Barrett’s esophagus, a chronic inflammatory condition caused by gastroesophageal reflux. It is known that communication between tumor cells and the immune system can alter the behavior of tumor cells, and chronic inflammation has been implicated in several types of human cancers, including cancer of the esophagus.

Esophageal xanthoma--report of two new cases and review of the literature.

PubMed

Becheanu, Gabriel; Dumbrava, Mona; Arbanas, Tudor; Diculescu, Mircea; Hoyeau-Idrissi, Nadia; Fléjou, Jean-François

2011-12-01

Esophageal xanthoma is a very rare lesion which can be incidentally discovered during endoscopy. Only eleven cases have been reported, including ours. We present two new cases of esophageal xanthoma localized in the lower esophagus in a 56-year-old woman and a 62-year-old man. Endoscopically, esophageal xanthoma appears as yellowish granular spots or a slightly elevated lesion. Microscopically, it consists of fat accumulation in foamy histiocytes beneath the squamous epithelium. The clinical and pathological importance of these lesions and what they mean in patients is discussed, along with a review of the literature.

Relationship between ABO blood group and clinicopathological factors and their effect on the survival of Japanese patients with esophageal squamous cell carcinoma.

PubMed

Shiratori, Fumiaki; Shimada, Hideaki; Yajima, Satoshi; Suzuki, Takashi; Oshima, Yoko; Nanami, Tatsuki; Ito, Masaaki; Kaneko, Hironori

2017-08-01

Several studies have evaluated the association between ABO blood group and the prognosis of various types of cancer; however, little is known about the relationship between ABO blood group and esophageal squamous cell carcinoma (SCC). We investigated how ABO blood group and clinicopathological characteristics are related to the survival of Japanese patients with esophageal SCC. We reviewed the medical records of 181 patients who underwent surgery for esophageal SCC between June, 2004 and December, 2015 and analyzed the association between ABO blood group and clinicopathological factors. Clinicopathological factors were also evaluated by univariate and multivariate analyses for possible association with survival. The prevalence of each blood group was as follows: A, 35.5%; B, 22.4%; O, 32.8%; and AB, 8.2%. The 5-year overall survival of all patients was 37.1%. Patients with non-type B blood had significantly worse 5-year overall survival than those with type B blood (30.2 vs. 58.8%, P < 0.05). ABO blood groups were associated with the survival of Japanese patients with esophageal SCC. Patients with non-B blood groups had significantly worse overall survival than those with the B blood group.

Nivolumab and Ipilimumab in Treating Patients With Rare Tumors

ClinicalTrials.gov

2018-06-27

Acinar Cell Carcinoma; Adenoid Cystic Carcinoma; Adrenal Cortex Carcinoma; Adrenal Gland Pheochromocytoma; Anal Canal Neuroendocrine Carcinoma; Anal Canal Undifferentiated Carcinoma; Appendix Mucinous Adenocarcinoma; Bartholin Gland Transitional Cell Carcinoma; Bladder Adenocarcinoma; Cervical Adenocarcinoma; Cholangiocarcinoma; Chordoma; Colorectal Squamous Cell Carcinoma; Desmoid-Type Fibromatosis; Endometrial Transitional Cell Carcinoma; Endometrioid Adenocarcinoma; Esophageal Neuroendocrine Carcinoma; Esophageal Undifferentiated Carcinoma; Extrahepatic Bile Duct Carcinoma; Fallopian Tube Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Fibromyxoid Tumor; Gastric Neuroendocrine Carcinoma; Gastric Squamous Cell Carcinoma; Gastrointestinal Stromal Tumor; Giant Cell Carcinoma; Intestinal Neuroendocrine Carcinoma; Intrahepatic Cholangiocarcinoma; Lung Carcinoid Tumor; Lung Sarcomatoid Carcinoma; Major Salivary Gland Carcinoma; Malignant Odontogenic Neoplasm; Malignant Peripheral Nerve Sheath Tumor; Malignant Testicular Sex Cord-Stromal Tumor; Metaplastic Breast Carcinoma; Metastatic Malignant Neoplasm of Unknown Primary Origin; Minimally Invasive Lung Adenocarcinoma; Mixed Mesodermal (Mullerian) Tumor; Mucinous Adenocarcinoma; Mucinous Cystadenocarcinoma; Nasal Cavity Adenocarcinoma; Nasal Cavity Carcinoma; Nasopharyngeal Carcinoma; Nasopharyngeal Papillary Adenocarcinoma; Nasopharyngeal Undifferentiated Carcinoma; Oral Cavity Carcinoma; Oropharyngeal Undifferentiated Carcinoma; Ovarian Adenocarcinoma; Ovarian Germ Cell Tumor; Ovarian Mucinous Adenocarcinoma; Ovarian Squamous Cell Carcinoma; Ovarian Transitional Cell Carcinoma; Pancreatic Acinar Cell Carcinoma; Pancreatic Neuroendocrine Carcinoma; Paraganglioma; Paranasal Sinus Adenocarcinoma; Paranasal Sinus Carcinoma; Parathyroid Gland Carcinoma; Pituitary Gland Carcinoma; Placental Choriocarcinoma; Placental-Site Gestational Trophoblastic Tumor; Primary Peritoneal High Grade Serous Adenocarcinoma; Pseudomyxoma Peritonei; Rare Disorder; Scrotal Squamous Cell Carcinoma; Seminal Vesicle Adenocarcinoma; Seminoma; Serous Cystadenocarcinoma; Small Intestinal Adenocarcinoma; Small Intestinal Squamous Cell Carcinoma; Spindle Cell Neoplasm; Squamous Cell Carcinoma of the Penis; Teratoma With Malignant Transformation; Testicular Non-Seminomatous Germ Cell Tumor; Thyroid Gland Carcinoma; Tracheal Carcinoma; Transitional Cell Carcinoma; Undifferentiated Gastric Carcinoma; Ureter Adenocarcinoma; Ureter Squamous Cell Carcinoma; Urethral Adenocarcinoma; Urethral Squamous Cell Carcinoma; Vaginal Adenocarcinoma; Vaginal Squamous Cell Carcinoma, Not Otherwise Specified; Vulvar Carcinoma

Chronic inflammation-associated genomic instability paves the way for human esophageal carcinogenesis

PubMed Central

Tian, Dongping; Lei, Zhijin; Chen, Donglin; Xu, Zexin; Su, Min

2016-01-01

Chronic inflammation is associated with increased risk of cancer development, whereas the link between chronic inflammation and esophageal carcinogenesis is still obscure heretofore. This study aimed to investigate the relationship between chronic inflammation and DNA damage, as well as the possible role of DNA damage in esophageal carcinogenic process. Endoscopic esophageal biopsies from 109 individuals from Chaoshan littoral, a high-risk region for esophageal squamous cell carcinoma (ESCC), were examined to evaluate the association between chronic inflammation and histological severity, while additional 204 esophageal non-tumor samples from patients with ESCC were collected. Immunohistochemistry was performed to detect the oxidative DNA damage and DNA double-strand breaks (DSBs). Significantly positive correlation was observed between degree of chronic inflammation and esophageal precursor lesions (rs = 0.37, P < 0.01). Immunohistochemical analysis showed that oxidative DNA damage level was positively correlated with the degree of chronic inflammation (rs = 0.21, P < 0.05). Moreover, the level of oxidative DNA damage positively correlated with histological severity (rs = 0.49, P < 0.01). We found that the extent of DSBs was progressively increased with inflammation degree (P < 0.01) and the progression of precancerous lesions (P < 0.001). Collectively, these findings provide evidence linking chronic inflammation-associated genomic instability with esophageal carcinogenesis and suggest possibilities for early detection and intervention of esophageal carcinogenesis. PMID:27028857

Risk Factors for Esophageal Fistula Associated With Chemoradiotherapy for Locally Advanced Unresectable Esophageal Cancer

PubMed Central

Tsushima, Takahiro; Mizusawa, Junki; Sudo, Kazuki; Honma, Yoshitaka; Kato, Ken; Igaki, Hiroyasu; Tsubosa, Yasuhiro; Shinoda, Masayuki; Nakamura, Kenichi; Fukuda, Haruhiko; Kitagawa, Yuko

2016-01-01

Abstract Esophageal fistula is a critical adverse event in patients treated with chemoradiotherapy (CRT) for locally advanced esophageal cancer. However, risk factors associated with esophageal fistula formation in patients receiving CRT have not yet been elucidated. We retrospectively analyzed data obtained from 140 patients who were enrolled in a phase II/III trial comparing low-dose cisplatin with standard-dose cisplatin administered in combination with 5-flurouracil and concomitant radiotherapy. Inclusion criteria were performance status (PS) 0 to 2 and histologically proven thoracic esophageal cancer clinically diagnosed as T4 and/or unresectable lymph node metastasis for which definitive CRT was applicable. Risk factors for esophageal fistula were examined with univariate analysis using Fisher exact test and multivariate analysis using logistic regression models. Esophageal fistula was observed in 31 patients (22%). Of these, 6 patients developed fistula during CRT. Median time interval between the date of CRT initiation and that of fistula diagnosis was 100 days (inter quartile range, 45–171). Esophageal stenosis was the only significant risk factor for esophageal fistula formation both in univariate (P = 0.026) and in multivariate analyses (odds ratio, 2.59; 95% confidence interval, 1.13–5.92, P = 0.025). Other clinicopathological factors, namely treatment arm, age, sex, PS, primary tumor location, T stage, lymph node invasion to adjacent organs, blood cell count, albumin level, and body mass index, were not risk factors fistula formation. Esophageal stenosis was a significant risk factor for esophageal fistula formation in patients treated with CRT for unresectable locally advanced thoracic esophageal squamous cell carcinoma. PMID:27196482

Robot-assisted thoracoscopic lymphadenectomy along the left recurrent laryngeal nerve for esophageal squamous cell carcinoma in the prone position: technical report and short-term outcomes.

PubMed

Suda, Koichi; Ishida, Yoshinori; Kawamura, Yuichiro; Inaba, Kazuki; Kanaya, Seiichiro; Teramukai, Satoshi; Satoh, Seiji; Uyama, Ichiro

2012-07-01

Meticulous mediastinal lymphadenectomy frequently induces recurrent laryngeal nerve palsy (RLNP). Surgical robots with impressive dexterity and precise dissection skills have been developed to help surgeons perform operations. The objective of this study was to determine the impact on short-term outcomes of robot-assisted thoracoscopic radical esophagectomy performed on patients in the prone position for the treatment of esophageal squamous cell carcinoma, including its impact on RLNP. A single-institution nonrandomized prospective study was performed. The patients (n = 36) with resectable esophageal squamous cell carcinoma were divided into two groups: patients who agreed to robot-assisted thoracoscopic esophagectomy with total mediastinal lymphadenectomy performed in the prone position (n = 16, robot-assisted group) without insurance reimbursement, and those who agreed to undergo the same operation without robot assistance but with health insurance coverage (n = 20, control group). These patients were observed for 30 days following surgery to assess short-term surgical outcomes, including the incidence of vocal cord palsy, hoarseness, and aspiration. Robot assistance significantly reduced the incidence of vocal cord palsy (p = 0.018) and hoarseness (p = 0.015) and the time on the ventilator (p = 0.025). There was no in-hospital mortality in either group. There were no significant differences between the two groups with respect to patient background, except for the use of preoperative therapy (robot-assisted group

Sparing the larynx and esophageal inlet expedites feeding tube removal in patients with stage III-IV oropharyngeal squamous cell carcinoma treated with intensity-modulated radiotherapy.

PubMed

Amin, Neha; Reddy, Krishna; Westerly, David; Raben, David; DeWitt, Peter; Chen, Changhu

2012-12-01

To evaluate the effect of larynx and esophageal inlet sparing on dysphagia recovery after intensity-modulated radiotherapy (IMRT) for stage III-IV oropharyngeal squamous cell carcinoma. Retrospective study. Of 88 patients treated with IMRT, 38 were planned with a larynx + esophageal inlet mean dose <50 Gy constraint, 27 with a larynx alone mean dose constraint of <50 Gy, and 23 without a larynx/esophagus constraint. All had a percutaneous endoscopic gastrostomy (PEG) tube placed before IMRT, which was removed when the patient could swallow and maintain weight. All IMRT plans were retrieved, and the larynx; esophageal inlet; and superior, middle, and inferior constrictors were contoured. Dosimetric data were correlated with PEG tube dependence duration. The PEG tube was removed within 3, 6, 9, and 12 months after IMRT in 24%, 61%, 71%, and 83% of patients, respectively. Median times to PEG tube removal were 3.7 and 8.6 months (P = .0029) in patients planned with or without a larynx/larynx + esophageal inlet dose constraint. A mean dose to the larynx + esophageal inlet of ≤60 Gy reduced the median PEG tube duration from 10.8 to 6.1 months (P = .02), compared to >60 Gy. Mean pharyngeal constrictor doses in patients receiving a mean dose to the larynx + esophageal inlet of ≤50 Gy versus >50 Gy were: 60 Gy and 69 Gy, 55 Gy and 67 Gy, and 47 Gy and 57 Gy, for the superior, middle, and inferior constrictors, respectively (P < .0001). A dose constraint on the larynx and esophageal inlet during IMRT planning reduces dose to pharyngeal constrictors and expedites PEG tube removal. Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.

Clinical implication of elevated human cervical cancer oncogene-1 expression in esophageal squamous cell carcinoma.

PubMed

Liu, Ying; Li, Ke; Ren, Zhonghai; Li, Shenglei; Zhang, Hongyan; Fan, Qingxia

2012-07-01

The human cervical cancer oncogene 1 (HCCR-1), a novel human oncoprotein, has been shown to be upregulated in various human tumors and plays a critical role in tumorigenesis and tumor progression. Here, the authors investigated HCCR-1 level in esophageal squamous cell carcinoma (ESCC) tissues and assessed the correlation between HCCR-1 level and prognosis of the patients with ESCC. HCCR-1 levels were investigated by immunohistochemistry, in situ hybridization, real-time quantitative RT-PCR and Western blotting methods; Kaplan-Meier curve was used to evaluate the prognostic value of HCCR-1 level in patients with ESCC using log-rank test. HCCR-1 displayed high levels in ESCC tissues compared to squamous dysplasia tissues and normal esophageal epithelial tissues. No significant correlation was observed between the levels of HCCR-1 mRNA and protein and gender and age (all p>0.05) but obviously related to histological grade, clinical stage, and lymph node metastasis (all p<0.001). Moreover, the survival rate of the patients with low HCCR-1 levels was higher than that of the patients with high HCCR-1 levels (both p<0.05). These data demonstrate that HCCR-1 may be used as a novel predictor for the prognosis of the patients with ESCC.

The effect of Glut1 and c-myc on prognosis in esophageal squamous cell carcinoma of Kazakh and Han patients.

PubMed

Zhou, Ya-Xing; Zhou, Ke-Ming; Liu, Qian; Wang, Hui; Wang, Wen; Shi, Yi; Ma, Yu-Qing

2018-04-09

Glucose transporter type 1 (Glut1) plays a crucial role in cancer-specific metabolism. We explored the expression of Glut1 and c-myc, the relationship between them and the effect of Glut1, c-myc on prognosis in esophageal squamous cell carcinoma. Immunohistochemistry was used to examine the expression of Glut1 and c-myc. χ 2 test analyzes the relationship between c-myc, Glut1 and pathological parameters. Spearman correlation analyzes the relationship between c-myc and Glut1. Survival analysis was used to investigate the effect of Glut1 and c-myc on prognosis. Glut1 positivity was associated with tumor size (p < 0.01), depth of invasion (p = 0.021), tumor, node, metastasis (TNM) stage (IA+IB,II+IIB,IIIA+IIIB,IVA+IVB ; p = 0.004), lymph node metastasis (p = 0.002) and nerve invasion (p = 0.050). C-myc positivity was associated with tumor location (p = 0.015), depth of invasion (p = 0.022) and lymph node metastasis (p = 0.035). There was a positive correlation between c-myc and Glut1 (r = 0.321). Patients with Glut1 c-myc co-expression had poorer prognosis. Inhibiting Glut1 c-myc co-expression may improve the prognosis of esophageal squamous cell carcinoma.

Reduced toxicity with three-dimensional conformal radiotherapy or intensity-modulated radiotherapy compared with conventional two-dimensional radiotherapy for esophageal squamous cell carcinoma: a secondary analysis of data from four prospective clinical trials.

PubMed

Deng, J-Y; Wang, C; Shi, X-H; Jiang, G-L; Wang, Y; Liu, Y; Zhao, K-L

2016-11-01

We conducted a retrospective analysis to assess the toxicity and long-term survival of esophageal squamous cell carcinoma patients treated with three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) versus conventional two-dimensional radiotherapy (2DRT). All data in the present study were based on four prospective clinical trials conducted at our institution from 1996 to 2004 and included 308 esophageal squamous cell carcinoma patients treated with 2DRT or 3DCRT/IMRT. Based on the inclusion and exclusion criteria, 254 patients were included in the analysis. Of these patients, 158 were treated with 2DRT, whereas 96 were treated with 3DCRT/IMRT. The rates of ≥Grade3 acute toxicity of the esophagus and lung were 11.5% versus 28.5% (P = 0.002) and 5.2% versus 10.8% (P = 0.127) in the 3DCRT/IMRT and 2DRT groups, respectively. The incidences of ≥Grade 3 late toxicity of the esophagus and lungs were 3.1% versus 10.7% (P = 0.028) and 3.1% versus 5.7% (P = 0.127) in the 3DCRT/IMRT and 2DRT groups, respectively. The 1-year, 3-year and 5-year estimated overall survival rates were 81%, 38% and 34% in the 3DCRT/IMRT group and 79%, 44% and 31% in the 2DRT group, respectively (P = 0.628). The 1-year, 3-year and 5-year local control rates were 88%, 71% and 66% in the 3DCRT/IMRT group and 84%, 66% and 60% in the 2DRT group, respectively (P = 0.412). Fewer incidences of acute and late toxicities were observed in esophageal squamous cell carcinoma patients treated with 3DCRT/IMRT compared with those treated with 2DRT. No significant survival benefit was observed with the use of 3DCRT/IMRT. © 2015 International Society for Diseases of the Esophagus.

Expression of Cat Podoplanin in Feline Squamous Cell Carcinomas.

PubMed

Itai, Shunsuke; Yamada, Shinji; Kaneko, Mika K; Harada, Hiroyuki; Kagawa, Yumiko; Konnai, Satoru; Kato, Yukinari

2017-12-01

Oral squamous cell carcinoma is an aggressive tumor in cats; however, molecular-targeted therapies against this tumor, including antibody therapy, have not been developed. Sensitive and specific monoclonal antibodies (mAbs) against highly expressed membrane proteins are needed to develop antibody therapies. Podoplanin, a type I transmembrane glycoprotein, is expressed in many human malignant tumors, including brain tumor, esophageal cancer, lung cancer, mesothelioma, and oral cancer. Podoplanin binds to C-type lectin-like receptor-2 (CLEC-2) and activates platelet aggregation, which is involved in cancer metastasis. Until now, we have established several mAbs against podoplanin in humans, mice, rats, rabbits, dogs, cattle, and cats. We have reported podoplanin expression in canine melanoma and squamous cell carcinomas using an anti-dog podoplanin mAb PMab-38. In this study, we investigated podoplanin expression in 40 feline squamous cell carcinomas (14 cases of mouth floor, 13 of skin, 9 of ear, and 4 of tongue) by immunohistochemical analysis using an anti-cat podoplanin mAb PMab-52, which we recently developed by cell-based immunization and screening (CBIS) method. Of the total 40 cases, 38 (95%) showed positive staining for PMab-52. In particular, 12 cases (30%) showed a strong membrane-staining pattern of squamous cell carcinoma cells. PMab-52 can be useful for antibody therapy against feline podoplanin-expressing squamous cell carcinomas.

Evaluating the effect of four extracts of avocado fruit on esophageal squamous carcinoma and colon adenocarcinoma cell lines in comparison with peripheral blood mononuclear cells.

PubMed

Vahedi Larijani, Laleh; Ghasemi, Maryam; AbedianKenari, Saeid; Naghshvar, Farshad

2014-01-01

Most patients with gastrointestinal cancers refer to the health centers at advanced stages of the disease and conventional treatments are not significantly effective for these patients. Therefore, using modern therapeutic approaches with lower toxicity bring higher chance for successful treatment and reduced adverse effects in such patients. The aim of this study is to evaluate the effect of avocado fruit extracts on inhibition of the growth of cancer cells in comparison with normal cells. In an experimental study, ethanol, chloroform, ethyl acetate, and petroleum extracts of avocado (Persea americana) fruit were prepared. Then, the effects if the extracts on the growth of esophageal squamous cell carcinoma and colon adenocarcinoma cell lines were evaluated in comparison with the control group using the MTT test in the cell culture medium. Effects of the four extracts of avocado fruit on three cells lines of peripheral blood mononuclear cells, esophageal squamous cell carcinoma, and colon adenocarcinoma were tested. The results showed that avocado fruit extract is effective in inhibition of cancer cell growth in comparison with normal cells (P<0.05). Avocado fruit is rich in phytochemicals, which play an important role in inhibition of growth of cancer cells. The current study for the first time demonstrates the anti-cancer effect of avocado fruit extracts on two cancers common in Iran. Therefore, it is suggested that the fruit extracts can be considered as appropriate complementary treatments in treatment of esophageal and colon cancers.

Prospective Comparison of Surgery Alone and Chemoradiotherapy With Selective Surgery in Resectable Squamous Cell Carcinoma of the Esophagus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ariga, Hisanori; Nemoto, Kenji; Miyazaki, Shukichi

Purpose: Esophagectomy remains the mainstay treatment for esophageal cancer, although retrospective studies have suggested that chemoradiotherapy (CRT) is as effective as surgery. To determine whether CRT can substitute for surgery as the primary treatment modality, we performed a prospective direct comparison of outcomes after treatment in patients with resectable esophageal cancer who had received CRT and those who had undergone surgery. Methods and Materials: Eligible patients had resectable T1-3N0-1M0 thoracic esophageal cancer. After the surgeon explained the treatments in detail, the patients selected either CRT (CRT group) or surgery (OP group). The CRT course consisted of two cycles of cisplatinmore » and fluorouracil with split-course concurrent radiotherapy of 60Gy in 30 fractions. Patients with progressive disease during CRT and/or with persistent or recurrent disease after CRT underwent salvage resection. Results: Of 99 eligible patients with squamous cell carcinoma registered between January 2001 and December 2005, 51 selected CRT and 48 selected surgery. Of the patients in the CRT group, 13 (25.5%) underwent esophagectomy as salvage therapy. The 3- and 5-year survival rates were 78.3% and 75.7%, respectively, in the CRT group compared with 56.9% and 50.9%, respectively, in the OP group (p = 0.0169). Patients in the OP group had significantly more metastatic recurrence than those in the CRT group. Conclusions: Treatment outcomes among patients with resectable thoracic esophageal squamous cell carcinoma were comparable or superior after CRT (with salvage therapy if needed) to outcomes after surgery alone.« less

Severe immune mucositis and esophagitis in metastatic squamous carcinoma of the larynx associated with pembrolizumab.

PubMed

Acero Brand, Fanny Zulay; Suter, Nicolas; Adam, Jean-Philippe; Faulques, Bernard; Maietta, Antonio; Soulières, Denis; Blais, Normand

2018-03-16

Pembrolizumab is an anti-programmed death 1 (PD-1) receptor monoclonal antibody that has shown activity as second line treatment for metastatic head and neck squamous cell carcinoma (HNSCC). Immune-related adverse events are now well described complications of PD-1 inhibitors and most organ sites have been shown to be potentially affected. We describe a 69-year old patient with a relapsed squamous cell carcinoma of the supraglottic larynx with lung metastasis after receiving adjuvant concurrent cisplatin and radiotherapy. This patient was treated with pembrolizumab and benefitted from therapy with major radiological improvement of disease. After 14 cycles of pembrolizumab 200 mg IV each 3 weeks, he experienced dysphagia that evolved to a grade 4 oral cavity and pharynx mucositis and esophagitis. Histologic analysis showed ulcerative esophagitis associated with granulation tissue. Pembrolizumab was discontinued and IV methylprednisolone 2 mg/kg/day was initiated. Two days later, the patient reported a 50% recovery in his symptoms which were completely resolved after 2 weeks. Methylprednisolone was switched to oral prednisone and a taper was planned over 8 weeks. During the fourth week of taper, the patient presented recurrence of grade 1 oral mucositis. Prednisone was increased 2 mg/kg/day for 2 weeks followed by slower tapering over a period of 5 months. Pembrolizumab was not reinitiated. This is the first described case of grade 4 immune mucositis and esophagitis associated with pembrolizumab. Because the use of pembrolizumab is increasing in oncology, pharmacists and physicians should be aware of this rare manifestation.

Metformin inhibits the radiation-induced invasive phenotype of esophageal squamous cell carcinoma.

PubMed

Nakayama, Akira; Ninomiya, Itasu; Harada, Shinichi; Tsukada, Tomoya; Okamoto, Koichi; Nakanuma, Shinichi; Sakai, Seisho; Makino, Isamu; Kinoshita, Jun; Hayashi, Hironori; Oyama, Katsunobu; Miyashita, Tomoharu; Tajima, Hidehiro; Takamura, Hiroyuki; Fushida, Sachio; Ohta, Tetsuo

2016-11-01

Esophageal cancer is one of the most aggressive tumor types because of its invasiveness and metastatic potential. Several reports have described an association between increased invasiveness after ionizing radiation (IR) treatment and epithelial-to-mesenchymal transition (EMT). The biguanide metformin is reported to prevent transforming growth factor-β (TGF-β)-induced EMT and proliferation of cancer. This study examined whether IR induces EMT and promotes the invasive potential of TE-9 esophageal squamous cell carcinoma cells and the effect of metformin on IR-induced EMT. After IR exposure, TE-9 cells showed a spindle-shaped morphology and lost cell-cell adhesion. Immunoblotting showed that IR induced expression of mesenchymal markers (vimentin and N-cadherin), transcription factors (Slug, Snail, and Twist), and matrix metalloproteinases. A scratch wound assay and Matrigel invasion assay showed that IR enhanced the invasive potential and migratory capacity of TE-9 cells. Expression of hypoxia-related factor-1α and TGF-β was increased after IR. IR also induced phosphorylation of Smad2 and Smad3. Metformin inhibited radiation-induced EMT-like morphological changes, and enhanced invasion and migration of TE-9 cells. Metformin inhibited IR-induced phosphorylation of Smad2 and Smad3. Although phosphorylation of AMP-activated protein kinase was enhanced by IR and metformin, phosphorylation of mammalian target of rapamycin was enhanced by IR and suppressed by metformin. These results indicated that metformin suppressed IR-induced EMT via suppression of the TGF-β-Smad phosphorylation pathway, and a part of the non-Smad pathway. Metformin might be useful to prevent IR-induced invasion and metastasis of esophageal squamous cell carcinoma.

Three-Dimensional mRNA Measurements Reveal Minimal Regional Heterogeneity in Esophageal Squamous Cell Carcinoma

PubMed Central

Yan, Wusheng; Shih, Joanna; Rodriguez-Canales, Jaime; Tangrea, Michael A.; Player, Audrey; Diao, Lixia; Hu, Nan; Goldstein, Alisa M.; Wang, Jing; Taylor, Philip R.; Lippman, Scott M.; Wistuba, Ignacio I.; Emmert-Buck, Michael R.; Erickson, Heidi S.

2014-01-01

The classic tumor clonal evolution theory postulates that cancers change over time to produce unique molecular subclones within a parent neoplasm, presumably including regional differences in gene expression. More recently, however, this notion has been challenged by studies showing that tumors maintain a relatively stable transcript profile. To examine these competing hypotheses, we microdissected discrete subregions containing approximately 3000 to 8000 cells (500 to 1500 μm in diameter) from ex vivo esophageal squamous cell carcinoma (ESCC) specimens and analyzed transcriptomes throughout three-dimensional tumor space. Overall mRNA profiles were highly similar in all 59 intratumor comparisons, in distinct contrast to the markedly different global expression patterns observed in other dissected cell populations. For example, normal esophageal basal cells contained 1918 and 624 differentially expressed genes at a greater than twofold level (95% confidence level of <5% false positives), compared with normal differentiated esophageal cells and ESCC, respectively. In contrast, intratumor regions had only zero to four gene changes at a greater than twofold level, with most tumor comparisons showing none. The present data indicate that, when analyzed using a standard array-based method at this level of histological resolution, ESCC contains little regional mRNA heterogeneity. PMID:23219752

Endoscopic diagnosis and treatment of early esophageal squamous neoplasia

PubMed Central

Shimamura, Yuto; Ikeya, Takashi; Marcon, Norman; Mosko, Jeffrey D

2017-01-01

Esophageal cancer is one of the leading causes of cancer-related death and is associated with high morbidity and mortality. It carries a poor prognosis as more than half of patients present with advanced and unresectable disease. One contributing factor is the increased risk of lymph node metastases at early stages of disease. As such, it is essential to detect squamous cell neoplasia (SCN) at an early stage. In order to risk stratify lesions, endoscopists must be able to perform image enhanced endoscopy including magnification and Lugol’s chromoendoscopy. The assessment of both the horizontal extent and depth of any lesion is also of utmost importance prior to treatment. Endoscopic mucosal resection and submucosal dissection remain the standard of care with literature supportive their respective use. Radiofrequency ablation and other endoscopic treatments are currently available although should not be considered first line at this time. Our objective is to review the current options for the endoscopic diagnosis and treatment of esophageal SCN. PMID:28979708

RNA editing of SLC22A3 drives early tumor invasion and metastasis in familial esophageal cancer

PubMed Central

Fu, Li; Qin, Yan-Ru; Ming, Xiao-Yan; Zuo, Xian-Bo; Diao, Yu-Wen; Zhang, Li-Yi; Ai, Jiaoyu; Liu, Bei-Lei; Huang, Tu-Xiong; Cao, Ting-Ting; Tan, Bin-Bin; Xiang, Di; Zeng, Chui-Mian; Gong, Jing; Zhang, Qiangfeng; Dong, Sui-Sui; Chen, Juan; Liu, Haibo; Wu, Jian-Lin; Qi, Robert Z.; Xie, Dan; Wang, Li-Dong

2017-01-01

Like many complex human diseases, esophageal squamous cell carcinoma (ESCC) is known to cluster in families. Familial ESCC cases often show early onset and worse prognosis than the sporadic cases. However, the molecular genetic basis underlying the development of familial ESCC is mostly unknown. We reported that SLC22A3 is significantly down-regulated in nontumor esophageal tissues from patients with familial ESCC compared with tissues from patients with sporadic ESCCs. A-to-I RNA editing of the SLC22A3 gene results in its reduced expression in the nontumor esophageal tissues of familial ESCCs and is significantly correlated with lymph node metastasis. The RNA-editing enzyme ADAR2, a familial ESCC susceptibility gene identified by our post hoc genome-wide association study, is positively correlated with the editing level of SLC22A3. Moreover, functional studies showed that SLC22A3 is a metastasis suppressor in ESCC, and deregulation of SLC22A3 facilitates cell invasion and filopodia formation by reducing its direct association with α-actinin-4 (ACTN4), leading to the increased actin-binding activity of ACTN4 in normal esophageal cells. Collectively, we now show that A-to-I RNA editing of SLC22A3 contributes to the early development and progression of familial esophageal cancer in high-risk individuals. PMID:28533408

Association between diet and esophageal cancer in Taiwan.

PubMed

Hung, Hsin-Chia; Huang, Meng-Chuan; Lee, Jang-Ming; Wu, Deng-Chyang; Hsu, Hon-Ki; Wu, Ming-Tsang

2004-06-01

Several studies have reported the importance of dietary factors in the development of esophageal cancer. The purpose of the present study was to evaluate the effects of several common dietary factors on the risk of squamous cell carcinoma of the esophagus in a Taiwanese population. The association between diet and esophageal cancer was examined in 284 male patients and 480 male controls, who were recruited during 6 year period. Consumption of preserved and overheated foods was found to be associated with increased risk of esophageal cancer, whereas intake of fresh fruits, vegetables, and tea was inversely associated with this risk. Men who consumed fermented bean products, salted food and preserved/pickled vegetables more than once a week after age 40 years had a 3.4-fold risk (95% confidence interval (CI): 1.9-6.2), 2.3-fold risk (95%CI: 1.2-4.2), and 2.5-fold risk (95%CI: 1.3-4.5), respectively, compared to men eating these items less than once a week. It was further found that these preserved foods were more strongly associated with esophageal cancer among men who consumed fruit less than once per day than those who consumed fruits one or more times per day. These results suggest that a high intake of preserved foods and overheated drinks might increase the risk of esophageal cancer, and intake of fruit, vegetables, and tea might be negatively associated with risk of esophageal cancer. The results also suggest that diet is an important factor in the development of esophageal cancer in Taiwan.

P21, COX-2, and E-cadherin are potential prognostic factors for esophageal squamous cell carcinoma.

PubMed

Lin, Yao; Shen, Lu-Yan; Fu, Hao; Dong, Bin; Yang, He-Li; Yan, Wan-Pu; Kang, Xiao-Zheng; Dai, Liang; Zhou, Hai-Tao; Yang, Yong-Bo; Liang, Zhen; Chen, Ke-Neng

2017-02-01

Much research effort has been devoted to identifying prognostic factors for esophageal squamous cell carcinoma (ESCC) by immunohistochemistry; however, no conclusive findings have been reached thus far. We hypothesized that certain molecules identified in previous studies might serve as useful prognostic markers for ESCC. Therefore, the aim of the current study was to validate the most relevant markers showing potential for ESCC prognosis in our prospective esophageal cancer database. A literature search was performed using the PubMed database for papers published between 1980 and 2015 using the following key words: 'esophageal cancer,' 'prognosis,' and 'immunohistochemistry.' Literature selection criteria were established to identify the most widely studied markers, and we further validated the selected markers in a cohort from our single-surgeon team, including 153 esophageal cancer patients treated from 2000 to 2010. A total of 1799 articles were identified, 82 of which met the selection criteria. Twelve markers were found to be the most widely studied, and the validation results indicated that only P21, COX-2, and E-cadherin were independent prognostic factors for ESCC patients in this series. The systemic review and cohort validation suggest that P21, COX-2, and E-cadherin are potential prognostic factors for ESCC, paving the way for more targeted prospective validation in the future. © 2016 International Society for Diseases of the Esophagus.

Esophageal Cancer: Genomic and Molecular Characterization, Stem Cell Compartment and Clonal Evolution

PubMed Central

Testa, Ugo; Castelli, Germana; Pelosi, Elvira

2017-01-01

Esophageal cancer (EC) is the eighth most common cancer and is the sixth leading cause of death worldwide. The incidence of histologic subtypes of EC, esophageal adenocarcinoma (EAC) and esophageal squamous carcinoma (ESCC), display considerable geographic variation. EAC arises from metaplastic Barrett’s esophagus (BE) in the context of chronic inflammation secondary to exposure to acid and bile. The main risk factors for developing ESCC are cigarette smoking and alcohol consumption. The main somatic genetic abnormalities showed a different genetic landscape in EAC compared to ESCC. EAC is a heterogeneous cancer dominated by copy number alterations, a high mutational burden, co-amplification of receptor tyrosine kinase, frequent TP53 mutations. The cellular origins of BE and EAC are still not understood: animal models supported a cellular origin either from stem cells located in the basal layer of esophageal epithelium or from progenitors present in the cardia region. Many studies support the existence of cancer stem cells (CSCs) able to initiate and maintain EAC or ESCC. The exact identification of these CSCs, as well as their role in the pathogenesis of EAC and ESCC remain still to be demonstrated. The reviewed studies suggest that current molecular and cellular characterization of EAC and ESCC should serve as background for development of new treatment strategies. PMID:28930282

A synthetic urinary probe–coated nanoparticles sensitive to fibroblast activation protein α for solid tumor diagnosis

PubMed Central

Feng, Xinwei; Wang, Qifan; Liao, Yuehua; Zhou, Xie; Wang, Yidan; Liu, Wanli; Zhang, Ge

2017-01-01

We developed fibroblast activation protein α (FAPα)-sensitive magnetic iron oxide nanoparticles (MNPs) by conjugating a substrate-reporter tandem peptide as a synthetic biomarker to the surface of MNPs (marker-MNPs). In vitro, the marker-MNPs showed stability when treated with serum or urine and exhibited high susceptibility and specificity for FAPα enzyme and 3T3/FAPα cell line. Furthermore, the marker-MNPs were administered to esophageal squamous cell carcinoma xenograft tumor mice; they reached the tumor tissues in the mice, where they were cleaved effectively by the local overexpressed FAPα to release the reporter peptide and filter it into the urine. The tumor targeting and biodistribution of marker-MNPs were verified by in vivo imaging. The cleaved reporter peptides in urine detected by enzyme-linked immunosorbent assay have high diagnostic accuracy for esophageal squamous cell carcinoma (area under the receiver-operating characteristic curve =1.0). Our study implies a promising strategy of utilizing the low-cost and noninvasive synthetic urinary probe–coated nanoparticles for the diagnosis of FAPα-positive solid tumors, except for in renal cancer. PMID:28794628

ErbB receptors in the biology and pathology of the aerodigestive tract

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morgan, Sarah; Suite 500, Pittsburgh, PA 15213; Grandis, Jennifer R.

2009-02-15

The most common sites of malignancies in the aerodigestive tract include the lung, head and neck and the esophagus. Esophageal adenocarcinomas (EA), esophageal squamous cell carcinomas (ESCC), and squamous cell carcinomas of the head and neck (SCCHN) are the primary focus of this review. Traditional treatment for aerodigestive tract cancers includes primary chemoradiotherapy (CRT) or surgical resection followed by radiation (or CRT). Recent developments in treatment have focused increasingly on molecular targeting strategies including cetuximab (a monoclonal antibody against epidermal growth factor receptor (EGFR)). Cetuximab was FDA approved in 2006 for treatment of SCCHN, underscoring the importance of understanding themore » biology of these malignancies. EGFR is a member of the ErbB family of growth factor receptor tyrosine kinases. The major pathways activated by ErbB receptors include Ras/Raf/MAPK; PI3K/AKT; PLC{gamma} and STATs, all of which lead to the transcription of target genes that may contribute to aerodigestive tumor progression. This review explores the expression of ErbB receptors in EA, ESCC and SCCHN and the signaling pathways of EGFR in SCCHN.« less

Diagnosis and treatment of superficial esophageal cancer.

PubMed

Barret, Maximilien; Prat, Frédéric

2018-01-01

Endoscopy allows for the screening, early diagnosis, treatment and follow up of superficial esophageal cancer. Endoscopic submucosal dissection has become the gold standard for the resection of superficial squamous cell neoplasia. Combinations of endoscopic mucosal resection and radiofrequency ablation are the mainstay of the management of Barrett's associated neoplasia. However, protruded, non-lifting or large lesions may be better managed by endoscopic submucosal dissection. Novel ablation tools, such as argon plasma coagulation with submucosal lifting and cryoablation balloons, are being developed for the treatment of residual Barrett's esophagus, since iatrogenic strictures still hamper the development of extensive circumferential resections in the esophagus. Optimal surveillance modalities after endoscopic resection are still to be determined. The assessment of the risk of lymph-node metastases, as well as of the need for additional treatments based on qualitative and quantitative histological criteria, balanced to the patient's condition, requires a dedicated multidisciplinary team decision process. The need for trained endoscopists, expert pathologists and surgeons, and specialized multidisciplinary meetings underlines the role of expert centers in the management of superficial esophageal cancer.

On endocytoscopy and posttherapy pathologic staging in esophageal cancers, and on evidence-based methodology.

PubMed

Chao, Yin-Kai; Kawada, Kenro; Kumagai, Youichi; Takubo, Kaiyo; Wang, Helen H

2014-09-01

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the value of endocytoscopy to replace biopsy histology for squamous cell carcinoma and the clinical significance of posttherapy pathologic stage in patients with esophageal adenocarcinoma following preoperative chemoradiation; a short discussion of evidence-based methodology is also included. © 2014 New York Academy of Sciences.

Morphological studies of the developing human esophageal epithelium.

PubMed

Ménard, D

1995-06-15

This article focusses on the structural development of human esophageal ciliated epithelium. A combination of transmission electron microscopic (TEM), scanning electron microscopic (SEM), radioautographic, and light microscopic (LM) analyses were carried out using intact fetal tissues between 8 and 20 weeks of gestation as well as cultured esophageal explants. Up to the age of 10 weeks, the stratified esophageal epithelium consisted of two longitudinal primary folds. The surface cells were undifferentiated and contained large glycogen aggregates. Between 11 and 16 weeks, the primary folds (now up to four) had developed secondary folds. The thickness of the epithelium drastically increased (123%) in concomittance with a differentiation of surface columnar ciliated cells. These highly specialized surface cells exhibited junctional complexes and well-developed organelles with numerous microvilli interspersed among the cilia. Transverse sections revealed the internal structure of the cilia with a consistent pattern of nine doublet microtubules surrounding a central pair of single microtubules. Freeze-fracture studies illustrated the presence of a ciliary necklace composed of 6 ring-like rows of intramembranous particles. They also revealed the structure of ciliary cell tight junctions consisting of up to nine anastomosing strands (P-face) or complementary grooves (E-face). Ultrastructural studies (LM, TEM, SEM) of the esophageal squamous epithelium obtained after 15 days of culture showed that the newly formed epithelium was similar to adult human epithelium. Finally LM and SEM observations established that the esophagogastric junction was not yet well delineated, consisting of a transitional area composed of a mixture of esophageal ciliated cells and gastric columnar mucous cells.

Processed food consumption and risk of esophageal squamous cell carcinoma: A case-control study in a high risk area.

PubMed

Song, Qingkun; Wang, Xiaorong; Yu, Ignatius Tak-sun; Huang, Chengyu; Zhou, Xiaoqiao; Li, Jun; Wang, Dong

2012-11-01

This study was conducted to investigate the association between consumption of processed foods and esophageal cancer risk. A population-based case-control study was designed. For the present study, 254 patients with esophageal squamous cell carcinoma with pathological diagnoses were selected from Yanting during 2008 and 2010 and 254 community-based controls were selected from the same area, individually matched with cases by age and sex. Data on demographic, lifestyle and dietary factors were collected using food frequency questionnaires. A conditional logistic regression model was used to estimate the odds ratio (OR) with adjustments for potential confounders. Compared to the frequency of <1 time/week, the intake frequency of >3 times/week of preserved vegetables had a significant association with esophageal cancer (OR = 5.01, 95% confidence interval [CI] 2.07, 12.17). In stratified analyses, the OR of increasing intake of preserved vegetables for esophageal cancer were 2.02 in men (95% CI 1.18, 3.48), 3.15 in women (95% CI 1.28, 7.75), 2.41 (95% CI 1.45 4.01) in the persons <65 years old and 1.28 (95% CI 0.35, 4.65) in persons ≥65 years old. Consumption of pickled vegetables was not associated significantly with esophageal cancer risk. Intake of salted meat with a frequency of ≥1 time/week meant that the OR increased to 2.57 (95%CI 1.02, 6.43), but no significant trend or association in subgroup analysis was observed. Preserved vegetable consumption was associated with increased risk of esophageal cancer, while no association was found with pickled vegetables. © 2012 Japanese Cancer Association.

Performance characteristics of optical coherence tomography in assessment of Barrett's esophagus and esophageal cancer: systematic review.

PubMed

Kohli, D R; Schubert, M L; Zfass, A M; Shah, T U

2017-11-01

Optical coherence tomography (OCT) can generate high-resolution images of the esophagus that allows cross-sectional visualization of esophageal wall layers. We conducted a systematic review to assess the utility of OCT for diagnosing of esophageal intestinal metaplasia (IM; Barrett's esophagus BE)), dysplasia, cancer and staging of early esophageal cancer. English language human observational studies and clinical trials published in PubMed and Embase were included if they assessed any of the following: (i) in-vivo features and accuracy of OCT at diagnosing esophageal IM, sub-squamous intestinal metaplasia (SSIM), dysplasia, or cancer, and (ii) accuracy of OCT in staging esophageal cancer. Twenty-one of the 2,068 retrieved citations met inclusion criteria. In the two prospective studies that assessed accuracy of OCT at identifying IM, sensitivity was 81%-97%, and specificity was 57%-92%. In the two prospective studies that assessed accuracy of OCT at identifying dysplasia and early cancer, sensitivity was 68%-83%, and specificity was 75%-82%. Observational studies described significant variability in the ability of OCT to accurately identify SSIM. Two prospective studies that compared the accuracy of OCT at staging early squamous cell carcinoma to histologic resection specimens reported accuracy of >90%. Risk of bias and applicability concerns was rated as low among the prospective studies using the QUADAS-2 questionnaire. OCT may identify intestinal metaplasia and dysplasia, but its accuracy may not meet recommended thresholds to replace 4-quadrant biopsies in clinical practice. OCT may be more accurate than EUS at staging early esophageal cancer, but randomized trials and cost-effective analyses are lacking. © The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A variable structure fuzzy neural network model of squamous dysplasia and esophageal squamous cell carcinoma based on a global chaotic optimization algorithm.

PubMed

Moghtadaei, Motahareh; Hashemi Golpayegani, Mohammad Reza; Malekzadeh, Reza

2013-02-07

Identification of squamous dysplasia and esophageal squamous cell carcinoma (ESCC) is of great importance in prevention of cancer incidence. Computer aided algorithms can be very useful for identification of people with higher risks of squamous dysplasia, and ESCC. Such method can limit the clinical screenings to people with higher risks. Different regression methods have been used to predict ESCC and dysplasia. In this paper, a Fuzzy Neural Network (FNN) model is selected for ESCC and dysplasia prediction. The inputs to the classifier are the risk factors. Since the relation between risk factors in the tumor system has a complex nonlinear behavior, in comparison to most of ordinary data, the cost function of its model can have more local optimums. Thus the need for global optimization methods is more highlighted. The proposed method in this paper is a Chaotic Optimization Algorithm (COA) proceeding by the common Error Back Propagation (EBP) local method. Since the model has many parameters, we use a strategy to reduce the dependency among parameters caused by the chaotic series generator. This dependency was not considered in the previous COA methods. The algorithm is compared with logistic regression model as the latest successful methods of ESCC and dysplasia prediction. The results represent a more precise prediction with less mean and variance of error. Copyright © 2012 Elsevier Ltd. All rights reserved.

Long-term outcomes of minimally invasive Ivor Lewis esophagostomy for esophageal squamous cell carcinoma: Compared with open approach.

PubMed

Zhang, Zhenghua; Xu, Meiqing; Guo, Mingfa; Liu, Xuegang

2017-09-01

To investigate the safety and long-term efficacy of combined thoraco-laparoscopic minimally invasive Ivor Lewis esophagostomy(MI-ILE) in the treatment of esophageal squamous cell carcinoma. The clinical data of patients with esophageal squamous cell carcinoma who underwent Ivor Lewis esophagostomy of esophageal cancer from October 2011 to June 2013 were retrospectively analyzed. Of which 90 patients received MI-ILE, 95 patients underwent open Ivor Lewis esophagostomy (O-ILE). The clinicopathological features, intraoperative records and incidences of postoperative complications of the two groups were compared with t-test and χ2 test. The primary end point of the study was 3-year disease-free survival (DFS) and 3-year overall survival (OS) was a secondary end point. There were no statistically significant differences in gender, age, preoperative comorbidities, American Society of Anesthesiologists score and position of the tumor between the two groups. There was also no significant difference in clinicopathological characteristics, operation time, length of tumor resection margin and number of resected lymph nodes between the two groups (P > 0.05). In MI-ILE group, the blood loss was lower than in the O-ILE group [(159.1 + 97.4) ml vs. (191.7 + 141.9) ml, t = 1.811, P = 1.811]and the postoperative hospital stay was shorter [(11.5 + 4.5) d vs. (13.9 + 6.2) d, t = 2.944, P = 0.004]. There was no significant difference in the incidences of perioperative mortality and major morbidities (P > 0.05). Minor complications including incision infection rate (1.1% vs 8.4%, χ2 = 3.873, P = 0.049) and pulmonary infection incidence (3.3% vs 11.57%, χ2 = 4.492, P = 0.034) is lower in MIILE group. There was no significant difference in 3-year disease-free survival (DFS) and 3-year overall survival (OS) between the two groups. MI-ILE is a technically safe and feasible approach for esophageal squamous cell carcinoma treatment. The oncologic outcomes of MI-ILE are comparable to that of O-ILE 3 years after resection. Copyright © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

Overexpression of SKP2 promotes the radiation resistance of esophageal squamous cell carcinoma.

PubMed

Wang, Xiao-Chun; Tian, Li-Li; Tian, Jing; Jiang, Xiao-Yan

2012-01-01

SKP2 is the substrate recognition subunit of the SCF(SKP2) ubiquitin ligase complex. It is implicated in ubiquitin-mediated degradation of the cyclin-dependent kinase (CDK) inhibitor p27(KIP1) and positively regulates the G(1)/S transition. Overexpression of SKP2 has been found in many kinds of tumors. In the present study, we found that SKP2 expression levels increased in esophageal squamous cell carcinoma tissues. Elevated expression of SKP2 correlated significantly with tumor stage and positive lymph node metastasis (P < 0.05). Moreover, a significantly negative correlation was found between SKP2 expression and the survival of patients who received radiotherapy (P < 0.05). At the molecular level, induced expression of SKP2 promoted the radioresistance of EC9706 cells. Knockdown of SKP2 expression sensitized cancer cells to radiation, and a wobble mutant of SKP2 that was resistant to SKP2 siRNA was able to rescue this effect. Increased or decreased expression levels of SKP2 had effects on Rad51 expression after irradiation. These results demonstrate for the first time that overexpression of SKP2 was correlated with the increased radioresistance of esophageal squamous cell carcinoma. Elevated expression of SKP2 promoted the radioresistance of cancer cells, and this effect was mediated at least in part by the Rad51 pathway.

Effects of Lugol staining on stenosis formation induced by radiofrequency ablation of esophageal squamous epithelium: a study in a porcine model.

PubMed

Schölvinck, D W; Alvarez Herrero, L; Visser, M; Bergman, J J G H M; Weusten, B L A M

2015-10-01

Preliminary data show higher stricture rates after radiofrequency ablation (RFA) for early esophageal squamous neoplasia compared with Barrett's esophagus. We studied the effects of Lugol stain (LS) directly prior to RFA on stricture formation in squamous epithelium. Of 16 pigs, the distal half of the esophagus was LS, followed by circumferential RFA (single application 12 J/cm(2) ) in the unstained and stained esophagus. Pigs were euthanized at day 0 (n = 4), 3 (n = 4), or 28 (n = 8). Histology was evaluated in four areas: blank-control (no RFA, no LS), blank-RFA (no LS), LS+RFA, and LS-control (no RFA). Stenosis severity in LS+RFA and blank-RFA at 28 days was assessed by the ratio of the mucosal diameter at the RFA area to the diameter 2 cm proximal of this zone. Histology showed submucosal edema in 50% of LS+RFA versus 0% in blank-RFA. Severity and depth of inflammation (day 3) was equal in LS+RFA and blank-RFA. Severity and depth of fibrosis (day 28) appeared more severe in LS+RFA. Consequently, stenosis was present in 100% (LS+RFA) versus 12.5% (blank-RFA). The stenosis-severity ratio was 0.40 (interquartile range 0.29-0.45) in LS+RFA versus 0.73 (interquartile range 0.64-0.78) in blank-RFA (P = 0.012). Limitations of this study were the difference in uptake of LS between pigs and humans, the difference in esophageal anatomy between pigs and humans, and between the proximal and distal esophagus within pigs. In conclusion, in the porcine squamous esophagus, stenosis rate and severity after RFA increased when preceded by LS. LS may be contributing in the altered response of squamous epithelium to RFA as compared with Barrett's esophagus. © 2014 International Society for Diseases of the Esophagus.

Constituents of areca chewing related to esophageal cancer risk in Taiwanese men.

PubMed

Wu, M-T; Wu, D-C; Hsu, H-K; Kao, E-L; Lee, J-M

2004-01-01

Two most common types of areca chewing are noted in Taiwan: raw betel fruit with Piper betle inflorescence or folded in betel leaf. Piper betle inflorescence contains carcinogens, whereas betel leaf includes anticarcinogenic agents. One hundred and twenty-six esophageal squamous-cell-carcinoma patients and 279 healthy controls, all men, were analyzed. Areca chewers were 4.4 times (95% CI, 2.2-8.8) more likely to develop esophageal cancer than non-chewers. Sixty-five of the patients were areca chewers, of which, 61 (93.9%) chewed areca with Piper betle inflorescence, none chewed it with betel leaf and four (6.1%) chewed both. Of the 24 controls who were chewers, 10 (41.7%), three (12.5%) and 11 (45.8%) chewed areca with Piper betle inflorescence, betel leaf, and both, respectively. Multivariate analysis showed that subjects who chewed areca with Piper betle inflorescence were 24.4 times (95% CI 3.9-154.4) more likely to develop esophageal cancer than those who chewed areca with betel leaf or with both leaf and inflorescence. Our epidemiologic findings suggest parts of the same Piper plant contains carcinogenic and anticarcinogenic substances.

Histologic definition of gastro-esophageal reflux disease.

PubMed

Chandrasoma, Parakrama T

2013-07-01

To review recent data supporting the development of new histology-based definitions of gastro-esophageal reflux disease (GERD). Three precisely definable columnar epithelial types--cardiac, oxyntocardiac and intestinal--may be interposed between esophageal squamous epithelium and gastric oxyntic (acid secreting) mucosa. This enables definition of a new histologic concept: the squamo-oxyntic gap. The squamo-oxyntic gap is zero or very small in autopsies performed on patients without evidence of GERD. The gap progressively increases in length with the severity of GERD, indicating that the squamo-oxyntic gap is a marker for chronic GERD. The distal part of the gap lines gastric-type rugal folds and, therefore, is distal to the present endoscopic definition of the gastro-esophageal junction. I contend that this distal gap segment (which has esophageal submucosal glands) is actually the dilated distal esophagus; this is the pathologic correlate of destruction of the abdominal segment of the lower esophageal sphincter. The dilated distal esophagus is mistaken for 'gastric cardia' by present endoscopic definitions. I believe that these data support the adoption of novel histologic definitions of GERD as follows: the presence of any squamo-oxyntic gap defines GERD; the length of the gap is a measure of severity of chronic GERD; and the presence of intestinal metaplasia in the gap defines Barrett esophagus and cancer risk.

Utility of the transnasal esophagoscope in the management of chemoradiation-induced esophageal stenosis.

PubMed

Peng, Kevin A; Feinstein, Aaron J; Salinas, Jonathan B; Chhetri, Dinesh K

2015-03-01

This study aimed to describe management of esophageal stenosis after chemoradiation therapy for head and neck squamous cell carcinoma (HNSCC), with particular emphasis on techniques and outcomes with the use of the transnasal esophagoscope (TNE) in the office as well as operating room settings. Retrospective analysis of all patients with esophageal stenosis following head and neck cancer radiation, with or without chemotherapy, and managed with TNE-assisted esophageal dilation over a 5-year period. Preoperative and postoperative swallowing function were assessed objectively with the Functional Outcome Swallowing Scale (FOSS; ranging from score 0, a normal diet, to score 5, complete dependence on nonoral nutrition). Twenty-five patients met inclusion criteria. The mean pretreatment FOSS score was 4.4, whereas the mean posttreatment FOSS score was 2.7 (Wilcoxon signed-rank test, P<.001). Prior to dilation, 16 patients were completely gastrostomy-tube dependent (FOSS 5), of whom 12 (75%) were able to tolerate oral nutrition for a majority of their diet following treatment according to our protocol. No complications were noted. Dysphagia following chemoradiation therapy for HNSCC is often related to esophageal stenosis. With the aid of TNE, we have developed a successful treatment strategy for esophageal stenosis with improved success rates. © The Author(s) 2014.

Gastroesophageal reflux disease: Update on inflammation and symptom perception.

PubMed

Altomare, Annamaria; Guarino, Michele Pier Luca; Cocca, Silvia; Emerenziani, Sara; Cicala, Michele

2013-10-21

Although gastroesophageal reflux disease (GERD) is a common disorder in Western countries, with a significant impact on quality of life and healthcare costs, the mechanisms involved in the pathogenesis of symptoms remain to be fully elucidated. GERD symptoms and complications may result from a multifactorial mechanism, in which acid and acid-pepsin are the important noxious factors involved. Prolonged contact of the esophageal mucosa with the refluxed content, probably caused by a defective anti-reflux barrier and luminal clearance mechanisms, would appear to be responsible for macroscopically detectable injury to the esophageal squamous epithelium. Receptors on acid-sensitive nerve endings may play a role in nociception and esophageal sensitivity, as suggested in animal models of chronic acid exposure. Meanwhile, specific cytokine and chemokine profiles would appear to underlie the various esophageal phenotypes of GERD, explaining, in part, the genesis of esophagitis in a subset of patients. Despite these findings, which show a significant production of inflammatory mediators and neurotransmitters in the pathogenesis of GERD, the relationship between the hypersensitivity and esophageal inflammation is not clear. Moreover, the large majority of GERD patients (up to 70%) do not develop esophageal erosions, a variant of the condition called non-erosive reflux disease. This summary aims to explore the inflammatory pathway involved in GERD pathogenesis, to better understand the possible distinction between erosive and non-erosive reflux disease patients and to provide new therapeutic approaches.

Worldwide Esophageal Cancer Collaboration: pathologic staging data.

PubMed

Rice, T W; Chen, L-Q; Hofstetter, W L; Smithers, B M; Rusch, V W; Wijnhoven, B P L; Chen, K L; Davies, A R; D'Journo, X B; Kesler, K A; Luketich, J D; Ferguson, M K; Räsänen, J V; van Hillegersberg, R; Fang, W; Durand, L; Cecconello, I; Allum, W H; Cerfolio, R J; Pera, M; Griffin, S M; Burger, R; Liu, J-F; Allen, M S; Law, S; Watson, T J; Darling, G E; Scott, W J; Duranceau, A; Denlinger, C E; Schipper, P H; Lerut, T E M R; Orringer, M B; Ishwaran, H; Apperson-Hansen, C; DiPaola, L M; Semple, M E; Blackstone, E H

2016-10-01

We report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for patients with pathologically staged cancer of the esophagus and esophagogastric junction after resection or ablation with no preoperative therapy from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted de-identified data using standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 13,300 patients, 5,631 had squamous cell carcinoma, 7,558 adenocarcinoma, 85 adenosquamous carcinoma, and 26 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (51%), little weight loss (1.8 kg), 0-2 ECOG performance status (83%), and a history of smoking (70%). Cancers were pT1 (24%), pT2 (15%), pT3 (50%), pN0 (52%), pM0 (93%), and pG2-G3 (78%); most involved distal esophagus (71%). Non-risk-adjusted survival for both squamous cell carcinoma and adenocarcinoma was monotonic and distinctive across pTNM. Survival was more distinctive for adenocarcinoma than squamous cell carcinoma when pT was ordered by pN. Survival for pTis-1 adenocarcinoma was better than for squamous cell carcinoma, although monotonic and distinctive for both. WECC pathologic staging data is improved over that of the 7th edition, with more patients studied and patient and cancer variables collected. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient, cancer, and treatment characteristics, and should direct 9th edition data collection. However, the role of pure pathologic staging as the principal point of reference for esophageal cancer staging is waning. © 2016 International Society for Diseases of the Esophagus.

Worldwide Esophageal Cancer Collaboration: pathologic staging data

PubMed Central

Rice, T. W.; Chen, L.-Q.; Hofstetter, W. L.; Smithers, B.M.; Rusch, V. W.; Wijnhoven, B. P. L.; Chen, K. L.; Davies, A. R.; D’Journo, X. B.; Kesler, K. A.; Luketich, J. D.; Ferguson, M. K.; Räsänen, J. V.; van Hillegersberg, R.; Fang, W.; Durand, L.; Cecconello, I.; Allum, W. H.; Cerfolio, R. J.; Pera, M.; Griffin, S. M.; Burger, R.; Liu, J.-F; Allen, M. S.; Law, S.; Watson, T. J.; Darling, G. E.; Scott, W. J.; Duranceau, A.; Denlinger, C. E.; Schipper, P. H.; Lerut, T. E. M. R.; Orringer, M. B.; Ishwaran, H.; Apperson-Hansen, C.; DiPaola, L. M.; Semple, M. E.; Blackstone, E. H.

2017-01-01

SUMMARY We report data—simple descriptions of patient characteristics, cancer categories, and non–risk-adjusted survival—for patients with pathologically staged cancer of the esophagus and esophagogastric junction after resection or ablation with no preoperative therapy from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted de-identified data using standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 13,300 patients, 5,631 had squamous cell carcinoma, 7,558 adenocarcinoma, 85 adenosquamous carcinoma, and 26 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (51%), little weight loss (1.8 kg), 0–2 ECOG performance status (83%), and a history of smoking (70%). Cancers were pT1 (24%), pT2 (15%), pT3 (50%), pN0 (52%), pM0 (93%), and pG2–G3 (78%); most involved distal esophagus (71%). Non–risk-adjusted survival for both squamous cell carcinoma and adenocarcinoma was monotonic and distinctive across pTNM. Survival was more distinctive for adenocarcinoma than squamous cell carcinoma when pT was ordered by pN. Survival for pTis-1 adenocarcinoma was better than for squamous cell carcinoma, although monotonic and distinctive for both. WECC pathologic staging data is improved over that of the 7th edition, with more patients studied and patient and cancer variables collected. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient, cancer, and treatment characteristics, and should direct 9th edition data collection. However, the role of pure pathologic staging as the principal point of reference for esophageal cancer staging is waning. PMID:27731547

Trypsin impaired epithelial barrier function and induced IL-8 secretion through basolateral PAR-2: a lesson from a stratified squamous epithelial model.

PubMed

Shan, Jing; Oshima, Tadayuki; Chen, Xin; Fukui, Hirokazu; Watari, Jiro; Miwa, Hiroto

2012-11-15

Immune-mediated injury by the protease-activated receptor-2-interleukin-8 (PAR-2-IL8) pathway may underlie the development of gastroesophageal reflux disease (GERD). However, the localization of PAR-2 and the mechanism of PAR-2 activation remain unclear. This study aimed to address these questions on an esophageal stratified squamous epithelial model and in the human esophageal mucosa of GERD patients. Normal human esophageal epithelial cells were cultured with the air-liquid interface system to establish the model. SLIGKV-NH2 (PAR-2 synthetic agonist), trypsin (PAR-2 natural activator), and weak acid (pH 4, 5, and 6) were added to either the apical or basolateral compartment to evaluate their effects on transepithelial electrical resistance (TEER) and IL-8 production. PAR-2 localization was examined both in the cell model and biopsies from GERD patients by immunohistochemistry. Apical trypsin stimulation induced IL-8 accompanied by decreased TEER in vitro, whereas the effective concentration from the basolateral side was 10 times lower. SLIGKV-NH2 from basolateral but not apical stimulation induced IL-8 production. Apical weak acid stimulation did not influence TEER or IL-8 production. Immunohistochemistry showed intense reactivity of PAR-2 in the basal and suprabasal layers after stimulation with trypsin. A similar PAR-2 reactivity that was mainly located at the basal and suprabasal layers was detected in GERD patients. In conclusion, the activation of the PAR-2-IL-8 pathway probably occurred at the basal and suprabasal layers, while the esophageal epithelial barrier may influence the activation of PAR-2. Under proton pump inhibitor therapy, refluxed trypsin may remain active and be a potential agent in the pathogenesis of refractory GERD.

Atlas of the thoracic lymph nodal delineation and recommendations for lymph nodal CTV of esophageal squamous cell cancer in radiation therapy from China.

PubMed

Huang, Wei; Huang, Yong; Sun, Jujie; Liu, Xibin; Zhang, Jian; Zhou, Tao; Zhang, Baijiang; Li, Baosheng

2015-07-01

To construct an anatomical atlas of thoracic lymph node regions of esophageal cancer (EC) based on definitions from The Japan Esophageal Society (JES) and generate a consensus to delineate the nodal clinical target volume (CTVn) for elective nodal radiation (ENI) of esophageal squamous cell carcinoma (ESCC). An interdisciplinary group including two dedicated radiation oncologists, an experienced radiologist, a pathologist and two thoracic surgeons were gathered to generate a three-dimensional radiological description for the mediastinal lymph node regions of EC on axial CT scans. Then the radiological boundaries of lymph node regions were validated by a relatively large number of physicians in multiple institutions. An atlas of detailed anatomic boundaries of lymph node station No. 105-114 was defined on axial CT, along with illustrations. From the previous work, the study provided a guide of CTVn contouring for ENI of thoracic ESCC from a single center. It is feasible to use such an atlas of thoracic lymph node stations for radiotherapy planning. A phase III study based on the atlas is ongoing in China to measure quantitatively the ENI received by patients with ESCC. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Assessment of the incidence of squamous cell papilloma of the esophagus and the presence of high-risk human papilloma virus.

PubMed

Pantham, Ganesh; Ganesan, Santhi; Einstadter, Douglas; Jin, Ge; Weinberg, Aaron; Fass, Ronnie

2017-01-01

There has been a recent increase in the incidence of oropharyngeal cancer (OPC) associated with high-risk human papilloma virus (HPV) infection. We investigated the incidence of esophageal papilloma and the presence of high-risk HPV infection. This is a cross-sectional study conducted at a County teaching hospital. Patients with esophageal papilloma between January 2000 and December 2013 were identified. Patients with sufficient specimens were tested for the HPV virus. Sixty patients with esophageal papilloma lesions were identified from 2000 to 2013. (31 males, age 51 ± 13 years). The incidence was 0.13% in 2000 and increased to 0.57% in 2013 (P < 0.0001). Twenty-nine patients (48.3%) had a papilloma that was more than 5 mm in size, and 20% had multiple lesions. The papilloma was located in the distal esophagus in 35 (58.3%) patients, mid esophagus in 17 (28.3%) patients, and proximal in 8 (13.3%) patients. Three (5%) patients had associated OPC, and 9 (47.4%) of the 19 patients tested were positive for high-risk HPV serotype 16. The incidence of esophageal papilloma has increased by fourfolds over the past 14 years. About half of the tested patients demonstrated high risk HPV. This may suggest a potential growing risk for esophageal squamous cell cancer in the future. © 2016 International Society for Diseases of the Esophagus.

Multilayered epithelium in a rat model and human Barrett's esophagus: Similar expression patterns of transcription factors and differentiation markers

PubMed Central

Chen, Xiaoxin; Qin, Rong; Liu, Ba; Ma, Yan; Su, Yinghao; Yang, Chung S; Glickman, Jonathan N; Odze, Robert D; Shaheen, Nicholas J

2008-01-01

Background In rats, esophagogastroduodenal anastomosis (EGDA) without concomitant chemical carcinogen treatment leads to gastroesophageal reflux disease, multilayered epithelium (MLE, a presumed precursor in intestinal metaplasia), columnar-lined esophagus, dysplasia, and esophageal adenocarcinoma. Previously we have shown that columnar-lined esophagus in EGDA rats resembled human Barrett's esophagus (BE) in its morphology, mucin features and expression of differentiation markers (Lab. Invest. 2004;84:753–765). The purpose of this study was to compare the phenotype of rat MLE with human MLE, in order to gain insight into the nature of MLE and its potential role in the development of BE. Methods Serial sectioning was performed on tissue samples from 32 EGDA rats and 13 patients with established BE. Tissue sections were immunohistochemically stained for a variety of transcription factors and differentiation markers of esophageal squamous epithelium and intestinal columnar epithelium. Results We detected MLE in 56.3% (18/32) of EGDA rats, and in all human samples. As expected, both rat and human squamous epithelium, but not intestinal metaplasia, expressed squamous transcription factors and differentiation markers (p63, Sox2, CK14 and CK4) in all cases. Both rat and human intestinal metaplasia, but not squamous epithelium, expressed intestinal transcription factors and differentiation markers (Cdx2, GATA4, HNF1α, villin and Muc2) in all cases. Rat MLE shared expression patterns of Sox2, CK4, Cdx2, GATA4, villin and Muc2 with human MLE. However, p63 and CK14 were expressed in a higher proportion of rat MLE compared to humans. Conclusion These data indicate that rat MLE shares similar properties to human MLE in its expression pattern of these markers, not withstanding small differences, and support the concept that MLE may be a transitional stage in the metaplastic conversion of squamous to columnar epithelium in BE. PMID:18190713

Multilayered epithelium in a rat model and human Barrett's esophagus: similar expression patterns of transcription factors and differentiation markers.

PubMed

Chen, Xiaoxin; Qin, Rong; Liu, Ba; Ma, Yan; Su, Yinghao; Yang, Chung S; Glickman, Jonathan N; Odze, Robert D; Shaheen, Nicholas J

2008-01-11

In rats, esophagogastroduodenal anastomosis (EGDA) without concomitant chemical carcinogen treatment leads to gastroesophageal reflux disease, multilayered epithelium (MLE, a presumed precursor in intestinal metaplasia), columnar-lined esophagus, dysplasia, and esophageal adenocarcinoma. Previously we have shown that columnar-lined esophagus in EGDA rats resembled human Barrett's esophagus (BE) in its morphology, mucin features and expression of differentiation markers (Lab. Invest. 2004;84:753-765). The purpose of this study was to compare the phenotype of rat MLE with human MLE, in order to gain insight into the nature of MLE and its potential role in the development of BE. Serial sectioning was performed on tissue samples from 32 EGDA rats and 13 patients with established BE. Tissue sections were immunohistochemically stained for a variety of transcription factors and differentiation markers of esophageal squamous epithelium and intestinal columnar epithelium. We detected MLE in 56.3% (18/32) of EGDA rats, and in all human samples. As expected, both rat and human squamous epithelium, but not intestinal metaplasia, expressed squamous transcription factors and differentiation markers (p63, Sox2, CK14 and CK4) in all cases. Both rat and human intestinal metaplasia, but not squamous epithelium, expressed intestinal transcription factors and differentiation markers (Cdx2, GATA4, HNF1alpha, villin and Muc2) in all cases. Rat MLE shared expression patterns of Sox2, CK4, Cdx2, GATA4, villin and Muc2 with human MLE. However, p63 and CK14 were expressed in a higher proportion of rat MLE compared to humans. These data indicate that rat MLE shares similar properties to human MLE in its expression pattern of these markers, not withstanding small differences, and support the concept that MLE may be a transitional stage in the metaplastic conversion of squamous to columnar epithelium in BE.

Vascular density of superficial esophageal squamous cell carcinoma determined by direct observation of resected specimen using narrow band imaging with magnifying endoscopy.

PubMed

Kikuchi, D; Iizuka, T; Hoteya, S; Nomura, K; Kuribayashi, Y; Toba, T; Tanaka, M; Yamashita, S; Furuhata, T; Matsui, A; Mitani, T; Inoshita, N; Kaise, M

2017-11-01

Observation of the microvasculature using narrow band imaging (NBI) with magnifying endoscopy is useful for diagnosing superficial squamous cell carcinoma. Increased vascular density is indicative of cancer, but not many studies have reported differences between cancerous and noncancerous areas based on an objective comparison. We observed specimens of endoscopic submucosal dissection (ESD) using NBI magnification, and determined the vascular density of cancerous and noncancerous areas. A total of 25 lesions of esophageal squamous cell carcinoma that were dissected en bloc by ESD between July 2013 and December 2013 were subjected to NBI magnification. We constructed a device that holds an endoscope and precisely controls the movement along the vertical axis in order to observe submerged specimens by NBI magnification. NBI image files of both cancerous (pathologically determined invasion depth, m1/2) and surrounding noncancerous areas were created and subjected to vascular density assessment by two endoscopists who were blinded to clinical information. The invasion depth was m1/2 in 20, m3/sm1 in four and sm2 in one esophageal cancer lesion. Mean vascular density was significantly increased in cancerous areas (37.6 ± 16.3 vessels/mm2) compared with noncancerous areas (17.6 ± 10.0 vessels/mm2) (P < 0.05). The correlation coefficients between vascular density determined by two endoscopists were 0.86 and 0.81 in cancerous and noncancerous areas, respectively. Receiver operating curve (ROC) analysis revealed that the area under the curve (AUC) of vascular density was 0.895 (95% CI, 0.804-0.986). For this ROC curve, sensitivity was 78.3% and specificity was 87.0% when the cutoff value of vascular density was 26 vessels/mm2. NBI magnification confirmed significant increases in vascular density in cancerous areas compared with noncancerous areas in esophageal squamous cell carcinoma. The rates of agreement between vascular density values determined by two independent operators were high. © The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Androgens and esophageal cancer: What do we know?

PubMed

Sukocheva, Olga A; Li, Bin; Due, Steven L; Hussey, Damian J; Watson, David I

2015-05-28

Significant disparities exist between genders for the development and progression of several gastro-intestinal (GI) diseases including cancer. Differences in incidence between men vs women for colon, gastric and hepatocellular cancers suggest a role for steroid sex hormones in regulation of GI carcinogenesis. Involvement of intrinsic gender-linked mechanisms is also possible for esophageal adenocarcinoma as its incidence is disproportionally high among men. However, the cause of the observed gender differences and the potential role of androgens in esophageal carcinogenesis remains unclear, even though the cancer-promoting role of androgen receptors (AR) shown in other cancers such as prostate and bladder suggests this aspect warrants exploration. Several studies have demonstrated expression of ARs in esophageal cancer. However, only one study has suggested a potential link between AR signaling and outcome - poorer prognosis. Two groups have analyzed data from cohorts with prostate cancer and one of these found a decreased incidence of esophageal squamous and adenocarcinoma after androgen deprivation therapy. However, very limited information is available about the effects of androgen and AR-initiated signaling on esophageal cancer cell growth in vitro and in vivo. Possible mechanisms for androgens/AR involvement in the regulation of esophageal cancer growth are considered, and the potential use of AR as a prognostic factor and clinical target is highlighted, although insufficient evidence is available to support clinical trials of novel therapies. As esophageal adenocarcinoma is a gender linked cancer with a large male predominance further studies are warranted to clarify the role of androgens and ARs in shaping intracellular signaling and genomic responses in esophageal cancer.

Recursive Partitioning Analysis for New Classification of Patients With Esophageal Cancer Treated by Chemoradiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nomura, Motoo, E-mail: excell@hkg.odn.ne.jp; Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya; Department of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya

2012-11-01

Background: The 7th edition of the American Joint Committee on Cancer staging system does not include lymph node size in the guidelines for staging patients with esophageal cancer. The objectives of this study were to determine the prognostic impact of the maximum metastatic lymph node diameter (ND) on survival and to develop and validate a new staging system for patients with esophageal squamous cell cancer who were treated with definitive chemoradiotherapy (CRT). Methods: Information on 402 patients with esophageal cancer undergoing CRT at two institutions was reviewed. Univariate and multivariate analyses of data from one institution were used to assessmore » the impact of clinical factors on survival, and recursive partitioning analysis was performed to develop the new staging classification. To assess its clinical utility, the new classification was validated using data from the second institution. Results: By multivariate analysis, gender, T, N, and ND stages were independently and significantly associated with survival (p < 0.05). The resulting new staging classification was based on the T and ND. The four new stages led to good separation of survival curves in both the developmental and validation datasets (p < 0.05). Conclusions: Our results showed that lymph node size is a strong independent prognostic factor and that the new staging system, which incorporated lymph node size, provided good prognostic power, and discriminated effectively for patients with esophageal cancer undergoing CRT.« less

[Epidemiology and risk factors of the esophageal squamous cell carcinoma].

PubMed

Szumiło, Justyna

2009-01-01

Esophageal carcinoma is the eighth most common malignancy in the world. In most countries, including Poland, the squamous cell carcinoma is a predominant histological type. It is characterized by extreme diversity in geographical distribution and incidence. High incidence is noted in regions located along with so-called "Asian esophageal cancer belt" beginning from eastern Turkey through Caspian littoral countries, northern Afghanistan to Central and Eastern Asia, as well as in Japan, South Africa and some South American countries. In Western Europe the highest incidence is observed in France, Portugal and northern Italy. Poland belongs to low-incidence countries with the age-standardized annual incidence exceeding 4.5 and 0.7/100,000, for men and women respectively. Etiology of the cancer is multi-factorial. In western countries the most important risk factors are tobacco smoking and alcohol consumption, and to a lesser extent, an inappropriate diet. In other countries, a diet lacking of fresh vegetables and fruits with vitamin and mineral deficiency and high level of sodium chloride, carbohydrates and animal fats is a predominant factor. Furthermore, preserving and processing food which facilitates accumulation of carcinogens, special dietary habits and viral infections are also attributed to the development of cancer. More recently, the significance of genetically determined increased susceptibility of some individuals versus environmental factors has been stressed. Previous studies proved the relationship between cancer susceptibility and polymorphisms in genes encoding some important molecules engaged in carcinogens metabolism or DNA repair.

Differences in displacement of the proximal and distal ends of mid-upper thoracic esophageal squamous cell carcinoma.

PubMed

Qiu, Guoqin; Wen, Dengshun; DU, Xianghui; Sheng, Liming; Zhou, Xia; Ji, Yongling; Bao, Wuan; Zhang, Danhong; Cheng, Lei

2016-07-01

In the present study, clips were used as markers to evaluate displacement differences between proximal and distal ends of esophageal tumors and to test whether their internal target volume (ITV) margins should be determined separately. A total of 23 patients with mid-upper thoracic esophageal squamous-cell carcinoma, a tumor length of ≤8 cm and an esophageal lumen suitable for endoscopic ultrasonography were recruited for the present study. Clips were implanted endoscopically at the proximal and distal ends of the esophageal tumor (upper and lower clips). In a further exploratory study on 16 of the patients, a third clip was placed at the distal esophagus 2 cm above the gastro-esophageal junction (GEJ) (cardiac clip). The clips were contoured for all 10 phases of the four-dimensional computed tomography and the maximum displacements of the clip centroids among different breathing phases in left-right (LR), superior-inferior (SI) and anterior-posterior (AP) directions were marked as x, y and z, respectively. The ITV margins that covered 95% of the LR, SI and AP motion were 2.89, 5.00 and 2.36 mm, respectively. Axial displacement (y) was greater than radial displacement (x, z; P<0.05). It was also revealed that LR(x), SI(y) and AP(z) displacement of cardiac clips was greater than that of upper or lower clips (P<0.05). Differences in the axial and radial displacement of the upper and lower clips indicated that axial and radial ITV margins should be determined separately. However, further study is required on patients in whom the distal tumor end is located in proximity to the GEJ.

Auraptene Attenuates Malignant Properties of Esophageal Stem-Like Cancer Cells.

PubMed

Saboor-Maleki, Saffiyeh; Rassouli, Fatemeh B; Matin, Maryam M; Iranshahi, Mehrdad

2017-08-01

The high incidence of esophageal squamous cell carcinoma has been reported in selected ethnic populations including North of Iran. Low survival rate of esophageal carcinoma is partially due to the presence of stem-like cancer cells with chemotherapy resistance. In the current study, we aimed to determine the effects of auraptene, an interesting dietary coumarin with various biological activities, on malignant properties of stem-like esophageal squamous cell carcinoma, in terms of sensitivity to anticancer drugs and expression of specific markers. To do so, the half maximal inhibitory concentration values of auraptene, cisplatin, paclitaxel, and 5-fluorouracil were determined on esophageal carcinoma cells (KYSE30 cell line). After administrating combinatorial treatments, including nontoxic concentrations of auraptene + cisplatin, paclitaxel, or 5-fluorouracil, sensitivity of cells to chemical drugs and also induced apoptosis were assessed. In addition, quantitative real-time polymerase chain reaction was used to study changes in the expression of tumor suppressor proteins 53 and 21 ( P53 and P21), cluster of differentiation 44 ( CD44), and B cell-specific Moloney murine leukemia virus integration site 1 ( BMI-1) upon treatments. Results of thiazolyl blue assay revealed that auraptene significantly ( P < .05) increased toxicity of cisplatin, paclitaxel, and 5-fluorouracil in KYSE30 cells, specifically 72 hours after treatment. Conducting an apoptosis assay using flow cytometry also confirmed the synergic effects of auraptene. Results of quantitative real-time polymerase chain reaction revealed significant ( P < .05) upregulation of P53 and P21 upon combinatorial treatments and also downregulation of CD44 and BMI-1 after auraptene administration. Current study provided evidence, for the first time, that auraptene attenuates the properties of esophageal stem-like cancer cells through enhancing sensitivity to chemical agents and reducing the expression of CD44 and BMI-1 markers.

Cutaneous and laryngeal squamous cell carcinoma in mixed epidermolysis bullosa, kindler syndrome.

PubMed

Mizutani, Hiromi; Masuda, Koji; Nakamura, Naomi; Takenaka, Hideya; Tsuruta, Daisuke; Katoh, Norito

2012-05-01

Kindler syndrome is a rare autosomal recessive genodermatosis characterized by trauma-induced acral blisters in infancy and childhood, photosensitivity, and progressive poikiloderma. Other clinical features include chronic erosive gingivitis, dysphagia, esophageal and urethral strictures, ectropion, and an increased risk of mucocutaneous squamous cell carcinoma. We describe a patient with Kindler syndrome associated with squamous cell carcinoma of the skin and larynx. He had squamous cell carcinoma on his left knee with simultaneous unresectable laryngeal carcinoma at the age of 43 years. The squamous cell carcinoma on his knee was excised and the laryngeal carcinoma was treated with radiation therapy. Although pathophysiology of Kindler syndrome and its frequency of association with cancer are still not fully elucidated, we speculate that long-term erosion and regeneration of mucosal and cutaneous surfaces may have induced squamous cell carcinoma on the patient's knee and larynx.

Study of single nucleotide polymorphisms of FBW7 and its substrate genes revealed a predictive factor for paclitaxel plus cisplatin chemotherapy in Chinese patients with advanced esophageal squamous cell carcinoma.

PubMed

Liu, Ying; Xu, Shu Ning; Chen, Yong Shun; Wu, Xiao Yuan; Qiao, Lei; Li, Ke; Yuan, Long

2016-07-12

Paclitaxel plays a major role in the treatment of advanced esophageal squamous cell carcinoma. However, there is no biomarker that could be used to predict the clinical response of paclitaxel. This work was conducted to investigate the association of genetic polymorphisms in FBW7 and its substrate genes and the clinical response of paclitaxel. Patients with advanced esophageal squamous cell carcinoma were treated with paclitaxel 175 mg/m2 over 3 hours day 1 and cisplatin 75 mg/m2 day 1, every 3 weeks. The genotypes of 11 FBW7 and its substrate gene polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Statistical analysis revealed that patients with mTOR rs1057079 AG (ORadjusted: 4.59; 95% CI: 1.78-11.86) genotype had significant correlation with the clinical response of paclitaxel when compared with AA genotype after adjustment for sex, age, and chemotherapy cycle. The median progression-free survival (PFS) of patients with advanced ESCC who received paclitaxel plus cisplatin (TP) as first-line treatment is 14.3 months (95% CI: 9.0-19.60 months). The median PFS (mPFS) of AG genotypes and AA genotypes in mTOR rs1057079 were 17.31 months (95% CI: 15.9-18.67 months) and 9.8 months (95% CI: 8.58-11.02 months) (p=0.019), respectively.

Fractionated irradiation-induced EMT-like phenotype conferred radioresistance in esophageal squamous cell carcinoma

PubMed Central

Zhang, Hongfang; Luo, Honglei; Jiang, Zhenzhen; Yue, Jing; Hou, Qiang; Xie, Ruifei; Wu, Shixiu

2016-01-01

The efficacy of radiotherapy, one major treatment modality for esophageal squamous cell carcinoma (ESCC) is severely attenuated by radioresistance. Epithelial-to-mesenchymal transition (EMT) is a cellular process that determines therapy response and tumor progression. However, whether EMT is induced by ionizing radiation and involved in tumor radioresistance has been less studied in ESCC. Using multiple fractionated irradiation, the radioresistant esophageal squamous cancer cell line KYSE-150R had been established from its parental cell line KYSE-150. We found KYSE-150R displayed a significant EMT phenotype with an elongated spindle shape and down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker N-cadherin in comparison with KYSE-150. Furthermore, KYSE-150R also possessed some stemness-like properties characterized by density-dependent growth promotion and strong capability for sphere formation and tumorigenesis in NOD-SCID mice. Mechanical studies have revealed that WISP1, a secreted matricellular protein, is highly expressed in KYSE-150R and mediates EMT-associated radioresistance both in ESCC cells and in xenograft tumor models. Moreover, WISP1 has been demonstrated to be closely associated with the EMT phenotype observed in ESCC patients and to be an independent prognosis factor of ESCC patients treated with radiotherapy. Our study highlighted WISP1 as an attractive target to reverse EMT-associated radioresistance in ESCC and can be used as an independent prognostic factor of patients treated with radiotherapy. PMID:27125498

High resolution microendoscopy for early detection of esophageal cancer in low-resource settings (Conference Presentation)

NASA Astrophysics Data System (ADS)

Richards-Kortum, Rebecca

2016-03-01

Esophageal squamous cell neoplasia (ESCN) is the sixth leading cause of cancer death worldwide. Most deaths due to ESCN occur in developing countries, with highest risk areas in northern China. Lugol's chromoendoscopy (LCE) is the gold-standard for ESCN screening; while the sensitivity of LCE for ESCN is >95%, LCE suffers poor specificity (< 65%) due to false positive findings from inflammatory lesions. High resolution microendoscopy (HRME) uses a low-cost, fiber-optic fluorescence microscope to image morphology of the surface epithelium without need for biopsy. We developed a tablet-interfaced HRME with automated, real-time image analysis. In an in vivo study of 177 patients referred for endoscopy in China, use of the algorithm identified neoplasia with a sensitivity and specificity of 95% and 91% compared to the gold standard of histology.

Diagnosis and treatment of superficial esophageal cancer

PubMed Central

Barret, Maximilien; Prat, Frédéric

2018-01-01

Endoscopy allows for the screening, early diagnosis, treatment and follow up of superficial esophageal cancer. Endoscopic submucosal dissection has become the gold standard for the resection of superficial squamous cell neoplasia. Combinations of endoscopic mucosal resection and radiofrequency ablation are the mainstay of the management of Barrett’s associated neoplasia. However, protruded, non-lifting or large lesions may be better managed by endoscopic submucosal dissection. Novel ablation tools, such as argon plasma coagulation with submucosal lifting and cryoablation balloons, are being developed for the treatment of residual Barrett’s esophagus, since iatrogenic strictures still hamper the development of extensive circumferential resections in the esophagus. Optimal surveillance modalities after endoscopic resection are still to be determined. The assessment of the risk of lymph-node metastases, as well as of the need for additional treatments based on qualitative and quantitative histological criteria, balanced to the patient’s condition, requires a dedicated multidisciplinary team decision process. The need for trained endoscopists, expert pathologists and surgeons, and specialized multidisciplinary meetings underlines the role of expert centers in the management of superficial esophageal cancer. PMID:29720850

Safety of dose escalation by simultaneous integrated boosting radiation dose within the primary tumor guided by (18)FDG-PET/CT for esophageal cancer.

PubMed

Yu, Wen; Cai, Xu-Wei; Liu, Qi; Zhu, Zheng-Fei; Feng, Wen; Zhang, Qin; Zhang, Ying-Jian; Yao, Zhi-Feng; Fu, Xiao-Long

2015-02-01

To observe the safety of selective dose boost to the pre-treatment high (18)F-deoxyglucose (FDG) uptake areas of the esophageal GTV. Patients with esophageal squamous cell carcinoma were treated with escalating radiation dose of 4 levels, with a simultaneous integrated boost (SIB) to the pre-treatment 50% SUVmax area of the primary tumor. Patients received 4 monthly cycles of cisplatin and fluorouracil. Dose-limiting toxicity (DLT) was defined as any Grade 3 or higher acute toxicities causing continuous interruption of radiation for over 1 week. From April 2012 to February 2014, dose has been escalated up to LEVEL 4 (70Gy). All of the 25 patients finished the prescribed dose without DLT, and 10 of them developed Grade 3 acute esophagitis. One patient of LEVEL 2 died of esophageal hemorrhage within 1 month after completion of radiotherapy, which was not definitely correlated with treatment yet. Late toxicities remained under observation. With median follow up of 8.9months, one-year overall survival and local control was 69.2% and 77.4%, respectively. Dose escalation in esophageal cancer based on (18)FDG-PET/CT has been safely achieved up to 70Gy using the SIB technique. Acute toxicities were well tolerated, whereas late toxicities and long-term outcomes deserved further observation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

[Epidermoid cancer of the thoracic esophagus following mediastinal irradiation].

PubMed

Fékété, F; Mosnier, H; Sogni, P; Belghiti, J; Molas, G

1986-03-01

Squamous cell carcinoma of the esophagus induced by radiation therapy is a rare entity. We report 4 cases observed during the past 4 years. Three women and one man aged from 47 to 78 years developed squamous cell carcinoma of the esophagus 8 to 11 years after radiation therapy. The 3 women had been irradiated for breast cancer and the man for Hodgkin's disease with 40 to 57.5 Gy. Three patients were operated on and the immediate postoperative course was uneventful. Culling data from this report and from the literature we reviewed the different steps concerning the diagnosis and the treatment of this complication of radiation therapy. We suggest that diagnostic and therapeutic modalities should follow the same guidelines as in other esophageal cancers.

Estrogen-Dependent Nrf2 Expression Protects Against Reflux-Induced Esophagitis.

PubMed

Torihata, Yudai; Asanuma, Kiyotaka; Iijima, Katsunori; Mikami, Tetsuhiko; Hamada, Shin; Asano, Naoki; Koike, Tomoyuki; Imatani, Akira; Masamune, Atsushi; Shimosegawa, Tooru

2018-02-01

Gastroesophageal reflux disease is more common in males than in females. The enhanced antioxidative capacity of estrogen in females might account for the gender difference. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in the host defense mechanism against oxidative stress. This study aimed to clarify the role of Nrf2 in reflux-induced esophageal inflammation, focusing on the gender difference and nitric oxide. Gastroesophageal reflux was surgically induced in male and female rats. Nitrite and ascorbic acid were administered for 1 week to provoke nitric oxide in the esophageal lumen. Male rats with gastroesophageal reflux were supplemented with 17β-estradiol or tert-butylhydroquinone, an Nrf2-inducing reagent. Esophageal squamous cell carcinoma KYSE30 cells were treated with 17β-estradiol. Nrf2 expression was examined by Western blotting and quantitative real-time PCR. Antioxidant gene expression profiles were examined by a PCR array. In the presence of nitric oxide, reflux-induced esophageal damage was less evident, whereas esophageal expression of Nrf2 and its target genes such as Nqo1 was more evident in female or male rats supplemented with 17β-estradiol than in male rats. 17β-Estradiol increased nuclear Nrf2 expression in KYSE30 cells. tert-Butylhydroquinone increased tissue Nqo1 mRNA expression, leading to a reduction in reflux-induced esophageal damage. Estrogen-dependent Nrf2 expression might contribute to protection against the development of gastroesophageal reflux disease in females.

Tolerance and dose-volume relationship of intrathoracic stomach irradiation after esophagectomy for patients with thoracic esophageal squamous cell carcinoma.

PubMed

Liu, Qi; Cai, Xu-Wei; Fu, Xiao-Long; Chen, Jun-Chao; Xiang, Jia-Qing

2015-10-13

To identify the tolerance of radiation with a high prescribed dose and predictors for the development of intrathoracic stomach toxicity in patients with thoracic esophageal squamous cell carcinoma (SCC) after esophagectomy followed by gastric conduit reconstruction. From 2011 to 2013, 105 patients after esophagectomy were treated with postoperative radiotherapy. The intrathoracic stomach was outlined with the calculation of a dose-volume histogram (DVH) for the initial intended treatment of 6020 cGy or 6300 cGy. The volume of the intrathoracic stomach receiving each dose was recorded at 10-Gy intervals between 10 and 40 Gy and at 5-Gy intervals between 40 and 60 Gy. The grade of toxicities was defined by the National Cancer Institute Common Toxicity Criteria version 4.0. The mean and maximum doses of the intrathoracic stomach were 2449 ± 986 cGy and 6519 ± 406 cGy, respectively. Sixteen (15.2%) and three (2.9%) experienced Common Toxicity Criteria Grade 2 and Grade 3 acute gastric toxicity. There were no Grade 4 toxicities. Fourteen patients (13.3%) exhibited late gastric complications possibly related to radiation. The volume percent of the intrathoracic stomach receiving at least 50 Gy (V50) was strongly associated with the degree of toxicity (p = 0.024, respectively). Multivariate analysis of patient and treatment-related factors revealed no other significant predictors of severe toxicities. The intrathoracic stomach is well tolerated with a high-dose irradiation for patients with esophageal SCC receiving radiotherapy after esophagectomy. A strong dose-volume relationship exists for the development of Grade 2 acute intrathoracic stomach toxicity in our study.

Tolerance and dose-volume relationship of intrathoracic stomach irradiation after esophagectomy for patients with thoracic esophageal squamous cell carcinoma

PubMed Central

Fu, Xiao-Long; Chen, Jun-Chao; Xiang, Jia-Qing

2015-01-01

Purpose To identify the tolerance of radiation with a high prescribed dose and predictors for the development of intrathoracic stomach toxicity in patients with thoracic esophageal squamous cell carcinoma (SCC) after esophagectomy followed by gastric conduit reconstruction. Methods and Materials From 2011 to 2013, 105 patients after esophagectomy were treated with postoperative radiotherapy. The intrathoracic stomach was outlined with the calculation of a dose-volume histogram (DVH) for the initial intended treatment of 6020 cGy or 6300 cGy. The volume of the intrathoracic stomach receiving each dose was recorded at 10-Gy intervals between 10 and 40 Gy and at 5-Gy intervals between 40 and 60 Gy. The grade of toxicities was defined by the National Cancer Institute Common Toxicity Criteria version 4.0. Results The mean and maximum doses of the intrathoracic stomach were 2449 ± 986 cGy and 6519 ± 406 cGy, respectively. Sixteen (15.2%) and three (2.9%) experienced Common Toxicity Criteria Grade 2 and Grade 3 acute gastric toxicity. There were no Grade 4 toxicities. Fourteen patients (13.3%) exhibited late gastric complications possibly related to radiation. The volume percent of the intrathoracic stomach receiving at least 50 Gy (V50) was strongly associated with the degree of toxicity (p = 0.024, respectively). Multivariate analysis of patient and treatment-related factors revealed no other significant predictors of severe toxicities. Conclusions The intrathoracic stomach is well tolerated with a high-dose irradiation for patients with esophageal SCC receiving radiotherapy after esophagectomy. A strong dose-volume relationship exists for the development of Grade 2 acute intrathoracic stomach toxicity in our study. PMID:26314958

Bile salt receptor TGR5 is highly expressed in esophageal adenocarcinoma and precancerous lesions with significantly worse overall survival and gender differences

PubMed Central

Pang, Chunhong; LaLonde, Amy; Godfrey, Tony E; Que, Jianwen; Sun, Jun; Wu, Tong Tong; Zhou, Zhongren

2017-01-01

Bile acid reflux in the esophagus plays an important role in the carcinogenesis of esophageal adenocarcinoma (EAC). The G-protein coupled bile acid receptor (TGR5) has been associated with the development of gastrointestinal cancer. However, little is known regarding the role of TGR5 in esophageal carcinoma and precancerous lesions. We analyzed genomic DNA from 116 EACs for copy number aberrations via Affymetrix SNP6.0 microarrays. The TGR5 gene locus was amplified in 12.7% (14/116) of the EACs. The TGR5 protein expression was also assessed using immunohistochemistry from tissue microarrays, including Barrett’s esophagus (BE), low-(LGD) and high-grade dysplasia (HGD), columnar cell metaplasia (CM), squamous epithelium (SE), EAC and squamous cell carcinoma. The TGR5 protein was highly expressed in 71% of EAC (75/106), 100% of HGD (11/11), 72% of LGD (13/18), 66% of BE (23/35), 84% of CM (52/62), and 36% of SE (30/83). The patients with high expression of TGR5 exhibited significantly worse overall survival compared to the patients with nonhigh expression. TGR5 high expression was significantly increased in the males compared to the females in all cases with an odds ratio of 1.9 times. The vitamin D receptor (VDR) was significantly correlated with TGR5 expression. Our findings indicated that TGR5 may play an important role in the development and prognosis of EAC through a bile acid ligand. Gender differences in TGR5 and VDR expression may explain why males have a higher incidence of EAC compared to females. PMID:28223834

Distinct effects of EGFR inhibitors on epithelial- and mesenchymal-like esophageal squamous cell carcinoma cells.

PubMed

Yoshioka, Masahiro; Ohashi, Shinya; Ida, Tomomi; Nakai, Yukie; Kikuchi, Osamu; Amanuma, Yusuke; Matsubara, Junichi; Yamada, Atsushi; Miyamoto, Shin'ichi; Natsuizaka, Mitsuteru; Nakagawa, Hiroshi; Chiba, Tsutomu; Seno, Hiroshi; Muto, Manabu

2017-08-01

Epidermal growth factor receptor (EGFR) plays a pivotal role in the pathophysiology of esophageal squamous cell carcinoma (ESCC). However, the clinical effects of EGFR inhibitors on ESCC are controversial. This study sought to identify the factors determining the therapeutic efficacy of EGFR inhibitors in ESCC cells. Immortalized-human esophageal epithelial cells (EPC2-hTERT), transformed-human esophageal epithelial cells (T-Epi and T-Mes), and ESCC cells (TE-1, TE-5, TE-8, TE-11, TE-11R, and HCE4) were treated with the EGFR inhibitors erlotinib or cetuximab. Inhibitory effects on cell growth were assessed by cell counting or cell-cycle analysis. The expression levels of genes and proteins such as involucrin and cytokeratin13 (a squamous differentiation marker), E-cadherin, and vimentin were evaluated by real-time polymerase chain reaction or western blotting. To examine whether mesenchymal phenotype influenced the effects of EGFR inhibitors, we treated T-Epi cells with TGF-β1 to establish a mesenchymal phenotype (mesenchymal T-Epi cells). We then compared the effects of EGFR inhibitors on parental T-Epi cells and mesenchymal T-Epi cells. TE-8 (mesenchymal-like ESCC cells)- or TE-11R (epithelial-like ESCC cells)-derived xenograft tumors in mice were treated with cetuximab, and the antitumor effects of EGFR inhibitors were evaluated. Cells were classified as epithelial-like or mesenchymal-like phenotypes, determined by the expression levels of E-cadherin and vimentin. Both erlotinib and cetuximab reduced cell growth and the ratio of cells in cell-cycle S phase in epithelial-like but not mesenchymal-like cells. Additionally, EGFR inhibitors induced squamous cell differentiation (defined as increased expression of involucrin and cytokeratin13) in epithelial-like but not mesenchymal-like cells. We found that EGFR inhibitors did not suppress the phosphorylation of EGFR in mesenchymal-like cells, while EGFR dephosphorylation was observed after treatment with EGFR inhibitors in epithelial-like cells. Furthermore, mesenchymal T-Epi cells showed resistance to EGFR inhibitors by circumventing the dephosphorylation of EGFR signaling. Cetuximab consistently showed antitumor effects, and increased involucrin expression in TE-11R (epithelial-like)-derived xenograft tumors but not TE-8 (mesenchymal-like)-derived xenograft tumors. The factor determining the therapeutic effects of EGFR inhibitors in ESCC cells is the phenotype representing the epithelial-like or mesenchymal-like cells. Mesenchymal-like ESCC cells are resistant to EGFR inhibitors because EGFR signaling is not blocked. EGFR inhibitors show antitumor effects on epithelial-like ESCC cells accompanied by promotion of squamous cell differentiation.

Combining radiation with autophagy inhibition enhances suppression of tumor growth and angiogenesis in esophageal cancer.

PubMed

Chen, Yongshun; Li, Xiaohong; Guo, Leiming; Wu, Xiaoyuan; He, Chunyu; Zhang, Song; Xiao, Yanjing; Yang, Yuanyuan; Hao, Daxuan

2015-08-01

Radiotherapy is an effective treatment for esophageal cancer; however, tumor resistance to radiation remains a major biological problem. The present study aimed to investigate whether inhibition of autophagy may decrease overall tumor resistance to radiation. The effects of the autophagy inhibitor 3-methyladenine (3-MA) on radiosensitivity were tested in the EC9706 human esophageal squamous cell carcinoma cell line by colony formation assay. Furthermore, the synergistic cytotoxic effects of 3-MA and radiation were assessed in a tumor xenograft model in nude mice. Mechanistic studies were performed using flow cytometry, immunohistochemistry and western blot analysis. The results of the present study demonstrated that radiation induced an accumulation of autophagosomes and 3-MA effectively inhibited radiation-induced autophagy. Inhibition of autophagy was shown to significantly increase the radiosensitivity of the tumors in vitro and in vivo. The enhancement ratio of sensitization in EC9706 cells was 1.76 when the cells were treated with 10 mM 3-MA, alongside ionizing radiation. In addition, autophagy inhibition increased apoptosis and reduced tumor cell proliferation. The combination of radiation and autophagy inhibition resulted in a significant reduction in tumor volume and vasculature in the murine model. The present study demonstrated in vitro and in vivo that radiation-induced autophagy has a protective effect against cell death, and inhibition of autophagy is able to enhance the radiosensitivity of esophageal squamous cell carcinoma.

Combining radiation with autophagy inhibition enhances suppression of tumor growth and angiogenesis in esophageal cancer

PubMed Central

CHEN, YONGSHUN; LI, XIAOHONG; GUO, LEIMING; WU, XIAOYUAN; HE, CHUNYU; ZHANG, SONG; XIAO, YANJING; YANG, YUANYUAN; HAO, DAXUAN

2015-01-01

Radiotherapy is an effective treatment for esophageal cancer; however, tumor resistance to radiation remains a major biological problem. The present study aimed to investigate whether inhibition of autophagy may decrease overall tumor resistance to radiation. The effects of the autophagy inhibitor 3-methyladenine (3-MA) on radiosensitivity were tested in the EC9706 human esophageal squamous cell carcinoma cell line by colony formation assay. Furthermore, the synergistic cytotoxic effects of 3-MA and radiation were assessed in a tumor xenograft model in nude mice. Mechanistic studies were performed using flow cytometry, immunohistochemistry and western blot analysis. The results of the present study demonstrated that radiation induced an accumulation of autophagosomes and 3-MA effectively inhibited radiation-induced autophagy. Inhibition of autophagy was shown to significantly increase the radiosensitivity of the tumors in vitro and in vivo. The enhancement ratio of sensitization in EC9706 cells was 1.76 when the cells were treated with 10 mM 3-MA, alongside ionizing radiation. In addition, autophagy inhibition increased apoptosis and reduced tumor cell proliferation. The combination of radiation and autophagy inhibition resulted in a significant reduction in tumor volume and vasculature in the murine model. The present study demonstrated in vitro and in vivo that radiation-induced autophagy has a protective effect against cell death, and inhibition of autophagy is able to enhance the radiosensitivity of esophageal squamous cell carcinoma. PMID:25891159

Status of epigenetic chromatin modification enzymes and esophageal squamous cell carcinoma risk in northeast Indian population.

PubMed

Singh, Virendra; Singh, Laishram C; Singh, Avninder P; Sharma, Jagannath; Borthakur, Bibhuti B; Debnath, Arundhati; Rai, Avdhesh K; Phukan, Rup K; Mahanta, Jagadish; Kataki, Amal C; Kapur, Sujala; Saxena, Sunita

2015-01-01

Esophageal cancer incidence is reported in high frequency in northeast India. The etiology is different from other population at India due to wide variations in dietary habits or nutritional factors, tobacco/betel quid chewing and alcohol habits. Since DNA methylation, histone modification and miRNA-mediated epigenetic processes alter the gene expression, the involvement of these processes might be useful to find out epigenetic markers of esophageal cancer risk in northeast Indian population. The present investigation was aimed to carryout differential expression profiling of chromatin modification enzymes in tumor and normal tissue collected from esophageal squamous cell carcinoma (ESCC) patients. Differential mRNA expression profiling and their validation was done by quantitative real time PCR and tissue microarray respectively. Univariate and multiple logistic regression analysis were used to analyze the epidemiological data. mRNA expression data was analyzed by Student t-test. Fisher exact test was used for tissue microarray data analysis. Higher expression of enzymes regulating methylation (DOT1L and PRMT1) and acetylation (KAT7, KAT8, KAT2A and KAT6A) of histone was found associated with ESCC risk. Tissue microarray done in independent cohort of 75 patients revealed higher nuclear protein expression of KAT8 and PRMT1 in tumor similar to mRNA expression. Expression status of PRMT1 and KAT8 was found declined as we move from low grade to high grade tumor. Betel nut chewing, alcohol drinking and dried fish intake were significantly associated with increased risk of esophageal cancer among the study subject. Study suggests the association of PRMT1 and KAT8 with esophageal cancer risk and its involvement in the transition process of low to high grade tumor formation. The study exposes the differential status of chromatin modification enzymes between tumor and normal tissue and points out that relaxed state of chromatin facilitates more transcriptionally active genome in esophageal carcinogenesis.

Endoscopic palliation of advanced esophageal cancer

PubMed Central

Mocanu, A; Bârla, R; Hoara, P; Constantinoiu, S

2015-01-01

Esophageal cancer represents one of the most aggressive digestive tumors, with a survival rate at 5 years of only 10%. Globally, during the last three decades, there has been an increasing incidence of the esophageal cancer, approx. 400,000 new esophageal cancers being currently diagnosed annually. This represents the eighth leading cause of cancer incidence and the sixth leading cause of cancer death overall. Taking into account the population’s global aging and thus, the increase in the number of patients who will not bear surgery, PCT and radiation, or the fact that they do not want it especially because of deficiencies and associated pathology, the endoscopic ablative techniques with palliation purposes represent the alternative. If we refer to the Western Europe countries and North America, we notice an increase of esophageal adenocarcinoma rate versus squamous cancer. As for the Asian region, referring in particular to China and Japan, 9 out of 10 esophageal cancers are squamous cell carcinomas. For at least half of the patients with EC (esophageal cancer) there is no hope of healing because of the advanced regional malignant invasion (T3-4, N+, M+) with no chemo and radiotherapy response, poor preoperative patients’ conditions or systemic metastasis. The low life expectancy does not justify the risky medical procedures, the goal of the therapy consisting in the improvement of the quality of life by eliminating dysphagia (reestablishing oral feeding) which represents the most common complication of EC, the respiratory tract complication caused by eso-tracheal fistulas or by eliminating chest pain. To treat dysphagia, which is the main target of palliation, combined methods like endoscopic, chemo and radio-therapy, can be used, each one with indications, benefits and risks. Abbreviations: SEPS = self expanding plastic stent, SREMS = self expanding metal stent, EBRT = Endoscopic brachy radiotherapy, EUS = Ultra sound endoscopy, CT = Computer tomograph, UGE = Upper gastro endoscopy, PET-CT = Positron Emission Tomography, APC = argon plasma coagulation, PDT = photo dynamic therapy, PCT = Poli-chemotherapy, RT = Radio-therapy PMID:25866578

Improvement of endocytoscopic findings after per oral endoscopic myotomy (POEM) in esophageal achalasia; does POEM reduce the risk of developing esophageal carcinoma? Per oral endoscopic myotomy, endocytoscopy and carcinogenesis

PubMed Central

2013-01-01

Background Per oral endoscopic myotomy (POEM) has been reported to be a new therapeutic option for esophageal achalasia. The possibility that POEM could reduce the risk of developing esophageal squamous cell carcinoma was evaluated. Methods This was a single-centre, retrospective study. Fifteen consecutive patients with esophageal achalasia who underwent POEM in our institution between August 2010 and January 2012 were enrolled. Ultra-high magnification with endocytoscopy was performed, and both histopathological and immunohistochemical evaluations for Ki-67 and p53 were assessed before and 3 months after POEM. Results POEM was successfully performed and effectively released the dysphagia symptom in all patients without severe complications. Subjective symptoms (mean Ekcardt score, before 7.4 vs. after 0.5, p<0.05) and manometric pressure studies (mean lower esophageal sphincter pressure), before 82.7 vs. after 22.9 mmHg, p<0.05) showed substantial improvement following POEM. The average numbers of esophageal epithelial nuclei before and after POEM on endocytoscopic images were 128.0 and 78.0, respectively (p<0.05). The mean Ki-67-positive ratio was 26.0 (median 25.4, range, 10.3-33.2) before and 20.7 (median 20.0, 13.1-29.9; p=0.07) after POEM, and the mean p53-positive ratio was 2.35 (median 2.61, 0.32-4.23) before and 0.97 (median 1.49, 0.32-1.56; p<0.05) after POEM. A significant positive correlation was seen between the number of nuclei and the Ki-67-positive ratio (p<0.05). Conclusions POEM appears to be an effective and less invasive treatment of choice against achalasia and may reduce the risk of esophageal carcinogenesis. Endocytoscopy can be useful for the assessment of esophageal cellular proliferation. PMID:23363448

Improvement of endocytoscopic findings after per oral endoscopic myotomy (POEM) in esophageal achalasia; does POEM reduce the risk of developing esophageal carcinoma? Per oral endoscopic myotomy, endocytoscopy and carcinogenesis.

PubMed

Minami, Hitomi; Yamaguchi, Naoyuki; Matsushima, Kayoko; Akazawa, Yuko; Ohnita, Ken; Takeshima, Fuminao; Nakayama, Toshiyuki; Hayashi, Tomayoshi; Inoue, Haruhiro; Nakao, Kazuhiko; Isomoto, Hajime

2013-01-30

Per oral endoscopic myotomy (POEM) has been reported to be a new therapeutic option for esophageal achalasia. The possibility that POEM could reduce the risk of developing esophageal squamous cell carcinoma was evaluated. This was a single-centre, retrospective study. Fifteen consecutive patients with esophageal achalasia who underwent POEM in our institution between August 2010 and January 2012 were enrolled. Ultra-high magnification with endocytoscopy was performed, and both histopathological and immunohistochemical evaluations for Ki-67 and p53 were assessed before and 3 months after POEM. POEM was successfully performed and effectively released the dysphagia symptom in all patients without severe complications. Subjective symptoms (mean Ekcardt score, before 7.4 vs. after 0.5, p<0.05) and manometric pressure studies (mean lower esophageal sphincter pressure), before 82.7 vs. after 22.9 mmHg, p<0.05) showed substantial improvement following POEM. The average numbers of esophageal epithelial nuclei before and after POEM on endocytoscopic images were 128.0 and 78.0, respectively (p<0.05). The mean Ki-67-positive ratio was 26.0 (median 25.4, range, 10.3-33.2) before and 20.7 (median 20.0, 13.1-29.9; p=0.07) after POEM, and the mean p53-positive ratio was 2.35 (median 2.61, 0.32-4.23) before and 0.97 (median 1.49, 0.32-1.56; p<0.05) after POEM. A significant positive correlation was seen between the number of nuclei and the Ki-67-positive ratio (p<0.05). POEM appears to be an effective and less invasive treatment of choice against achalasia and may reduce the risk of esophageal carcinogenesis. Endocytoscopy can be useful for the assessment of esophageal cellular proliferation.

Clinical outcome of endoscopic mucosal resection for esophageal squamous cell cancer invading muscularis mucosa and submucosal layer.

PubMed

Yoshii, T; Ohkawa, S; Tamai, S; Kameda, Y

2013-07-01

When a tumor invades the muscularis mucosa and submucosal layer (T1a-MM and T1b in Japan), esophageal squamous cell cancer poses 10-50% risk of lymph node metastasis. By this stage of esophageal cancer, surgery, although very invasive, is the standard radical therapy for the patients. Endoscopic mucosal resection (EMR) is the absolutely curable treatment for cancer in the superficial mucosal layer. Because of its minimal invasiveness, the indications of EMR may be expanded to include the treatment of T1a-MM and T1b esophageal carcinoma. To date, the clinical outcomes of EMR for T1a-MM and T1b patients have not been fully elucidated. Here, the retrospective analysis of the clinical outcomes is reported. Between January 1994 and December 2007, 247 patients underwent EMR at Kanagawa Cancer Center. Of these individuals, 44 patients with 44 lesions fulfilled the following criteria: (i) extended EMR treatment for clinical T1a-MM and T1b tumor; (ii) diagnosis of clinical N0M0; and (iii) follow up for at least 1 year, and negative vertical margin. These patients were reviewed for their clinical features and outcomes. Statistical analyses were performed by the Kaplan-Meier methods, the Chi-square test, and the Cox proportional hazard model. P-value of <0.05 was considered statistically significant. The data were analyzed in February 2009. Based on the informed consent and their general health conditions, 44 patients decided the following treatments immediately after the EMR: 2 underwent surgery, 1 underwent adjuvant chemotherapy, and 41 selected follow up without any additional therapy. Of the 41 patients, 20 selected this course by choice, 12 because of severe concurrent diseases, 2 because of poor performance status, and 7 because of other multiple primary cancers. Twelve patients died; two were cause specific (4.5%), eight from multiple primary cancers, one from severe concurrent diseases, and one from unknown causes. No critical complications were noted. Median follow-up time was 51 months (12-126). Five patients ultimately developed lymph node metastasis. One patient with adjuvant chemotherapy required surgery, and another was treated with chemotherapy whose subsequent death was cause specific. The other three patients received chemoradiotherapy and have not shown cause-specific death. Overall and cause-specific survival rates at 5 years were 67.3% and 91.8%, respectively. Among 41 patients treated by EMR alone, only one died from primary esophageal cancer (2.4%), and overall and cause-specific survival rates at 5 years were 75.6% and 97.6%, respectively. Multivariate analysis revealed that severe concurrent diseases including multiple primary cancers and the administration of 5-fluorouracil-based chemotherapy for multiple primary cancers significantly influenced survival (P= 0.025, hazard ratio [HR] 13.1 [95% confidence interval 1.5-114]) and (P= 0.037, HR 0.213 [95% confidence interval 0.05-0.914]), respectively. Eight and six patients developed metachronous esophageal squamous cell cancer and local recurrence, respectively. With the exception of one patient, they could be retreated endoscopically. EMR is a reasonable option for the patients with T1a-MM and T1b esophageal carcinoma without clinical metastasis, especially for the individuals with severe concurrent diseases. The prognostic factors for the benefit of EMR in such cases should be further examined. © 2012 Copyright the Authors. Journal compilation © 2012, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.

Fruit Consumption Reduces the Risk of Esophageal Cancer in Yanting, People's Republic of China.

PubMed

Song, Qingkun; Zhao, Lin; Li, Jun; Ren, Jun

2015-05-01

This study aimed to investigate the contribution of fruit and family history to esophageal cancer, among residents with abnormal esophagus discovered in screening. The study was a frequency-matched case-control design in groups of normal esophagus, abnormal esophagus but not carcinoma, and esophageal squamous cell carcinoma. Odds ratio (OR) was estimated by unconditional logistic regression. Fruit intake (OR = 0.19, 95% CI = 0.06-0.56) and positive family history of esophageal cancer (OR = 3.87, 95% CI = 1.41-10.63) were associated with esophageal cancer compared to individuals with abnormal conditions of the esophagus. In individuals who consumed fruits at least once per week, the OR for family cancer history is reduced to a nonsignificant level (OR = 1.06, 95% CI = 0.07-15.91). In the individuals with abnormal esophagus at screening, fruit intake was possibly protective against esophageal cancer, even in the ones with positive family history. Local public health strategies should focus on the improvement in fruit intake. © 2014 APJPH.

Bile Acids Down-Regulate Caveolin-1 in Esophageal Epithelial Cells through Sterol Responsive Element-Binding Protein

PubMed Central

Prade, Elke; Tobiasch, Moritz; Hitkova, Ivana; Schäffer, Isabell; Lian, Fan; Xing, Xiangbin; Tänzer, Marc; Rauser, Sandra; Walch, Axel; Feith, Marcus; Post, Stefan; Röcken, Christoph; Schmid, Roland M.; Ebert, Matthias P.A.

2012-01-01

Bile acids are synthesized from cholesterol and are major risk factors for Barrett adenocarcinoma (BAC) of the esophagus. Caveolin-1 (Cav1), a scaffold protein of membrane caveolae, is transcriptionally regulated by cholesterol via sterol-responsive element-binding protein-1 (SREBP1). Cav1 protects squamous epithelia by controlling cell growth and stabilizing cell junctions and matrix adhesion. Cav1 is frequently down-regulated in human cancers; however, the molecular mechanisms that lead to this event are unknown. We show that the basal layer of the nonneoplastic human esophageal squamous epithelium expressed Cav1 mainly at intercellular junctions. In contrast, Cav1 was lost in 95% of tissue specimens from BAC patients (n = 100). A strong cytoplasmic expression of Cav1 correlated with poor survival in a small subgroup (n = 5) of BAC patients, and stable expression of an oncogenic Cav1 variant (Cav1-P132L) in the human BAC cell line OE19 promoted proliferation. Cav1 was also detectable in immortalized human squamous epithelial, Barrett esophagus (CPC), and squamous cell carcinoma cells (OE21), but was low in BAC cell lines (OE19, OE33). Mechanistically, bile acids down-regulated Cav1 expression by inhibition of the proteolytic cleavage of 125-kDa pre-SREBP1 from the endoplasmic reticulum/Golgi apparatus and nuclear translocation of active 68-kDa SREBP1. This block in SREBP1's posttranslational processing impaired transcriptional activation of SREBP1 response elements in the proximal human Cav1 promoter. Cav1 was also down-regulated in esophagi from C57BL/6 mice on a diet enriched with 1% (wt/wt) chenodeoxycholic acid. Mice deficient for Cav1 or the nuclear bile acid receptor farnesoid X receptor showed hyperplasia and hyperkeratosis of the basal cell layer of esophageal epithelia, respectively. These data indicate that bile acid-mediated down-regulation of Cav1 marks early changes in the squamous epithelium, which may contribute to onset of Barrett esophagus metaplasia and progression to BAC. PMID:22474125

Erlotinib Hydrochloride and Cetuximab in Treating Patients With Advanced Gastrointestinal Cancer, Head and Neck Cancer, Non-Small Cell Lung Cancer, or Colorectal Cancer

ClinicalTrials.gov

2015-09-28

Adenocarcinoma of the Colon; Adenocarcinoma of the Rectum; Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Gastrointestinal Stromal Tumor; Metastatic Gastrointestinal Carcinoid Tumor; Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adult Primary Liver Cancer; Recurrent Anal Cancer; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Colon Cancer; Recurrent Esophageal Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Intestine Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Small Intestine Adenocarcinoma; Small Intestine Leiomyosarcoma; Small Intestine Lymphoma; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Anal Cancer; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Colon Cancer; Stage IV Esophageal Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Gastric Cancer; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Non-small Cell Lung Cancer; Stage IV Pancreatic Cancer; Stage IV Rectal Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Tongue Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

Emerging indications of endoscopic radiofrequency ablation

PubMed Central

Becq, Aymeric; Camus, Marine; Rahmi, Gabriel; de Parades, Vincent; Marteau, Philippe

2015-01-01

Introduction Radiofrequency ablation (RFA) is a well-validated treatment of dysplastic Barrett's esophagus. Other indications of endoscopic RFA are under evaluation. Results Four prospective studies (total 69 patients) have shown that RFA achieved complete remission of early esophageal squamous intra-epithelial neoplasia at a rate of 80%, but with a substantial risk of stricture. In the setting of gastric antral vascular ectasia, two prospective monocenter studies, and a retrospective multicenter study, (total 51 patients), suggest that RFA is efficacious in terms of reducing transfusion dependency. In the setting of chronic hemorrhagic radiation proctopathy, a prospective monocenter study and a retrospective multicenter study (total 56 patients) suggest that RFA is an efficient treatment. A retrospective comparative study (64 patients) suggests that RFA improves stents patency in malignant biliary strictures. Conclusions Endoscopic RFA is an upcoming treatment modality in early esophageal squamous intra-epithelial neoplasia, as well as in gastric, rectal, and biliary diseases. PMID:26279839

Down-regulation of 5S rRNA by miR-150 and miR-383 enhances c-Myc-rpL11 interaction and inhibits proliferation of esophageal squamous carcinoma cells.

PubMed

Wang, Xinyu; Ren, Yanli; Wang, Zhiqiong; Xiong, Xiangyu; Han, Sichong; Pan, Wenting; Chen, Hongwei; Zhou, Liqing; Zhou, Changchun; Yuan, Qipeng; Yang, Ming

2015-12-21

5S rRNA plays an important part in ribosome biology and is over-expression in multiple cancers. In this study, we found that 5S rRNA is a direct target of miR-150 and miR-383 in esophageal squamous cell carcinoma (ESCC). Overexpression of miR-150 and miR-383 inhibited ESCC cell proliferation in vitro and in vivo. Moreover, 5S rRNA silencing by miR-150 and miR-383 might intensify rpL11-c-Myc interaction, which attenuated role of c-Myc as an oncogenic transcriptional factor and dysregulation of multiple c-Myc target genes. Taken together, our results highlight the involvement of miRNAs in ribosomal regulation during tumorigenesis. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

International cancer seminars: a focus on esophageal squamous cell carcinoma.

PubMed

Murphy, G; McCormack, V; Abedi-Ardekani, B; Arnold, M; Camargo, M C; Dar, N A; Dawsey, S M; Etemadi, A; Fitzgerald, R C; Fleischer, D E; Freedman, N D; Goldstein, A M; Gopal, S; Hashemian, M; Hu, N; Hyland, P L; Kaimila, B; Kamangar, F; Malekzadeh, R; Mathew, C G; Menya, D; Mulima, G; Mwachiro, M M; Mwasamwaja, A; Pritchett, N; Qiao, Y-L; Ribeiro-Pinto, L F; Ricciardone, M; Schüz, J; Sitas, F; Taylor, P R; Van Loon, K; Wang, S-M; Wei, W-Q; Wild, C P; Wu, C; Abnet, C C; Chanock, S J; Brennan, P

2017-09-01

The International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) have initiated a series of cancer-focused seminars [Scelo G, Hofmann JN, Banks RE et al. International cancer seminars: a focus on kidney cancer. Ann Oncol 2016; 27(8): 1382-1385]. In this, the second seminar, IARC and NCI convened a workshop in order to examine the state of the current science on esophageal squamous cell carcinoma etiology, genetics, early detection, treatment, and palliation, was reviewed to identify the most critical open research questions. The results of these discussions were summarized by formulating a series of 'difficult questions', which should inform and prioritize future research efforts. Published by Oxford University Press on behalf of the European Society for Medical Oncology 2017. This work is written by US Government employees and is in the public domain in the US.

Biomarker Discovery and Verification of Esophageal Squamous Cell Carcinoma Using Integration of SWATH/MRM.

PubMed

Hou, Guixue; Lou, Xiaomin; Sun, Yulin; Xu, Shaohang; Zi, Jin; Wang, Quanhui; Zhou, Baojin; Han, Bo; Wu, Lin; Zhao, Xiaohang; Lin, Liang; Liu, Siqi

2015-09-04

We propose an efficient integration of SWATH with MRM for biomarker discovery and verification when the corresponding ion library is well established. We strictly controlled the false positive rate associated with SWATH MS signals and carefully selected the target peptides coupled with SWATH and MRM. We collected 10 samples of esophageal squamous cell carcinoma (ESCC) tissues paired with tumors and adjacent regions and quantified 1758 unique proteins with FDR 1% at protein level using SWATH, in which 467 proteins were abundance-dependent with ESCC. After carefully evaluating the SWATH MS signals of the up-regulated proteins, we selected 120 proteins for MRM verification. MRM analysis of the pooled and individual esophageal tissues resulted in 116 proteins that exhibited similar abundance response modes to ESCC that were acquired with SWATH. Because the ESCC-related proteins consisted of a high percentile of secreted proteins, we conducted the MRM assay on patient sera that were collected from pre- and postoperation. Of the 116 target proteins, 42 were identified in the ESCC sera, including 11 with lowered abundances postoperation. Coupling SWATH and MRM is thus feasible and efficient for the discovery and verification of cancer-related protein biomarkers.

KH-type splicing regulatory protein is involved in esophageal squamous cell carcinoma progression.

PubMed

Fujita, Yuji; Masuda, Kiyoshi; Hamada, Junichi; Shoda, Katsutoshi; Naruto, Takuya; Hamada, Satoshi; Miyakami, Yuko; Kohmoto, Tomohiro; Watanabe, Miki; Takahashi, Rizu; Tange, Shoichiro; Saito, Masako; Kudo, Yasusei; Fujiwara, Hitoshi; Ichikawa, Daisuke; Tangoku, Akira; Otsuji, Eigo; Imoto, Issei

2017-11-24

KH-type splicing regulatory protein (KHSRP) is a multifunctional RNA-binding protein, which is involved in several post-transcriptional aspects of RNA metabolism, including microRNA (miRNA) biogenesis. It affects distinct cell functions in different tissues and can have an impact on various pathological conditions. In the present study, we investigated the oncogenic functions of KHSRP and their underlying mechanisms in the pathogenesis of esophageal squamous cell carcinoma (ESCC). KHSRP expression levels were elevated in ESCC tumors when compared with those in non-tumorous tissues by immunohistochemistry, and cytoplasmic KHSRP overexpression was found to be an independent prognosticator for worse overall survival in a cohort of 104 patients with ESCC. KHSRP knockdown inhibited growth, migration, and invasion of ESCC cells. KHSRP knockdown also inhibited the maturation of cancer-associated miRNAs, such as miR-21, miR-130b, and miR-301, and induced the expression of their target mRNAs, such as BMP6, PDCD4, and TIMP3, resulting in the inhibition of epithelial-to-mesenchymal transition. Our findings uncover a novel oncogenic function of KHSRP in esophageal tumorigenesis and implicate its use as a marker for prognostic evaluation and as a putative therapeutic target in ESCC.

Dietary Inflammatory Index and risk of esophageal squamous cell cancer in a case-control study from Iran

PubMed Central

Shivappa, Nitin; Hébert, James R.; Rashidkhani, Bahram

2015-01-01

Background Diet and inflammation have been suggested to be important risk factors for esophageal squamous cell carcinoma (ESCC). In this study, we examined the ability of the dietary inflammatory index (DII) to predict ESCC in a case-control study conducted in Iran. Methods This study included 47 ESCC cases and 96 controls hospitalized for acute non-neoplastic diseases. The DII was computed based on dietary intake assessed by a previously validated food frequency questionnaire. Logistic regression models were used to estimate odds ratios (ORs) adjusted for age, energy, sex, BMI, years of education, physical activity, smoking and gastro-esophageal reflux. Results Subjects with higher DII scores (i.e., with a more pro-inflammatory diet) had a higher risk of ESCC, with the DII being used as both a continuous variable (ORcontinuous 3.58, 95% confidence interval, CI, 1.76–7.26; one unit increase corresponding to ≈16% of its range in the current study) and a categorical variable (ORdii>1.20 vs ≤ 1.208.24, 95%CI 2.03–33.47). Conclusion These results indicate that a pro-inflammatory diet is associated with increased risk of ESCC. PMID:26400625

Synergistic function of Smad4 and PTEN in suppressing forestomach squamous cell carcinoma in the mouse.

PubMed

Teng, Yan; Sun, An-Na; Pan, Xiao-Chen; Yang, Guan; Yang, Lei-Lei; Wang, Ming-Rong; Yang, Xiao

2006-07-15

The genetic bases underlying esophageal tumorigenesis are poorly understood. Our previous studies have shown that coordinated deletion of the Smad4 and PTEN genes results in accelerated hair loss and skin tumor formation in mice. Herein, we exemplify that the concomitant inactivation of Smad4 and PTEN accelerates spontaneous forestomach carcinogenesis at complete penetrance during the first 2 months of age. All of the forestomach tumors were invasive squamous cell carcinomas (SCCs), which recapitulated the natural history and pathologic features of human esophageal SCCs. A small population of the SCC lesions was accompanied by adenocarcinomas at the adjacent submucosa region in the double mutant mice. The rapid progression of forestomach tumor formation in the Smad4 and PTEN double knockout mice corresponded to a dramatic increase in esophageal and forestomach epithelial proliferation. The decreased expression of p27, p21, and p16 together with the overexpression of cyclin D1 contributed cooperatively to the accelerated forestomach tumorigenesis in the double mutant mice. Our results point strongly to the crucial relevance of synergy between Smad4 and PTEN to suppress forestomach tumorigenesis through the cooperative induction of cell cycle inhibitors.

Autoreactive T Cells and Chronic Fungal Infection Drive Esophageal Carcinogenesis

PubMed Central

Zhu, Feng; Willette-Brown, Jami; Song, Na-Young; Lomada, Dakshayani; Song, Yongmei; Xue, Liyan; Gray, Zane; Zhao, Zitong; Davis, Sean R.; Sun, Zhonghe; Zhang, Peilin; Wu, Xiaolin; Zhan, Qimin; Richie, Ellen R.; Hu, Yinling

2018-01-01

SUMMARY Humans with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a T cell–driven autoimmune disease caused by impaired central tolerance, are susceptible to developing chronic fungal infection and esophageal squamous cell carcinoma (ESCC). However, the relationship between autoreactive T cells and chronic fungal infection in ESCC development remains unclear. We find that kinase-dead Ikkα knockin mice develop phenotypes reminiscent of APECED, including impaired central tolerance, autoreactive T cells, chronic fungal infection, and ESCCs expressing specific human ESCC markers. Using this model, we investigated the potential link between ESCC and fungal infection. Autoreactive CD4 T cells permit fungal infection and incite tissue injury and inflammation. Antifungal treatment or depletion of autoreactive CD4 T cells rescues, whereas oral fungal administration promotes, ESCC development. Inhibition of inflammation or EGFR activity decreases fungal burden. Importantly, fungal infection is highly associated with ESCCs in non-autoimmune human patients. Therefore, autoreactive T cells and chronic fungal infection, fostered by inflammation and epithelial injury, promote ESCC development. PMID:28407484

Prospective, open, multicentre Phase I/II trial to assess safety and efficacy of neoadjuvant radiochemotherapy with docetaxel and cisplatin for esophageal carcinoma.

PubMed

Ma, Hong-Bing; Di, Zheng-Li; Wen, Jiao; Ke, Yue; Sun, Xiaodong; Ren, Juan

2015-02-01

Esophageal squamous cell carcinoma is increasingly treated with trimodality therapy. The objective of this Phase I/II clinical study is to assess the efficacy and safety of neoadjuvant radiochemotherapy with docetaxel and cisplatin and radiotherapy in patients with esophagectomy for locally advanced squamous cell carcinoma of the esophagus with neoadjuvant chemoradiotherapy. Patients with esophageal squamous cell carcinoma received radiochemotherapy (50 Gy/25 fractions during Weeks 1-5) using a three-dimensional conformal radiation therapy or intensity-modulated radiation therapy technique together with weekly docetaxel (20 mg/m(2) at dose levels 1 and 2, 25 mg/m(2) at dose level 3 on Weeks 1-5) and cisplatin (30 mg/m(2) at dose level 1, 40 mg/m(2) at dose levels 2 and 3 on Weeks 1-5) from January 2009 to December 2011. The dose-limiting toxicities and maximum tolerated dose were the primary endpoints and overall response rate and progression-free survival were the secondary endpoints. Over this timeframe, a total of 49 patients completed trimodality therapy. Thirteen patients were treated at dose level 1, 21 patients at dose level 2 and 15 patients at dose level 3.The maximum tolerated dose for docetaxel was 20 mg/m(2) and cisplatin 40 mg/m(2). The complete response or partial response was observed in 26.5% (13/49) of patients. Thirty-four patients (69.4%) were treated with neoadjuvant radiochemotherapy followed by surgical resection. The median progression-free survival and median overall survival for all patients (n = 49) were 8 and 17.2 months, respectively. The median overall survival was 27.5 months for patients treated at dose level 2. Neoadjuvant radiochemotherapy with docetaxel 20 mg/m(2) and cisplatin 40 mg/m(2) was effective and tolerable induction regimen in patients with esophageal tumors. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Current advances in esophageal cancer proteomics.

PubMed

Uemura, Norihisa; Kondo, Tadashi

2015-06-01

We review the current status of proteomics for esophageal cancer (EC) from a clinician's viewpoint. The ultimate goal of cancer proteomics is the improvement of clinical outcome. The proteome as a functional translation of the genome is a straightforward representation of genomic mechanisms that trigger carcinogenesis. Cancer proteomics has identified the mechanisms of carcinogenesis and tumor progression, detected biomarker candidates for early diagnosis, and provided novel therapeutic targets for personalized treatments. Our review focuses on three major topics in EC proteomics: diagnostics, treatment, and molecular mechanisms. We discuss the major histological differences between EC types, i.e., esophageal squamous cell carcinoma and adenocarcinoma, and evaluate the clinical significance of published proteomics studies, including promising diagnostic biomarkers and novel therapeutic targets, which should be further validated prior to launching clinical trials. Multi-disciplinary collaborations between basic scientists, clinicians, and pathologists should be established for inter-institutional validation. In conclusion, EC proteomics has provided significant results, which after thorough validation, should lead to the development of novel clinical tools and improvement of the clinical outcome for esophageal cancer patients. This article is part of a Special Issue entitled: Medical Proteomics. Copyright © 2014 Elsevier B.V. All rights reserved.

Evaluation of the 7(th) edition of the UICC-AJCC tumor, node, metastasis classification for esophageal cancer in a Chinese cohort.

PubMed

Huang, Yan; Guo, Weigang; Shi, Shiming; He, Jian

2016-07-01

To assess and evaluate the prognostic value of the 7(th) edition of the Union for International Cancer Control-American Joint Committee on Cancer (UICC-AJCC) tumor, node, metastasis (TNM) staging system for Chinese patients with esophageal cancer in comparison with the 6(th) edition. A retrospective review was performed on 766 consecutive esophageal cancer patients treated with esophagectomy between 2008 and 2012. Patients were staged according to the 6(th) and 7(th) editions for esophageal cancer respectively. Survival was calculated by the Kaplan-Meier method, and multivariate analysis was performed using Cox regression model. Overall 3-year survival rate was 59.5%. There were significant differences in 3-year survival rates among T stages both according to the 6(th) edition and the 7(th) edition (P<0.001). According to the 7(th) edition, the 3-year survival rates of N0 (75.4%), N1 (65.2%), N2 (39.7%) and N3 (27.3%) patients were significant differences (P<0.001). Kaplan-Meier curve revealed a good discriminatory ability from stage I to IV, except for stage IB, IIA and IIB in the 7(th) edition staging system. Based on the 7(th) edition, the degree of differentiation, tumor length and tumor location were not independent prognostic factors on multivariate analysis. The multivariate analyses suggested that pT-, pN-, pTNM-category were all the independent prognostic factors based on the 6(th) and 7(th) edition staging system. The 7(th) edition of AJCC TNM staging system of esophageal cancer should discriminate pT2-3N0M0 (stage IB, IIA and IIB) better when considering the esophageal squamous cell cancer patients. Therefore, to improve and optimize the AJCC TNM classification for Chinese patients with esophageal cancer, more considerations about the value of tumor grade and tumor location in pT2-3N0M0 esophageal squamous cell cancer should be taken in the next new TNM staging system.

Development and Stem Cells of the Esophagus

PubMed Central

Zhang, Yongchun; Jiang, Ming; Kim, Eugene; Lin, Sijie; Liu, Kuancan; Lan, Xiaopeng; Que, Jianwen

2017-01-01

The esophagus is derived from the anterior portion of the developmental intermediate foregut, a structure that also gives rise to other organs including the trachea, lung, and stomach. Genetic studies have shown that multiple signaling pathways (e.g. Bmp) and transcription factors (e.g. SOX2) are required for the separation of the esophagus from the neighboring respiratory system. Notably, some of these signaling pathways and transcription factors continue to play essential roles in the subsequent morphogenesis of the esophageal epithelium which undergoes a simple columnar-to-stratified squamous conversion. Reactivation of the relevant signaling pathways has also been associated with pathogenesis of esophageal diseases that affect the epithelium and its stem cells in adults. In this review we will summarize these findings. We will also discuss new data regarding the cell-of-origin for the striated and smooth muscles surrounding the esophagus and how they are differentiated from the mesenchyme during development. PMID:28007661

High dose radiation with chemotherapy followed by salvage esophagectomy among patients with locally advanced esophageal squamous cell carcinoma.

PubMed

Lertbutsayanukul, Chawalit; Tharavej, Chadin; Klaikeaw, Naruemon; Prayongrat, Anussara; Lowanitchai, Chutinan; Sriuranpong, Virote

2017-05-01

Locoregional failure is a major problem associated with chemoradiation treatment for squamous cell esophageal carcinoma. The aim of this study was to assess the feasibility, efficacy, and toxicity of preoperative radiation (dose > 50 Gy) with platinum-based chemotherapy followed by esophagectomy in locally advanced squamous cell carcinoma. Data of patients with cT2-cT4 or node positive squamous cell carcinoma of the esophagus who received trimodality treatment between February 2006 and June 2015 were reviewed. Forty-four patients were treated with intensity-modulated radiation therapy, volumetric-modulated arc therapy or three-dimensional radiation therapy. The median radiation dose was 60 Gy. The average volume of the lungs receiving 10 Gy was 48.1%, 20 Gy was 24.5%, and the average mean lung dose was 14 Gy. After chemoradiation, R0 resection was achieved in 31 patients (71%). Patients who received >60 Gy had a higher pathologic complete remission rate than those in the lower dose group (59.1% vs. 36.4%). R0 resection and radiation dose >60 Gy were associated with better overall survival in Cox proportional hazards regression analysis. The median follow-up duration was 22.4 months and median survival was 25.6 months. Two-year overall, progression-free survival and locoregional control rates were 55.9%, 28.6%, and 56%, respectively. The most common grade 3-4 toxicities were esophagitis (63.6%) and neutropenia (25%). Grade 3-4 postoperative morbidities included surgical wound infection (2.3%), acute renal failure (2.3%), and anastomosis stricture (2.3%). Trimodality treatment with a high preoperative radiation dose and chemotherapy yielded a good pathologic complete response rate, and long-term survival with low toxicities. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Basaloid squamous cell carcinoma of the esophagus.

PubMed

Chen, Shao-Bin; Weng, Hong-Rui; Wang, Geng; Yang, Jie-Sheng; Yang, Wei-Ping; Li, Hua; Liu, Di-Tian; Chen, Yu-Ping

2012-07-01

Basaloid squamous cell carcinoma (BSCC) of the esophagus is a rare carcinoma with distinct characteristics. No standard treatment has been established. This retrospective study was designed to investigate the clinical and pathological characteristics, diagnosis, treatment, and prognosis of esophageal BSCC. Clinical data were retrospectively analyzed from 26 patients with pathologically confirmed esophageal BSCC who underwent transthoracic esophagectomy with lymphadenectomy between January 1995 and June 2010 at the Cancer Hospital of Shantou University Medical College. Clinicopathologic data between BSCC patients and different histologic grades of esophageal squamous cell carcinoma (ESCC) patients were statistically compared by means of the χ(2) test or Fisher's exact test. The Kaplan-Meier and log-rank methods were used to estimate and compare survival rates. Microscopically, BSCC was characterized by a nesting, lobular, or trabecular arrangement of small crowded cells with scant cytoplasm. None of the histologic specimens taken at preoperative esophagoscopy were diagnosed as BSCC. The median survival time (MST) of the 26 patients was 29.0 months (95% confidence interval, 9.0-49.0), and the 1-, 3-, and 5-year overall survival rates were 73.1, 42.7, and 36.6%, respectively. The MST for BSCC patients was significantly lower than that of well-differentiated SCC patients (P = 0.024), but there were no significant differences between the MST for BSCC patients and that of moderately or poorly differentiated SCC patients (P > 0.05). BSCC of the esophagus is a rare but distinctive disease and is prone to be misdiagnosed by endoscopic biopsy. The prognosis is poorer than well-differentiated SCC, but similar to moderately or poorly differentiated SCC.

Genetic features of metachronous esophageal cancer developed in Hodgkin's lymphoma or breast cancer long-term survivors: an exploratory study.

PubMed

Boldrin, Elisa; Rumiato, Enrica; Fassan, Matteo; Cappellesso, Rocco; Rugge, Massimo; Chiarion-Sileni, Vanna; Ruol, Alberto; Alfieri, Rita; Cagol, Matteo; Castoro, Carlo; Amadori, Alberto; Saggioro, Daniela

2015-01-01

Development of novel therapeutic drugs and regimens for cancer treatment has led to improvements in patient long-term survival. This success has, however, been accompanied by the increased occurrence of second primary cancers. Indeed, patients who received regional radiotherapy for Hodgkin's Lymphoma (HL) or breast cancer may develop, many years later, a solid metachronous tumor in the irradiated field. Despite extensive epidemiological studies, little information is available on the genetic changes involved in the pathogenesis of these solid therapy-related neoplasms. Using microsatellite markers located in 7 chromosomal regions frequently deleted in sporadic esophageal cancer, we investigated loss of heterozygosity (LOH) and microsatellite instability (MSI) in 46 paired (normal and tumor) samples. Twenty samples were of esophageal carcinoma developed in HL or breast cancer long-term survivors: 14 squamous cell carcinomas (ESCC) and 6 adenocarcinomas (EADC), while 26 samples, used as control, were of sporadic esophageal cancer (15 ESCC and 11 EADC). We found that, though the overall LOH frequency at the studied chromosomal regions was similar among metachronous and sporadic tumors, the latter exhibited a statistically different higher LOH frequency at 17q21.31 (p = 0.018). By stratifying for tumor histotype we observed that LOH at 3p24.1, 5q11.2 and 9p21.3 were more frequent in ESCC than in EADC suggesting a different role of the genetic determinants located nearby these regions in the development of the two esophageal cancer histotypes. Altogether, our results strengthen the genetic diversity among ESCC and EADC whether they occurred spontaneously or after therapeutic treatments. The presence of histotype-specific alterations in esophageal carcinoma arisen in HL or breast cancer long-term survivors suggests that their transformation process, though the putative different etiological origin, may retrace sporadic ESCC and EADC carcinogenesis.

Aberrant Epithelial-Mesenchymal Hedgehog Signaling Characterizes Barrett's Metaplasia

PubMed Central

Wang, David H.; Clemons, Nicholas J.; Miyashita, Tomoharu; Dupuy, Adam J.; Zhang, Wei; Szczepny, Anette; Corcoran-Schwartz, Ian M.; Wilburn, Daniel L.; Montgomery, Elizabeth A.; Wang, Jean S.; Jenkins, Nancy A.; Copeland, Neal A.; Harmon, John W.; Phillips, Wayne A.; Watkins, D. Neil

2010-01-01

Background & Aims The molecular mechanism underlying epithelial metaplasia in Barrett's esophagus remains unknown. Recognizing that Hedgehog signaling is required for early esophageal development, we sought to determine if the Hedgehog pathway is reactivated in Barrett's esophagus, and if genes downstream of the pathway could promote columnar differentiation of esophageal epithelium. Methods Immunohistochemistry, immunofluorescence, and quantitative real-time PCR were used to analyze clinical specimens, human esophageal cell lines, and mouse esophagi. Human esophageal squamous epithelial (HET-1A) and adenocarcinoma (OE33) cells were subjected to acid treatment and used in transfection experiments. Swiss Webster mice were used in a surgical model of bile reflux injury. An in vivo transplant culture system was created using esophageal epithelium from Sonic hedgehog transgenic mice. Results Marked upregulation of Hedgehog ligand expression, which can be induced by acid or bile exposure, occurs frequently in Barrett's epithelium and is associated with stromal expression of the Hedgehog target genes PTCH1 and BMP4. BMP4 signaling induces expression of SOX9, an intestinal crypt transcription factor, which is highly expressed in Barrett's epithelium. We further show that expression of DMBT1, the human homologue of the columnar cell factor Hensin, occurs in Barrett's epithelium and is induced by SOX9. Finally, transgenic expression of Sonic hedgehog in mouse esophageal epithelium induces expression of stromal Bmp4, epithelial Sox9 and columnar cytokeratins. Conclusions Epithelial Hedgehog ligand expression may contribute to the initiation of Barrett's esophagus through induction of stromal BMP4, which triggers reprogramming of esophageal epithelium in favor of a columnar phenotype. PMID:20138038

Coffee consumption and risk of esophageal cancer incidence: A meta-analysis of epidemiologic studies.

PubMed

Zhang, Juan; Zhou, Bin; Hao, Chuanzheng

2018-04-01

In epidemiologic studies, association between coffee consumption and esophageal cancer risk is inconsistent. The aim of tjis study was to evaluate the effect of coffee on esophageal cancer by combining several similar studies. We conducted a meta-analysis for association of coffee intake and esophageal cancer incidence. Eleven studies, including 457,010 participants and 2628 incident cases, were identified. A relative risk (RR, for cohort study) or odds ratio (OR, for case-control study) of heavy coffee drinkers was calculated, compared with light coffee drinkers or non-drinkers. The analysis was also stratified by cancer types (esophageal squamous cell carcinoma and esophageal adenocarcinoma), sex, and geographic region. The summarized OR of having esophageal cancer in heavy coffee drinkers was 0.93 (95% confidence interval [CI]: 0.73-1.12), compared with light coffee drinkers. When stratified by sex, pathologic type of esophageal cancer, and type of epidemiologic study, we did not find any association of coffee consumption and esophageal cancer incidence. However, an inverse association between coffee consumption and incidence of esophageal cancer was found in East Asia participants with OR of 0.64 (95% CI: 0.44-0.83), but not in Euro-America participants (OR = 1.05; 95% CI: 0.81-1.29). There is a protective role of coffee consumption against esophageal cancer in East Asians, but not in Euro-Americans.

Cervical esophageal cancer: a gap in cancer knowledge.

PubMed

Hoeben, A; Polak, J; Van De Voorde, L; Hoebers, F; Grabsch, H I; de Vos-Geelen, J

2016-09-01

The aim of this systematic review is to provide an overview of the diagnosis, treatment options and treatment-related complications of cervical esophageal carcinoma (CEC) and to subsequently provide recommendations to improve quality of care. Studies were identified in PubMed, EMBASE and Web of Science. A total of 107 publications fulfilled the inclusion criteria and were included. CEC is uncommon, accounting for 2%-10% of all esophageal carcinomas. These tumors are often locally advanced at presentation and have a poor prognosis, with a 5-year overall survival of 30%. Tobacco and alcohol consumption seem to be the major risk factors for developing CEC. Surgery is usually not possible due to the very close relationship to other organs such as the larynx, trachea and thyroid gland. Therefore, the current standard of care is definitive chemoradiation (dCRT) with curative intent. Treatment regimens used to treat CEC are adapted by established regimens in lower esophageal squamous cell carcinoma and head and neck squamous cell carcinoma. However, dCRT may be accompanied by severe side-effects and complications. Several diagnostic and predictive markers have been studied, but currently, there is no other biomarker than clinical stage to determine patient management. Suggestions to improve patient outcomes are to determine the exact radiation dose needed for adequate locoregional control and to combine radiotherapy with optimal systemic therapy backbone. CEC remains unchartered territory for many practising physicians and patients with CEC have a poor prognosis. To improve the outcome for CEC patients, future studies should focus on the identification of new diagnostic biomarkers or targets for radiosensitizers, amelioration of radiation schedules, optimal combination of chemotherapeutic agents and/or new therapeutic targets. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Prevention of esophageal strictures after endoscopic submucosal dissection

PubMed Central

Kobayashi, Shinichiro; Kanai, Nobuo; Ohki, Takeshi; Takagi, Ryo; Yamaguchi, Naoyuki; Isomoto, Hajime; Kasai, Yoshiyuki; Hosoi, Takahiro; Nakao, Kazuhiko; Eguchi, Susumu; Yamamoto, Masakazu; Yamato, Masayuki; Okano, Teruo

2014-01-01

Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have recently been accepted as less invasive methods for treating patients with early esophageal cancers such as squamous cell carcinoma and dysplasia of Barrett’s esophagus. However, the large defects in the esophageal mucosa often cause severe esophageal strictures, which dramatically reduce the patient’s quality of life. Although preventive endoscopic balloon dilatation can reduce dysphagia and the frequency of dilatation, other approaches are necessary to prevent esophageal strictures after ESD. This review describes several strategies for preventing esophageal strictures after ESD, with a particular focus on anti-inflammatory and tissue engineering approaches. The local injection of triamcinolone acetonide and other systemic steroid therapies are frequently used to prevent esophageal strictures after ESD. Tissue engineering approaches for preventing esophageal strictures have recently been applied in basic research studies. Scaffolds with temporary stents have been applied in five cases, and this technique has been shown to be safe and is anticipated to prevent esophageal strictures. Fabricated autologous oral mucosal epithelial cell sheets to cover the defective mucosa similarly to how commercially available skin products fabricated from epidermal cells are used for skin defects or in cases of intractable ulcers. Fabricated autologous oral-mucosal-epithelial cell sheets have already been shown to be safe. PMID:25386058

The importance of exposure rate on odds ratios by cigarette smoking and alcohol consumption for esophageal adenocarcinoma and squamous cell carcinoma in the Barrett's Esophagus and Esophageal Adenocarcinoma Consortium.

PubMed

Lubin, Jay H; Cook, Michael B; Pandeya, Nirmala; Vaughan, Thomas L; Abnet, Christian C; Giffen, Carol; Webb, Penelope M; Murray, Liam J; Casson, Alan G; Risch, Harvey A; Ye, Weimin; Kamangar, Farin; Bernstein, Leslie; Sharp, Linda; Nyrén, Olof; Gammon, Marilie D; Corley, Douglas A; Wu, Anna H; Brown, Linda M; Chow, Wong-Ho; Ward, Mary H; Freedman, Neal D; Whiteman, David C

2012-06-01

Cigarette smoking is associated with esophageal adenocarcinoma (EAC), esophagogastric junctional adenocarcinoma (EGJA) and esophageal squamous cell carcinoma (ESCC), and alcohol consumption with ESCC. However, no analyses have examined how delivery rate modifies the strength of odds ratio (OR) trends with total exposure, i.e., the impact on the OR for a fixed total exposure of high exposure rate for short duration compared with low exposure rate for long duration. The authors pooled data from 12 case-control studies from the Barrett's Esophagus and Esophageal Adenocarcinoma Consortium (BEACON), including 1242 (EAC), 1263 (EGJA) and 954 (ESCC) cases and 7053 controls, modeled joint ORs for cumulative exposure and exposure rate for cigarette smoking and alcohol consumption, and evaluated effect modification by sex, body mass index (BMI), age and self-reported acid reflux. For smoking, all sites exhibited inverse delivery rate effects, whereby ORs with pack-years increased, but trends weakened with increasing cigarettes/day. None of the examined factors modified associations, except for ESCC where younger ages at diagnosis enhanced smoking effects (P<0.01). For EAC and EGJA, ORs with drink-years exhibited inverse associations in <5 drinks/day consumers and no association in heavier consumers. For ESCC, ORs with drink-years increased, with trends strengthening with greater drinks/day. There was no significant effect modification, except for EAC and EGJA where acid reflux mitigated the inverse associations (P=0.02). For ESCC, younger ages at diagnosis enhanced drinking-related ORs (P<0.01). Patterns of ORs by pack-years and drink-years, delivery rate effects and effect modifiers revealed common as well as distinct etiologic elements for these diseases. Published by Elsevier Ltd.

Postoperative radiation in esophageal squamous cell carcinoma and target volume delineation

PubMed Central

Zhu, Yingming; Li, Minghuan; Kong, Li; Yu, Jinming

2016-01-01

Esophageal cancer is the sixth leading cause of cancer death worldwide, and patients who are treated with surgery alone, without neoadjuvant therapies, experience frequent relapses. Whether postoperative therapies could reduce the recurrence or improve overall survival is still controversial for these patients. The purpose of our review is to figure out the value of postoperative adjuvant therapy and address the disputes about target volume delineation according to published data. Based on the evidence of increased morbidity and disadvantages on patient survival caused by postoperative chemotherapy or radiotherapy (RT) alone provided by studies in the early 1990s, the use of postoperative adjuvant therapies in cases of esophageal squamous cell carcinoma has diminished substantially and has been replaced gradually by neoadjuvant chemoradiation. With advances in surgery and RT, accumulating evidence has recently rekindled interest in the delivery of postoperative RT or chemoradiotherapy in patients with stage T3/T4 or N1 (lymph node positive) carcinomas after radical surgery. However, due to complications with the standard radiation field, a nonconforming modified field has been adopted in most studies. Therefore, we analyze different field applications and provide suggestions on the optimization of the radiation field based on the major sites of relapse and the surgical non-clearance area. For upper and middle thoracic esophageal carcinomas, the bilateral supraclavicular and superior mediastinal areas remain common sites of recurrence and should be encompassed within the clinical target volume. In contrast, a consensus has yet to be reached regarding lower thoracic esophageal carcinomas; the “standard” clinical target volume is still recommended. Further studies of larger sample sizes should focus on different recurrence patterns, categorized by tumor locations, refined classifications, and differing molecular biology, to provide more information on the delineation of target volumes. PMID:27471393

Three-dimensional conformal radiation for esophageal squamous cell carcinoma with involved-field irradiation may deliver considerable doses of incidental nodal irradiation.

PubMed

Ji, Kai; Zhao, Lujun; Yang, Chengwen; Meng, Maobin; Wang, Ping

2012-11-27

To quantify the incidental irradiation dose to esophageal lymph node stations when irradiating T1-4N0M0 thoracic esophageal squamous cell carcinoma (ESCC) patients with a dose of 60 Gy/30f. Thirty-nine patients with medically inoperable T1-4N0M0 thoracic ESCC were treated with three-dimensional conformal radiation (3DCRT) with involved-field radiation (IFI). The conformal clinical target volume (CTV) was re-created using a 3-cm margin in the proximal and distal direction beyond the barium esophagogram, endoscopic examination and CT scan defined the gross tumor volume (GTV) and a 0.5-cm margin in the lateral and anteroposterior directions of the CT scan-defined GTV. The PTV encompassed 1-cm proximal and distal margins and 0.5-cm radial margin based on the CTV. Nodal regions were delineated using the Japanese Society for Esophageal Diseases (JSED) guidelines and an EORTC-ROG expert opinion. The equivalent uniform dose (EUD) and other dosimetric parameters were calculated for each nodal station. Nodal regions with a metastasis rate greater than 5% were considered a high-risk lymph node subgroup. Under a 60 Gy dosage, the median D mean and EUD was greater than 40 Gy in most high-risk nodal regions except for regions of 104, 106tb-R in upper-thoracic ESCC and 101, 104-R, 105, 106rec-L, 2, 3&7 in middle-thoracic ESCC and 107, 3&7 in lower-thoracic ESCC. In the regions with an EUD less than 40 Gy, most incidental irradiation doses were significantly associated with esophageal tumor length and location. Lymph node stations near ESCC receive considerable incidental irradiation doses with involved-field irradiation that may contribute to the elimination of subclinical lesions.

The predictive value of 18F-FDG PET for pathological response of primary tumor in patients with esophageal cancer during or after neoadjuvant chemoradiotherapy: a meta-analysis.

PubMed

Cong, Lihong; Wang, Shikun; Gao, Teng; Hu, Likuan

2016-12-01

We want to review the value of 18-fluoro-deoxy-glucose positron emission tomography for response prediction of primary tumor in patients with esophageal cancer during or after neoadjuvant chemoradiotherapy. Studies were searched in Pubmed, Embase and Cochrane Library with specific search strategy. The published articles were included according to the criteria established in advance. The included studies were divided into two groups according to the time of the repeat positron emission tomography: during (Group A) or after neoadjuvant chemoradiotherapy (Group B). The studies that performed the repeat positron emission tomography after neoadjuvant chemoradiotherapy were graded Quality Assessment of Diagnostic Accuracy Studies. The pooled sensitivity, specificity and diagnostic odds ratio were obtained for both groups on the basis of no-existing of threshold effect. Fifteen studies were included in the present study. The threshold effect did not exist in both groups. The pooled sensitivity, specificity and diagnostic odds ratio were 85%, 59%, 6.82 with 95% confidence interval 76-91%, 48-69%, 2.25-20.72 in Group A. The equivalent values were 67%, 69%, 6.34 with 95% confidence interval 60-73%, 63-74%, 2.08-19.34 in Group B. The pooled sensitivity was 90% in four studies that enrolled patients with esophageal squamous cell carcinoma merely in Group B. According to the present data, positron emission tomography should not be used routinely to guide treatment strategy in esophageal cancer patients. We speculated that positron emission tomography could be used as a tool to predict treatment response after neoadjuvant chemoradiotherapy in patients with esophageal squamous cell carcinoma. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The Spatial Predilection for Early Esophageal Squamous Cell Neoplasia: A "Hot Zone" for Endoscopic Screening and Surveillance.

PubMed

Wang, Wen-Lun; Chang, I-Wei; Chen, Chien-Chuan; Chang, Chi-Yang; Lin, Jaw-Town; Mo, Lein-Ray; Wang, Hsiu-Po; Lee, Ching-Tai

2016-04-01

Early esophageal squamous cell neoplasias (ESCNs) are easily missed with conventional white-light endoscopy. This study aimed to assess whether early ESCNs have a spatial predilection and the patterns of recurrence after endoscopic treatment. We analyzed the circumferential and longitudinal location of early ESCNs, as well as their correlations with exposure to carcinogens in a cohort of 162 subjects with 248 early ESCNs; 219 of which were identified by screening and 29 by surveillance endoscopy. The circumferential location was identified using a clock-face orientation, and the longitudinal location was identified according to the distance from the incisor. The most common circumferential and longitudinal distributions of the early ESCNs were found in the 6 to 9 o'clock quadrant (38.5%) and at 26 to 30 cm from the incisor (41.3%), respectively. A total of 163 lesions (75%) were located in the lower hemisphere arc, and 149 (68.4%) were located at 26 to 35 cm from the incisor. One hundred eleven (51%) early ESCNs were centered within the "hot zone" (i.e., lower hemisphere arc of the esophagus at 26 to 35 cm from the incisor), which comprised 20% of the esophageal area. Exposure to alcohol, betel nut, or cigarette was risk factors for the development of early ESCNs in the lower hemisphere. After complete endoscopic treatment, the mean annual incidence of metachronous tumors was 10%. In addition, 43% of the metachronous recurrent neoplasias developed within the "hot zone." Cox regression analysis revealed that the index tumor within the hot zone (hazard ratio [HR]: 3.19; 95% confidence interval [CI]: 1.17-8.68; P = 0.02) and the presence of numerous Lugol-voiding lesions in the esophageal background mucosa were independent predictors for metachronous recurrence (HR: 4.61; 95% CI: 1.36-15.56; P = 0.01). We identified a hot zone that may be used to enhance the detection of early ESCNs during endoscopic screening and surveillance, especially in areas that lack resources and have a high prevalence of ESCNs.

Elective nodal irradiation (ENI) in definitive chemoradiotherapy (CRT) for squamous cell carcinoma of the thoracic esophagus.

PubMed

Onozawa, Masakatsu; Nihei, Keiji; Ishikura, Satoshi; Minashi, Keiko; Yano, Tomonori; Muto, Manabu; Ohtsu, Atsushi; Ogino, Takashi

2009-08-01

There are some reports indicating that prophylactic three-field lymph node dissection for esophageal cancer can lead to improved survival. But the benefit of ENI in CRT for thoracic esophageal cancer remains controversial. The purpose of the present study is to retrospectively evaluate the efficacy of elective nodal irradiation (ENI) in definitive chemoradiotherapy (CRT) for thoracic esophageal cancer. Patients with squamous cell carcinoma (SCC) of the thoracic esophagus newly diagnosed between February 1999 and April 2001 in our institution was recruited from our database. Definitive chemoradiotherapy consisted of two cycles of cisplatin/5FU repeated every 5 weeks, with concurrent radiation therapy of 60 Gy in 30 fractions. Up to 40 Gy radiation therapy was delivered to the cervical, periesophageal, mediastinal and perigastric lymph nodes as ENI. One hundred two patients were included in this analysis, and their characteristics were as follows: median age, 65 years; male/female, 85/17; T1/T2/T3/T4, 16/11/61/14; N0/N1, 48/54; M0/M1, 84/18. The median follow-up period for the surviving patients was 41 months. Sixty patients achieved complete response (CR). After achieving CR, only one (1.0%; 95% CI, 0-5.3%) patient experienced elective nodal failure without any other site of recurrence. In CRT for esophageal SCC, ENI is effective for preventing regional nodal failure. Further evaluation of whether ENI leads to an improved overall survival is needed.

Contribution of MAML1 in esophageal squamous cell carcinoma tumorigenesis.

PubMed

Hashemi Bidokhti, Mahnaz; Abbaszadegan, Mohammad Reza; Sharifi, Noorieh; Abbasi Sani, Soodabeh; Forghanifard, Mohammad Mahdi

2017-04-01

Notch signaling pathway is involved in different cellular and developmental processes including cell proliferation, differentiation and apoptosis. Mastermind like1 (MAML1) is a critical key transcription coactivator of this pathway. In this study, we aimed to examine MAML1 protein expression in esophageal squamous cell carcinoma (ESCC) and reveal its association with clinicopathological variables of the patients. Tumoral and their margin normal tissues from 56 ESCC patients were recruited for protein expression analysis using immunohistochemistry (IHC). Furthermore, MAML1 expression was analyzed in ESCC cell line KYSE-30 using immunocytochemistry. Overexpression of MAML1 was detected in 59% of tumor samples. It was significantly associated with different indices of poor prognosis including depth of tumor invasion (P=0.026), grade of tumor differentiation (P=0.002), stage of tumor progression (P=0.004) and sex (P=0.027). Beside the appearing evidences explaining MAML1 role in different cellular processes and its deviations in different malignancies and also based on its correlation with different clinicopathological variables of ESCC, MAML1 can be proposed as potentially novel molecular marker for ESCC progression and tumorigenesis as well as therapeutic target to inhibit and reverse progression and development of the disease. Copyright © 2017 Elsevier Inc. All rights reserved.

TM4SF1 promotes the self-renewal of esophageal cancer stem-like cells and is regulated by miR-141.

PubMed

Xue, Lei; Yu, Xiying; Jiang, Xingran; Deng, Xin; Mao, Linlin; Guo, Liping; Fan, Jinhu; Fan, Qinqxia; Wang, Liuxing; Lu, Shih-Hsin

2017-03-21

Cancer stem-like cells have been identified in primary human tumors and cancer cell lines. Previously we found TM4SF1 gene was highly expressed in side population (SP) cells from esophageal squamous cell carcinoma (ESCC) cell lines, but the role and underlying mechanism of TM4SF1 in ESCC remain unclear. In this study, we observed TM4SF1 was up-regulated but miR-141 was down-regulated in SP cells isolated from ESCC cell lines. TM4SF1 could stimulate the self-renewal ability and carcinogenicity of esophageal cancer stem-like cells, and promote cell invasion and migration. In miR-141 overexpression cells, the expression of TM4SF1 was significantly reduced. We also found that overexpression of miR-141 could abolish the self-renewal ability and carcinogenicity of esophageal cancer stem-like cells and decrease cell invasion and migration by suppressing TM4SF1. Consequently, TM4SF1 is a direct target gene of miR-141. The regulation of TM4SF1 by miR-141 may play an important role in controlling self-renewals of esophageal cancer stem-like cells. It may also promote the development of new therapeutic strategies and efficient drugs to target ESCC stem-like cells.

Multiphoton imaging of low grade, high grade intraepithelial neoplasia and intramucosal invasive cancer of esophagus

NASA Astrophysics Data System (ADS)

Xu, Jian; Jiang, Liwei; Kang, Deyong; Wu, Xuejing; Xu, Meifang; Zhuo, Shuangmu; Zhu, Xiaoqin; Lin, Jiangbo; Chen, Jianxin

2017-04-01

Esophageal squamous cell carcinoma (ESCC) is devastating because of its aggressive lymphatic spread and clinical course. It is believed to occur through low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and intramucosal invasive cancer (IMC) before transforming to submucosal cancer. In particular, these early lesions (LGIN, HGIN and IMC), which involve no lymph node nor distant metastasis, can be cured by endoscopic treatment. Therefore, early identification of these lesions is important so as to offer a curative endoscopic resection, thus slowing down the development of ESCC. In this work, spectral information and morphological features of the normal esophageal mucosa are first studied. Then, the morphological changes of LGIN, HGIN and IMC are described. Lastly, quantitative parameters are also extracted by calculating the nuclear-to-cytoplasmic ratio of epithelial cells and the pixel density of collagen in the lamina propria. These results show that multiphoton microscopy (MPM) has the ability to identify normal esophageal mucosa, LGIN, HGIN and IMC. With the development of multiphoton endoscope systems for in vivo imaging, combined with a laser ablation system, MPM has the potential to provide immediate pathologic diagnosis and curative treatment of ESCC before the transformation to submucosal cancer in the future.

Microscopic esophagitis and Barrett's esophagus: the histology report.

PubMed

Fiocca, Roberto; Mastracci, Luca; Milione, Massimo; Parente, Paola; Savarino, Vincenzo

2011-03-01

Gastro-esophageal reflux disease (GERD) is the most common digestive disease in industrialized countries (Europe and North America) and is associated with microscopic changes in the squamous epithelium. However, biopsy is not presently included in the routine diagnostic flow chart of GERD. In contrast, esophageal biopsy is mandatory when diagnosing Barrett's esophagus. High quality histology reports are necessary to provide information on diagnosis and can also be important for research and epidemiological studies. It has been evident for decades that pathology reports vary between institutions and even within a single institution. Standardization of reporting is the best way to ensure that information necessary for patient management is included in pathology reports. This paper details the histological criteria for diagnosing GERD-associated microscopic esophagitis, other forms of esophagitis with specific features and columnar metaplasia in the lower esophagus (Barrett's esophagus). It provides a detailed description of appropriate sampling criteria, individual lesions and how they contribute to the histology report. Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd.. All rights reserved.

Synchronous second primary cancers in patients with squamous esophageal cancer: clinical features and survival outcome.

PubMed

Lee, Jin Seo; Ahn, Ji Yong; Choi, Kee Don; Song, Ho June; Kim, Yong Hee; Lee, Gin Hyug; Jung, Hwoon-Yong; Ryu, Jin-Sook; Kim, Sung-Bae; Kim, Jong Hoon; Park, Seung-Il; Cho, Kyung-Ja; Kim, Jin-Ho

2016-03-01

Unexpected diagnosis of synchronous second primary cancers (SPC) complicates physicians' decision-making because clinical details of squamous esophageal cancer (EC) patients with SPC have been limited. We evaluated clinical features and treatment outcomes of patients with synchronous SPC detected during the initial staging of squamous EC. We identified a total of 317 consecutive patients diagnosed with squamous EC. Relevant clinical and cancer-specific information were reviewed retrospectively. EC patients with synchronous SPC were identified in 21 patients (6.6%). There were significant differences in median age (70 years vs. 63 years, p = 0.01), serum albumin level (3.3 g/dL vs. 3.9 g/dL, p < 0.01) and body mass index (20.4 kg/m(2) vs. 22.8 kg/m(2), p = 0.01) between EC patients with and without SPC. Head and neck, lung and gastric cancers accounted for 18.2%, 22.7%, and 18.2% of SPC, respectively. Positron emission tomography-computed tomography (PET-CT) detected four cases (18.2%) of SPC that were missed on CT. Management plans were altered in 13 of 21 patients (61.9%) with detected SPC. Curative esophagectomy was attempted in 28.6% of EC patients with SPC (vs. 59.1% of patients without SPC; p = 0.006). EC patients with SPC had significantly lower 5-year survival than patients without SPC (10.6% vs. 36.7%, p = 0.008). Synchronous SPC were found in 6.6% of squamous EC patients, and PET-CT contributed substantially to the detection of synchronous SPC. EC patients with SPC had poor survival due to challenges of providing stage-appropriate treatment.

Receptor Interactive Protein Kinase 3 Promotes Cisplatin-Triggered Necrosis in Apoptosis-Resistant Esophageal Squamous Cell Carcinoma Cells

PubMed Central

Zhao, Nan; Zhou, Lanping; Liu, Fang; Cichacz, Zbigniew; Zhang, Lin; Zhan, Qimin; Zhao, Xiaohang

2014-01-01

Cisplatin-based chemotherapy is currently the standard treatment for locally advanced esophageal cancer. Cisplatin has been shown to induce both apoptosis and necrosis in cancer cells, but the mechanism by which programmed necrosis is induced remains unknown. In this study, we provide evidence that cisplatin induces necrotic cell death in apoptosis-resistant esophageal cancer cells. This cell death is dependent on RIPK3 and on necrosome formation via autocrine production of TNFα. More importantly, we demonstrate that RIPK3 is necessary for cisplatin-induced killing of esophageal cancer cells because inhibition of RIPK1 activity by necrostatin or knockdown of RIPK3 significantly attenuates necrosis and leads to cisplatin resistance. Moreover, microarray analysis confirmed an anti-apoptotic molecular expression pattern in esophageal cancer cells in response to cisplatin. Taken together, our data indicate that RIPK3 and autocrine production of TNFα contribute to cisplatin sensitivity by initiating necrosis when the apoptotic pathway is suppressed or absent in esophageal cancer cells. These data provide new insight into the molecular mechanisms underlying cisplatin-induced necrosis and suggest that RIPK3 is a potential marker for predicting cisplatin sensitivity in apoptosis-resistant and advanced esophageal cancer. PMID:24959694

KH-type splicing regulatory protein is involved in esophageal squamous cell carcinoma progression

PubMed Central

Shoda, Katsutoshi; Naruto, Takuya; Hamada, Satoshi; Miyakami, Yuko; Kohmoto, Tomohiro; Watanabe, Miki; Takahashi, Rizu; Tange, Shoichiro; Saito, Masako; Kudo, Yasusei; Fujiwara, Hitoshi; Ichikawa, Daisuke; Tangoku, Akira; Otsuji, Eigo; Imoto, Issei

2017-01-01

KH-type splicing regulatory protein (KHSRP) is a multifunctional RNA-binding protein, which is involved in several post-transcriptional aspects of RNA metabolism, including microRNA (miRNA) biogenesis. It affects distinct cell functions in different tissues and can have an impact on various pathological conditions. In the present study, we investigated the oncogenic functions of KHSRP and their underlying mechanisms in the pathogenesis of esophageal squamous cell carcinoma (ESCC). KHSRP expression levels were elevated in ESCC tumors when compared with those in non-tumorous tissues by immunohistochemistry, and cytoplasmic KHSRP overexpression was found to be an independent prognosticator for worse overall survival in a cohort of 104 patients with ESCC. KHSRP knockdown inhibited growth, migration, and invasion of ESCC cells. KHSRP knockdown also inhibited the maturation of cancer-associated miRNAs, such as miR-21, miR-130b, and miR-301, and induced the expression of their target mRNAs, such as BMP6, PDCD4, and TIMP3, resulting in the inhibition of epithelial-to-mesenchymal transition. Our findings uncover a novel oncogenic function of KHSRP in esophageal tumorigenesis and implicate its use as a marker for prognostic evaluation and as a putative therapeutic target in ESCC. PMID:29254151

Tumor-promoting function and prognostic significance of the RNA-binding protein T-cell intracellular antigen-1 in esophageal squamous cell carcinoma

PubMed Central

Fujita, Yuji; Naruto, Takuya; Kohmoto, Tomohiro; Miyakami, Yuko; Watanabe, Miki; Kudo, Yasusei; Fujiwara, Hitoshi; Ichikawa, Daisuke; Otsuji, Eigo; Imoto, Issei

2016-01-01

T-cell intracellular antigen-1 (TIA1) is an RNA-binding protein involved in many regulatory aspects of mRNA metabolism. Here, we report previously unknown tumor-promoting activity of TIA1, which seems to be associated with its isoform-specific molecular distribution and regulation of a set of cancer-related transcripts, in esophageal squamous cell carcinoma (ESCC). Immunohistochemical overexpression of TIA1 ectopically localized in the cytoplasm of tumor cells was an independent prognosticator for worse overall survival in a cohort of 143 ESCC patients. Knockdown of TIA1 inhibited proliferation of ESCC cells. By exogenously introducing each of two major isoforms, TIA1a and TIA1b, only TIA1a, which was localized to both the nucleus and cytoplasm, promoted anchorage-dependent and anchorage-independent ESCC cell proliferation. Ribonucleoprotein immunoprecipitation, followed by microarray analysis or massive-parallel sequencing, identified a set of TIA1-binding mRNAs, including SKP2 and CCNA2. TIA1 increased SKP2 and CCNA2 protein levels through the suppression of mRNA decay and translational induction, respectively. Our findings uncover a novel oncogenic function of TIA1 in esophageal tumorigenesis, and implicate its use as a marker for prognostic evaluation and as a therapeutic target in ESCC. PMID:26958940

Tumor-promoting function and prognostic significance of the RNA-binding protein T-cell intracellular antigen-1 in esophageal squamous cell carcinoma.

PubMed

Hamada, Junichi; Shoda, Katsutoshi; Masuda, Kiyoshi; Fujita, Yuji; Naruto, Takuya; Kohmoto, Tomohiro; Miyakami, Yuko; Watanabe, Miki; Kudo, Yasusei; Fujiwara, Hitoshi; Ichikawa, Daisuke; Otsuji, Eigo; Imoto, Issei

2016-03-29

T-cell intracellular antigen-1 (TIA1) is an RNA-binding protein involved in many regulatory aspects of mRNA metabolism. Here, we report previously unknown tumor-promoting activity of TIA1, which seems to be associated with its isoform-specific molecular distribution and regulation of a set of cancer-related transcripts, in esophageal squamous cell carcinoma (ESCC). Immunohistochemical overexpression of TIA1 ectopically localized in the cytoplasm of tumor cells was an independent prognosticator for worse overall survival in a cohort of 143 ESCC patients. Knockdown of TIA1 inhibited proliferation of ESCC cells. By exogenously introducing each of two major isoforms, TIA1a and TIA1b, only TIA1a, which was localized to both the nucleus and cytoplasm, promoted anchorage-dependent and anchorage-independent ESCC cell proliferation. Ribonucleoprotein immunoprecipitation, followed by microarray analysis or massive-parallel sequencing, identified a set of TIA1-binding mRNAs, including SKP2 and CCNA2. TIA1 increased SKP2 and CCNA2 protein levels through the suppression of mRNA decay and translational induction, respectively. Our findings uncover a novel oncogenic function of TIA1 in esophageal tumorigenesis, and implicate its use as a marker for prognostic evaluation and as a therapeutic target in ESCC.

Identification and validation of FGFR2 peptide for detection of early Barrett's neoplasia

PubMed Central

Zhou, Juan; He, Lei; Pang, Zhijun; Appelman, Henry D.; Kuick, Rork; Beer, David G.; Li, Meng; Wang, Thomas D.

2017-01-01

The incidence of esophageal adenocarcinoma (EAC) is rising rapidly, and early detection within the precursor state of Barrett's esophagus (BE) is challenged by flat premalignant lesions that are difficult detect with conventional endoscopic surveillance. Overexpression of cell surface fibroblast growth factor receptor 2 (FGFR2) is an early event in progression of BE to EAC, and is a promising imaging target. We used phage display to identify the peptide SRRPASFRTARE that binds specifically to the extracellular domain of FGFR2. We labeled this peptide with a near-infrared fluorophore Cy5.5, and validated the specific binding to FGFR2 overexpressed in cells in vitro. We found high affinity kd = 68 nM and rapid binding k = 0.16 min−1 (6.2 min). In human esophageal specimens, we found significantly greater peptide binding to high-grade dysplasia (HGD) versus either BE or normal squamous epithelium, and good correlation with anti-FGFR2 antibody. We also observed significantly greater peptide binding to excised specimens of esophageal squamous cell carcinoma and gastric cancer compared to normal mucosa. These results demonstrate potential for this FGFR2 peptide to be used as a clinical imaging agent to guide tissue biopsy and improve methods for early detection of EAC and potentially other epithelial-derived cancers. PMID:29152066

Inhibitor of Differentiation/DNA Binding 1 (ID1) Inhibits Etoposide-induced Apoptosis in a c-Jun/c-Fos-dependent Manner.

PubMed

Zhao, Yahui; Luo, Aiping; Li, Sheng; Zhang, Wei; Chen, Hongyan; Li, Yi; Ding, Fang; Huang, Furong; Liu, Zhihua

2016-03-25

ID1 (inhibitor of differentiation/DNA binding 1) acts an important role in metastasis, tumorigenesis, and maintenance of cell viability. It has been shown that the up-regulation of ID1 is correlated with poor prognosis and the resistance to chemotherapy of human cancers. However, the underlying molecular mechanism remains elusive. Here, we determined for the first time that up-regulating ID1 upon etoposide activation was mediated through AP-1 binding sites within theID1promoter and confirmed that ID1 enhanced cell resistance to DNA damage-induced apoptosis in esophageal squamous cell carcinoma cells. Ablation of c-Jun/c-Fos or ID1 expression enhanced etoposide-mediated apoptosis through increasing activity of caspase 3 and PARP cleavage. Moreover, c-Jun/c-Fos and ID1 were positively correlated in human cancers. More importantly, simultaneous high expression of ID1 and c-Jun or c-Fos was correlated with poor survival in cancer patients. Collectively, we demonstrate the importance of c-Jun/c-Fos-ID1 signaling pathway in chemoresistance of esophageal cancer cells and provide considerable insight into understanding the underlying molecular mechanisms in esophageal squamous cell carcinoma cell biology. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

[Clinical and endoscopic findings and magnitude of gastric and duodenal reflux in patients with cardial intestinal metaplasia, short Barrett esophagus, compared with controls].

PubMed

Csendes, A; Burdiles, P; Smok, G; Rojas, J; Flores, N; Domic, S; Quiroz, J; Henríquez, A

1999-11-01

The diagnosis of patients with short segments of intestinal metaplasia in the distal esophagus, has increased in recent years. To assess the clinical, pathological and functional features of patients with esophageal intestinal metaplasia. A prospective study was performed in 95 control subjects, 115 patients with cardial intestinal metaplasia and 89 patients with short Barret esophagus with intestinal metaplasia. All had clinical and endoscopic assessments, esophageal manometry and determination of 24 h esophageal exposure to acid and duodenal content. Control patients were younger and, in this group, the pathological findings in the mucosa distal to the squamous-columnar change, showed a preponderance of fundic over cardial mucosa. In patients with intestinal metaplasia and short Barret esophagus, there was only cardial mucosa, that is the place where intestinal metaplasia implants. Low grade dysplasia was only seen in the presence of intestinal metaplasia. Gastroesophageal sphincter pressure decreased and gastric and duodenal reflux increased along with increases in the extension of intestinal metaplasia. These findings confirm the need to obtain multiple biopsies from the squamous-columnar mucosal junction in all patients with gastroesophageal reflux symptoms, for the detection of early pathological changes of Barret esophagus and eventual dysplasia.

Endoscopic submucosal dissection for esophageal squamous cell neoplasms.

PubMed

Fujishiro, Mitsuhiro; Kodashima, Shinya; Goto, Osamu; Ono, Satoshi; Niimi, Keiko; Yamamichi, Nobutake; Oka, Masashi; Ichinose, Masao; Omata, Masao

2009-04-01

Endoscopic submucosal dissection (ESD) has gradually gained acceptance as one of the standard treatments for early esophageal cancer, as well as for early gastric cancer in Japan, but standardization of the knowledge is still incomplete. The final goal to perform ESD is not to resect the lesion in an en bloc fashion, but to save the patient from esophageal cancer-related death. Thus, the indications should be considered based on the entire patient, not just the target lesion itself, and pre-, peri- and postoperative management of the patient is also very important, as well as technical aspects of ESD. In terms of the techniques of ESD, owing to refinement of the procedural strategy, invention of the devices, and the learning curve, acceptable safety and favorable middle-term efficacy have been obtained. We believe that ESD will become a standard treatment for early esophageal cancer not only in Japan but also worldwide in the near future.

Hypoxia induces IGFBP3 in esophageal squamous cancer cells through HIF-1α-mediated mRNA transcription and continuous protein synthesis

PubMed Central

Natsuizaka, Mitsuteru; Naganuma, Seiji; Kagawa, Shingo; Ohashi, Shinya; Ahmadi, Azal; Subramanian, Harry; Chang, Sanders; Nakagawa, Kei J.; Ji, Xinjun; Liebhaber, Stephen A.; Klein-Szanto, Andres J.; Nakagawa, Hiroshi

2012-01-01

Insulin-like growth factor binding protein (IGFBP)-3 regulates cell proliferation and apoptosis in esophageal squamous cell carcinoma (ESCC) cells. We have investigated how the hypoxic tumor microenvironment in ESCC fosters the induction of IGFBP3. RNA interference experiments revealed that hypoxia-inducible factor (HIF)-1α, but not HIF-2α, regulates IGFBP3 mRNA induction. By chromatin immunoprecipitation and transfection assays, HIF-1α was found to transactivate IGFBP3 through a novel hypoxia responsive element (HRE) located at 57 kb upstream from the transcription start site. Metabolic labeling experiments demonstrated hypoxia-mediated inhibition of global protein synthesis. 7-Methyl GTP-cap binding assays suggested that hypoxia suppresses cap-dependent translation. Experiments using pharmacological inhibitors for mammalian target of rapamycin (mTOR) suggested that a relatively weak mTOR activity may be sufficient for cap-dependent translation of IGFBP3 under hypoxic conditions. Bicistronic RNA reporter transfection assays did not validate the possibility of an internal ribosome entry site as a potential mechanism for cap-independent translation for IGFBP3 mRNA. Finally, IGFBP3 mRNA was found enriched to the polysomes. In aggregate, our study establishes IGFBP3 as a direct HIF-1α target gene and that polysome enrichment of IGFBP3 mRNA may permit continuous translation under hypoxic conditions.—Natsuizaka, M., Naganuma, S., Kagawa, S., Ohashi, S., Ahmadi, A., Subramanian, H., Chang, S., Nakagawa, K. J., Ji, X., Liebhaber, S. A., Klein-Szanto, A. J., Nakagawa, H. Hypoxia induces IGFBP3 in esophageal squamous cancer cells through HIF-1α-mediated mRNA transcription and continuous protein synthesis. PMID:22415309

Efficacy of 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a in photodynamic therapy of human esophageal squamous cancer cells.

PubMed

Wu, Dengpan; Liu, Zhen; Fu, Yanni; Zhang, Yuan; Tang, Nan; Wang, Qin; Tao, Liang

2013-10-01

The present study investigated the effects of 2-(1-hexyloxyethyl)-2-devinylpyro pheophorbide-a (HPPH)-mediated photodynamic therapy (PDT) on in vitro cell survival and in vivo tumor growth derived from human esophageal squamous cancer cells (Eca109). A cell counting kit 8 (CCK8) assay was used to assess the phototoxicity of HPPH-mediated PDT in cultured Eca109 cells. The inhibition of tumor growth was determined by the changes in the relative tumor volume (RTV) and tumor weight. The results revealed that HPPH, in the range of 0.005-1 μg/ml, exhibited no cytotoxicity in the Eca109 cells without light exposure and that the in vitro efficiency of HPPH-mediated PDT was higher compared with that of Photofrin ® -mediated PDT. The in vivo results indicated that graded doses of HPPH-mediated PDT significantly inhibited the xenograft tumor growth derived from the Eca109 cells in a dose-dependent manner. The inhibition efficacy of 0.6 and 1.0 mg/kg HPPH-mediated PDT was similar to that of 10 mg/kg Photofrin-mediated PDT. Furthermore, HPPH possessed a lower toxicity than Photofrin at the dose that achieved the same efficacy in mice bearing Eca109 subcutaneous tumors. The histopathological findings indicated that the tumor tissues in the photosensitizer (PS)-treated mice demonstrated varying degrees of necrosis. HPPH and Photofrin exhibited vascular cytotoxicity on the treated tumors. In conclusion, the present study demonstrated that the phototoxicity of HPPH-mediated PDT is higher than that of Photofrin-mediated PDT of the same dose. HPPH possessed lower toxicity than Photofrin at the dose that achieved the same efficacy. Therefore, HPPH may be a promising agent for treating human esophageal squamous cell cancer (ESCC).

Efficacy of 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a in photodynamic therapy of human esophageal squamous cancer cells

PubMed Central

WU, DENGPAN; LIU, ZHEN; FU, YANNI; ZHANG, YUAN; TANG, NAN; WANG, QIN; TAO, LIANG

2013-01-01

The present study investigated the effects of 2-(1-hexyloxyethyl)-2-devinylpyro pheophorbide-a (HPPH)-mediated photodynamic therapy (PDT) on in vitro cell survival and in vivo tumor growth derived from human esophageal squamous cancer cells (Eca109). A cell counting kit 8 (CCK8) assay was used to assess the phototoxicity of HPPH-mediated PDT in cultured Eca109 cells. The inhibition of tumor growth was determined by the changes in the relative tumor volume (RTV) and tumor weight. The results revealed that HPPH, in the range of 0.005–1 μg/ml, exhibited no cytotoxicity in the Eca109 cells without light exposure and that the in vitro efficiency of HPPH-mediated PDT was higher compared with that of Photofrin®-mediated PDT. The in vivo results indicated that graded doses of HPPH-mediated PDT significantly inhibited the xenograft tumor growth derived from the Eca109 cells in a dose-dependent manner. The inhibition efficacy of 0.6 and 1.0 mg/kg HPPH-mediated PDT was similar to that of 10 mg/kg Photofrin-mediated PDT. Furthermore, HPPH possessed a lower toxicity than Photofrin at the dose that achieved the same efficacy in mice bearing Eca109 subcutaneous tumors. The histopathological findings indicated that the tumor tissues in the photosensitizer (PS)-treated mice demonstrated varying degrees of necrosis. HPPH and Photofrin exhibited vascular cytotoxicity on the treated tumors. In conclusion, the present study demonstrated that the phototoxicity of HPPH-mediated PDT is higher than that of Photofrin-mediated PDT of the same dose. HPPH possessed lower toxicity than Photofrin at the dose that achieved the same efficacy. Therefore, HPPH may be a promising agent for treating human esophageal squamous cell cancer (ESCC). PMID:24137473

Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma.

PubMed

Krause, Lutz; Nones, Katia; Loffler, Kelly A; Nancarrow, Derek; Oey, Harald; Tang, Yue Hang; Wayte, Nicola J; Patch, Ann Marie; Patel, Kalpana; Brosda, Sandra; Manning, Suzanne; Lampe, Guy; Clouston, Andrew; Thomas, Janine; Stoye, Jens; Hussey, Damian J; Watson, David I; Lord, Reginald V; Phillips, Wayne A; Gotley, David; Smithers, B Mark; Whiteman, David C; Hayward, Nicholas K; Grimmond, Sean M; Waddell, Nicola; Barbour, Andrew P

2016-04-01

The incidence of esophageal adenocarcinoma (EAC) has risen significantly over recent decades. Although survival has improved, cure rates remain poor, with <20% of patients surviving 5 years. This is the first study to explore methylome, transcriptome and ENCODE data to characterize the role of methylation in EAC. We investigate the genome-wide methylation profile of 250 samples including 125 EAC, 19 Barrett's esophagus (BE), 85 squamous esophagus and 21 normal stomach. Transcriptome data of 70 samples (48 EAC, 4 BE and 18 squamous esophagus) were used to identify changes in methylation associated with gene expression. BE and EAC showed similar methylation profiles, which differed from squamous tissue. Hypermethylated sites in EAC and BE were mainly located in CpG-rich promoters. A total of 18575 CpG sites associated with 5538 genes were differentially methylated, 63% of these genes showed significant correlation between methylation and mRNA expression levels. Pathways involved in tumorigenesis including cell adhesion, TGF and WNT signaling showed enrichment for genes aberrantly methylated. Genes involved in chromosomal segregation and spindle formation were aberrantly methylated. Given the recent evidence that chromothripsis may be a driver mechanism in EAC, the role of epigenetic perturbation of these pathways should be further investigated. The methylation profiles revealed two EAC subtypes, one associated with widespread CpG island hypermethylation overlapping H3K27me3 marks and binding sites of the Polycomb proteins. These subtypes were supported by an independent set of 89 esophageal cancer samples. The most hypermethylated tumors showed worse patient survival. © The Author 2016. Published by Oxford University Press.

[Endoscopic screening for upper gastrointestinal second primary malignancies in patients with hypopharyngeal squamous cell carcinoma].

PubMed

Tian, J J; Xu, W; Lyu, Z H; Ma, J K; Cui, P; Sa, N; Cao, H Y

2018-04-07

Objective: To evaluate the usefullness of flexible esophagoscopy and chromoendoscopy with Lugol's solution in the detection of synchronous esophageal neoplasm in patients with hypopharyngeal squamous cell carcinoma (HSCC). Methods: A retrospective review of 96 cases with HSCC that received surgical treatment from March 2016 to March 2017 was accomplished. In these patients, the site of origin were pyriform sinus ( n =75), posterior pharyngeal wall ( n =11) and postcricoid ( n =10). Esophagoscopy was prospectively performed on all patients before treatment for HSCC. All patients underwent conventional white-light endoscopic examination with Lugol chromoendoscopy and narrow band image. Suspicious areas of narrow band image or Lugol-voiding lesions were observed and biopsied. The treatment strategy of primary HSCC was modified according to the presence of synchronous esophageal squamous cell neoplasms by a multidisciplinary approach. Results: Ninety-six patients were enrolled (age ranging from 37-80 years). All patients did not have previous treatment.Histopathological analysis revealed middle to high-grade dysplasia in 5 cases, Tis cancer in 5 cases, cancer in 16 cases and inflammation or normal findings in the others. Four cases were treated with endoscopic submucosal dissection before hypopharygeal surgery, 3 cases with lower esophageal cancers were treated with gastric pull-up combined with free jejunal flap after total circumferential pharyngolaryngectomy (TCPL) and certical esophagectomy, and 14 cases were treated with TCPL, total esophagectomy and gastric pull-up. Conclusions: Esophagoscopy is a feasible and justified procedure in HSCC cases as it enhances the detection of premalignant lesion or second primary cancer. Routine esophagoscopy for detecting synchronous second primary tumor should be recommended for patients with HSCC. The treatment strategy for primary HSCC is modified according to the presence of synchronous second primary tumor.

Three-dimensional positron emission tomography image texture analysis of esophageal squamous cell carcinoma: relationship between tumor 18F-fluorodeoxyglucose uptake heterogeneity, maximum standardized uptake value, and tumor stage.

PubMed

Dong, Xinzhe; Xing, Ligang; Wu, Peipei; Fu, Zheng; Wan, Honglin; Li, Dengwang; Yin, Yong; Sun, Xiaorong; Yu, Jinming

2013-01-01

To explore the relationship of a new PET image parameter, (18)F-fluorodeoxyglucose ((18)F-FDG) uptake heterogeneity assessed by texture analysis, with maximum standardized uptake value (SUV(max)) and tumor TNM staging. Forty consecutive patients with esophageal squamous cell carcinoma were enrolled. All patients underwent whole-body preoperative (18)F-FDG PET/CT. Heterogeneity of intratumoral (18)F-FDG uptake was assessed on the basis of the textural features (entropy and energy) of the three-dimensional images using MATLAB software. The correlations between the textural parameters and SUV(max), histological grade, tumor location, and TNM stage were analyzed. Tumors with higher SUV(max) were seen to be more heterogenous on (18)F-FDG uptake. Significant correlations were observed between T stage and SUV(max) (r(s)=0.390, P=0.013), entropy (rs=0.693, P<0.001), and energy (r(s)=-0.469, P=0.002). Correlations were also found between SUV(max), entropy, energy, and N stage (r(s)=0.326, P=0.04; r(s)=0.501, P=0.001; r(s)=-0.413, P=0.008). The American Joint Committee on Cancer stage correlated significantly with all metabolic parameters. The receiver-operating characteristic curve demonstrated an entropy of 4.699 as the optimal cutoff point for detecting tumors above stage II(b) with an areas under the ROC curve of 0.789 (P<0.001). This study provides initial evidence for the relationship between the new parameter of tumor uptake heterogeneity and the commonly used simplistic parameter of SUV and tumor stage. Our findings suggest a complementary role of these parameters in the staging and prognosis of esophageal squamous cell carcinoma.

Aquaporin-4 antibody positive neuromyelitis optica spectrum disorder associated with esophageal cancer.

PubMed

Kon, Tomoya; Ueno, Tatsuya; Suzuki, Chieko; Nunomura, Jinichi; Igarashi, Shohei; Sato, Tsugumi; Tomiyama, Masahiko

2017-08-15

Autoimmune diseases are sometimes associated with neoplasms. A 70-year-old Japanese woman with myelitis, seropositive for aquaporin-4 (AQP4) antibody, was diagnosed with neuromyelitis optica spectrum disorder (NMOSD); thereafter an esophageal squamous cell carcinoma was identified. Immunohistochemically, her cancer was anti-AQP4 antibody negative. Her symptoms, imaging findings and AQP4 titer markedly improved with corticosteroid and anti-cancer therapies. Although AQP4 may be a paraneoplastic antigen, paraneoplastic syndrome could not be definitively diagnosed in this case. Nevertheless, this is the first report of an association between AQP4 antibody-seropositive NMOSD and esophageal cancer. The possibility of underlying malignancy should be considered in patients diagnosed with NMOSD. Copyright © 2017 Elsevier B.V. All rights reserved.

A human esophageal epithelial cell model for study of radiation induced cancer and DNA repair

NASA Astrophysics Data System (ADS)

Huff, Janice; Patel, Zarana; Hada, Megumi; Cucinotta, Francis A.

For cancer risk assessment in astronauts and for countermeasure development, it is essential to understand the molecular mechanisms of radiation carcinogenesis and how these mechanisms are influenced by exposure to the types of radiation found in space. We are developing an in vitro model system for the study of radiation-induced initiation and progression of esophageal carcinoma. Development of squamous cell carcinoma of the esophagus is associated with radiation exposure, as revealed by the significant enhanced in incidence rates for this type of cancer in the survivors of the atomic bomb detonations in Japan. It is also associated with poor nutritional status and micronutrient deficiencies, which are also important issues for long duration spaceflight. The possible synergies between nutritional issues and radiation exposure are unknown. Here we present the results of preliminary characterization of both normal and hTERT-immortalized esophageal epithelial cells grown in 2-dimensional culture. We analyzed DNA repair capacity by measuring the kinetics of formation and loss of gamma-H2AX foci following radiation exposure. Additionally, we analyzed induction of chromosomal aberrations using 3-color fluorescence in situ hybridization (FISH). Data were generated using both low LET (gamma rays) and high LET ions (1000 MeV/nucleon iron.

Unchanging pattern of prevalence of esophageal cancer, overall and by histological subtype, in the endoscopy service of the main referral hospital in the central region of Rio Grande do Sul State, in Southern Brazil.

PubMed

Fagundes, R B; de Carli, D; Xaubet, R V; Cantarelli, J C

2016-08-01

Squamous cell carcinoma (SCC) and adenocarcinoma (ADC) are the two main histological types of esophageal cancer. Southern Brazil has the highest rates of esophageal cancer in South America, and the most prevalent subtype of esophageal cancer has been SCC. This study assessed the trend changes in the histological types of esophageal cancer, in a 20-year period, in the central region of Rio Grande do Sul State, Brazil. We searched all cases of esophageal cancer from 1993 to 2012 by their histological diagnosis, grouping the patients in 4-year time periods to evaluate time trends. Among 18 441 upper gastrointestinal endoscopies we identified 686 cases of esophageal cancer. Histological study confirmed the diagnosis of SCC in 640 (93.3%) patients and ADC in 46 (6.7%). Overall, 522 men were diagnosed with esophageal carcinoma; from these, 489 (93.6%) presented SCC, and 33 (6.3%) ADC. Among women, 164 had the diagnosis of esophageal cancer, 151 (92%) SCC, and 13 (7.9%) ADC. The proportion found among men and women was 3.1:1, respectively. The prevalence rate of esophageal cancer, along a 20 year-period, remained stable, as well as the rates of SCC and ADC. SCC was the most common type of esophageal cancer, and ADC presented very low prevalence. © 2015 International Society for Diseases of the Esophagus.

Generation and Characterization of an Immortalized Human Esophageal Myofibroblast Line.

PubMed

Niu, Chao; Chauhan, Uday; Gargus, Matthew; Shaker, Anisa

2016-01-01

Stromal cells with a myofibroblast phenotype present in the normal human esophagus are increased in individuals with gastro-esophageal reflux disease (GERD). We have previously demonstrated that myofibroblasts stimulated with acid and TLR4 agonists increase IL-6 and IL-8 secretion using primary cultures of myofibroblasts established from normal human esophagus. While primary cultures have the advantage of reflecting the in vivo environment, a short life span and unavoidable heterogeneity limits the usefulness of this model in larger scale in vitro cellular signaling studies. The major aim of this paper therefore was to generate a human esophageal myofibroblast line with an extended lifespan. In the work presented here we have generated and characterized an immortalized human esophageal myofibroblast line by transfection with a commercially available GFP-hTERT lentivirus. Immortalized human esophageal myofibroblasts demonstrate phenotypic, genotypic and functional similarity to primary cultures of esophageal myofibroblasts we have previously described. We found that immortalized esophageal myofibroblasts retain myofibroblast spindle-shaped morphology at low and high confluence beyond passage 80, and express α-SMA, vimentin, and CD90 myofibroblast markers. Immortalized human esophageal myofibroblasts also express the putative acid receptor TRPV1 and TLR4 and retain the functional capacity to respond to stimuli encountered in GERD with secretion of IL-6. Finally, immortalized human esophageal myofibroblasts also support the stratified growth of squamous esophageal epithelial cells in 3D organotypic cultures. This newly characterized immortalized human esophageal myofibroblast cell line can be used in future cellular signaling and co-culture studies.

Increased expression of HSP27 inhibits invasion and metastasis in human esophageal squamous cell carcinoma.

PubMed

Xue, Lin; Yang, Lei; Jin, Zhi-an; Gao, Fei; Kang, Jian-qin; Xu, Guang-hui; Liu, Bing; Li, Hong; Wang, Xiao-juan; Liu, Li-juan; Wang, Biao-luo; Liang, Shu-hui; Ding, Jie

2014-07-01

Previous studies have indicated that heat shock protein 27 (HSP27) had high correlation with the development and progression in several tumors. However, the roles of HSP27 in esophageal squamous cell carcinoma (ESCC) were uncertain. The aim in this study is to investigate the potential roles of HSP27 in the metastasis of ESCC. The expression of HSP27 in ESCC tissues and four human esophageal cancer cell lines were examined by immunohistochemistry and Western blotting, respectively. Wound healing assays, transwell assays, and in vivo assays were used to identify the differences of metastasis potential between normal and HSP27 overexpressed cells. HSP27 expression was downregulated in cancer tissue compared to the matched normal tissue. And the positive staining was mainly located in the cytoplasm. Statistical analyses showed that the expression of HSP27 in ESCC was significantly correlated with the tumor differentiation (P = 0.023), the patient's TNM stage (P = 0.013), lymph metastasis (P = 0.020), and distant metastasis (P = 0.017). HSP27 expression was significantly lower in highly metastatic cells than the less ones. The metastatic potentials of EC9706-H and EC109-H cells were higher than EC9706-L and EC109-L cells. In vitro and in vivo assays showed that overexpression of HSP27 in highly metastatic cells dramatically decreased their metastatic capacity. This study indicated that the expression level of HSP27 may be inversely correlated with the metastasis behavior of ESCC, and HSP27 may play an important role in this progression. HSP27 may be a potential molecular target for the therapy and prognosis of patients with ESCC.

Three-dimensional conformal radiation therapy for esophageal squamous cell carcinoma: is elective nodal irradiation necessary?

PubMed

Zhao, Kuai-le; Ma, Jin-bo; Liu, Guang; Wu, Kai-liang; Shi, Xue-hui; Jiang, Guo-liang

2010-02-01

To evaluate the local control, survival, and toxicity associated with three-dimensional conformal radiotherapy (3D-CRT) for squamous cell carcinoma (SCC) of the esophagus, to determine the appropriate target volumes, and to determine whether elective nodal irradiation is necessary in these patients. A prospective study of 3D-CRT was undertaken in patients with esophageal SCC without distant metastases. Patients received 68.4 Gy in 41 fractions over 44 days using late-course accelerated hyperfractionated 3D-CRT. Only the primary tumor and positive lymph nodes were irradiated. Isolated out-of-field regional nodal recurrence was defined as a recurrence in an initially uninvolved regional lymph node. All 53 patients who made up the study population tolerated the irradiation well. No acute or late Grade 4 or 5 toxicity was observed. The median survival time was 30 months (95% confidence interval, 17.7-41.8). The overall survival rate at 1, 2, and 3 years was 77%, 56%, and 41%, respectively. The local control rate at 1, 2, and 3 years was 83%, 74%, and 62%, respectively. Thirty-nine of the 53 patients (74%) showed treatment failure. Seventeen of the 39 (44%) developed an in-field recurrence, 18 (46%) distant metastasis with or without regional failure, and 3 (8%) an isolated out-of-field nodal recurrence only. One patient died of disease in an unknown location. In patients treated with 3D-CRT for esophageal SCC, the omission of elective nodal irradiation was not associated with a significant amount of failure in lymph node regions not included in the planning target volume. Local failure and distant metastases remained the predominant problems. Copyright 2010 Elsevier Inc. All rights reserved.

Protein-coding genes combined with long noncoding RNA as a novel transcriptome molecular staging model to predict the survival of patients with esophageal squamous cell carcinoma.

PubMed

Guo, Jin-Cheng; Wu, Yang; Chen, Yang; Pan, Feng; Wu, Zhi-Yong; Zhang, Jia-Sheng; Wu, Jian-Yi; Xu, Xiu-E; Zhao, Jian-Mei; Li, En-Min; Zhao, Yi; Xu, Li-Yan

2018-04-09

Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal carcinoma in China. This study was to develop a staging model to predict outcomes of patients with ESCC. Using Cox regression analysis, principal component analysis (PCA), partitioning clustering, Kaplan-Meier analysis, receiver operating characteristic (ROC) curve analysis, and classification and regression tree (CART) analysis, we mined the Gene Expression Omnibus database to determine the expression profiles of genes in 179 patients with ESCC from GSE63624 and GSE63622 dataset. Univariate cox regression analysis of the GSE63624 dataset revealed that 2404 protein-coding genes (PCGs) and 635 long non-coding RNAs (lncRNAs) were associated with the survival of patients with ESCC. PCA categorized these PCGs and lncRNAs into three principal components (PCs), which were used to cluster the patients into three groups. ROC analysis demonstrated that the predictive ability of PCG-lncRNA PCs when applied to new patients was better than that of the tumor-node-metastasis staging (area under ROC curve [AUC]: 0.69 vs. 0.65, P < 0.05). Accordingly, we constructed a molecular disaggregated model comprising one lncRNA and two PCGs, which we designated as the LSB staging model using CART analysis in the GSE63624 dataset. This LSB staging model classified the GSE63622 dataset of patients into three different groups, and its effectiveness was validated by analysis of another cohort of 105 patients. The LSB staging model has clinical significance for the prognosis prediction of patients with ESCC and may serve as a three-gene staging microarray.

NY-ESO-1 autoantibody as a tumor-specific biomarker for esophageal cancer: screening in 1969 patients with various cancers.

PubMed

Oshima, Yoko; Shimada, Hideaki; Yajima, Satoshi; Nanami, Tatsuki; Matsushita, Kazuyuki; Nomura, Fumio; Kainuma, Osamu; Takiguchi, Nobuhiro; Soda, Hiroaki; Ueda, Takeshi; Iizasa, Toshihiko; Yamamoto, Naoto; Yamamoto, Hiroshi; Nagata, Matsuo; Yokoi, Sana; Tagawa, Masatoshi; Ohtsuka, Seiko; Kuwajima, Akiko; Murakami, Akihiro; Kaneko, Hironori

2016-01-01

Although serum NY-ESO-1 antibodies (s-NY-ESO-1-Abs) have been reported in patients with esophageal carcinoma, this assay system has not been used to study a large series of patients with various other cancers. Serum samples of 1969 cancer patients [esophageal cancer (n = 172), lung cancer (n = 269), hepatocellular carcinoma (n = 91), prostate cancer (n = 358), gastric cancer (n = 313), colorectal cancer (n = 262), breast cancer (n = 365)] and 74 healthy individuals were analyzed using an originally developed enzyme-linked immunosorbent assay system for s-NY-ESO-1-Abs. The optical density cut-off value, determined as the mean plus three standard deviations for serum samples from the healthy controls, was fixed at 0.165. Conventional tumor markers were also evaluated in patients with esophageal carcinoma. The positive rate of s-NY-ESO-1-Abs in patients with esophageal cancer (31 %) was significantly higher than that in the other groups: patients with lung cancer (13 %), patients with hepatocellular carcinoma (11 %), patients with prostate cancer (10 %), patients with gastric cancer (10 %), patients with colorectal cancer (8 %), patients with breast cancer (7 %), and healthy controls (0 %). The positive rate of s-NY-ESO-1-Abs was comparable to that of serum p53 antibodies (33 %), squamous cell carcinoma antigen (36 %), carcinoembryonic antigen (26 %), and CYFRA 21-1 (18 %) and gradually increased with the tumor stage. The positive rate of s-NY-ESO-1-Abs was significantly higher in patients with esophageal cancer than in patients with the other types of cancers. On the basis of its high specificity and sensitivity, even in patients with stage I tumors, s-NY-ESO-1-Abs may be one of the first choices for esophageal cancer.

Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma.

PubMed

Hao, Jia-Jie; Lin, De-Chen; Dinh, Huy Q; Mayakonda, Anand; Jiang, Yan-Yi; Chang, Chen; Jiang, Ye; Lu, Chen-Chen; Shi, Zhi-Zhou; Xu, Xin; Zhang, Yu; Cai, Yan; Wang, Jin-Wu; Zhan, Qi-Min; Wei, Wen-Qiang; Berman, Benjamin P; Wang, Ming-Rong; Koeffler, H Phillip

2016-12-01

Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, but little is known about its spatial intratumoral heterogeneity (ITH) and temporal clonal evolutionary processes. To address this, we performed multiregion whole-exome sequencing on 51 tumor regions from 13 ESCC cases and multiregion global methylation profiling for 3 of these 13 cases. We found an average of 35.8% heterogeneous somatic mutations with strong evidence of ITH. Half of the driver mutations located on the branches of tumor phylogenetic trees targeted oncogenes, including PIK3CA, NFE2L2 and MTOR, among others. By contrast, the majority of truncal and clonal driver mutations occurred in tumor-suppressor genes, including TP53, KMT2D and ZNF750, among others. Interestingly, phyloepigenetic trees robustly recapitulated the topological structures of the phylogenetic trees, indicating a possible relationship between genetic and epigenetic alterations. Our integrated investigations of spatial ITH and clonal evolution provide an important molecular foundation for enhanced understanding of tumorigenesis and progression in ESCC.

Essential role of STX6 in esophageal squamous cell carcinoma growth and migration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Du, Jin; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028; Liu, Xiang

Abnormalities in endosomes, or dysregulation in their trafficking, play an important role directly in many diseases including oncogenesis. Syntaxin-6 (STX6) is involved in diverse cellular functions in a variety of cell types and has been shown to regulate many intracellular membrane trafficking events such as endocytosis, recycling and anterograde and retrograde trafficking. However, its expression pattern and biological functions in esophageal squamous cell carcinoma (ESCC) remained unknown. Here, we have found that the expression of STX6 was up-regulated in ESCC samples, its expression was significantly correlated with tumor size, histological differentiation, lymph node metastasis and depth. On one hand, STX6more » silencing inhibited ESCC cells viability and proliferation in a p53-dependent manner. On the other hand, STX6 effect integrin trafficking and regulate ESCC cells migration. Taken together, our study revealed the oncogenic roles of STX6 in the progression of ESCC, and it might be a valuable target for ESCC therapy.« less

A pilot study of nimotuzumab combined with cisplatin and 5-FU in patients with advanced esophageal squamous cell carcinoma

PubMed Central

Ling, Yang; Chen, Jia; Tao, Min; Chu, Xiaoyuan; Zhang, Xizhi

2012-01-01

Objective To observe the short-term effect and adverse reaction of Nimotuzumab in combination with chemotherapy on advanced esophageal squamous cell carcinoma (ESCC). Method 19 patients were treated with the following protocol: Nimotuzumab 400mg/time/week in the 1st week, 200mg/time/week from the 2nd to 8th week, intravenous drip (IVD); Cisplatin 80 mg/m2, IVD, 4 weeks a cycle and repeated again; 5-FU 750 mg/m2, continuous 24-hours pump-in × 5 days, 4 weeks a cycle and repeated again. Result 16 of all 19 patients can be evaluated. After treatment, RP is 42.1% (95% CI, 19.9-64.3%) and DCR is 68.4%; the main side effects include arrest of bone marrow, gastrointestinal reactions, asthenia, etc. Conclusion Nimotuzumab in combination with cisplatin/5-FU regimens in patients with advanced ESCC is safe and effective, which deserves a further expanded sample research. PMID:22295168

Decoy receptor 3 expression in esophageal squamous cell carcinoma: correlation with tumour invasion and metastasis.

PubMed

Xiong, Gang; Guo, Hong; Ge, Xiaodong; Xu, Xueqing; Yang, Xiaoya; Yang, Kang; Jiang, Yaoguang; Bai, Yun

2011-03-01

Decoy receptor 3 (DcR3) is a soluble receptor, which can bind to and inactivate the apoptosis-inducing ligands. We studied a possible association between DcR3 expression and clinicopathologic features in patients with esophageal squamous cell carcinoma (ESCC). The mRNA expression of DcR3 was examined by RT-PCR in 109 primary ESCC patients. For the 52 pairs of DcR3 positive tissues, the protein expression was determined by immunohistochemistry. There was a strong correlation among DcR3 mRNA expression and tumor invasion (P=0.01) and lymph node metastasis (P=0.036). We also found that there was a correlation between DcR3 overexpression with lymph node metastasis (P=0.014) in 52 pairs of DCR3 mRNA positive tissues. Our finding suggested that the overexpression of DcR3 is significantly related with ESCC clinical staging. DcR3 might be a candidate as a tumor specific biomarker for ESCC.

A novel rapid quantitative method reveals stathmin-1 as a promising marker for esophageal squamous cell carcinoma.

PubMed

Yan, Lu; Dong, Xiu; Gao, Jiajia; Liu, Fang; Zhou, Lanping; Sun, Yulin; Zhao, Xiaohang

2018-05-01

Stathmin-1 is a microtubule depolymerization protein that regulates cell division, growth, migration, and invasion. Overexpression of stathmin-1 has been observed to be associated with metastasis, poor prognosis, and chemoresistance in various human cancers. Our previous studies found that serum stathmin-1 was significantly elevated in patients with esophageal squamous cell carcinoma (ESCC) by ELISAs. Here, we constructed high-affinity monoclonal antibodies and then developed a competitive AlphaLISA for rapid, accurate quantitation of stathmin-1 in serum. Compared to ELISA, our homogeneous AlphaLISA showed better sensitivity and accuracy, a lower limit of detection, and a wider linear range. The measurements of nearly 1000 clinical samples showed that serum stathmin-1 level increased dramatically in patients with squamous cell carcinoma (SCC), especially in ESCC, with a sensitivity and a specificity of 81% and 94%, respectively. Even for early stage ESCC, stathmin-1 achieved an area under the receiver operating characteristic curve (AUC) of 0.88. Meanwhile, raised concentrations of stathmin-1 were associated with lymph node metastasis and advanced cancer stage. Notably, various types of SCC showed significantly higher AUCs in serum stathmin-1 detection compared to adenocarcinoma. Furthermore, we confirmed that stathmin-1 was enriched in the oncogenic exosomes, which can explain the reason why it enters into the blood to serve as a tumor surrogate. In conclusion, this large-scale and systematic study of serum stathmin-1 measured by our newly established AlphaLISA showed that stathmin-1 is a very promising diagnostic and predictive marker for SCC in the clinic, especially for ESCC. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Aberrant chimeric RNA GOLM1-MAK10 encoding a secreted fusion protein as a molecular signature for human esophageal squamous cell carcinoma

PubMed Central

Zhang, Hao; Lin, Wan; Kannan, Kalpana; Luo, Liming; Li, Jing; Chao, Pei-Wen; Wang, Yan; Chen, Yu-Ping; Gu, Jiang; Yen, Laising

2013-01-01

It is increasingly recognized that chimeric RNAs may exert a novel layer of cellular complexity that contributes to oncogenesis and cancer progression, and could be utilized as molecular biomarkers and therapeutic targets. To date yet no fusion chimeric RNAs have been identified in esophageal cancer, the 6th most frequent cause of cancer death in the world. While analyzing the expression of 32 recurrent cancer chimeric RNAs in esophageal squamous cell carcinoma (ESCC) from patients and cancer cell lines, we identified GOLM1-MAK10, as a highly cancer-enriched chimeric RNA in ESCC. In situ hybridization revealed that the expression of the chimera is largely restricted to cancer cells in patient tumors, and nearly undetectable in non-neoplastic esophageal tissue from normal subjects. The aberrant chimera closely correlated with histologic differentiation and lymph node metastasis. Furthermore, we demonstrate that chimera GOLM1-MAK10 encodes a secreted fusion protein. Mechanistic studies reveal that GOLM1-MAK10 is likely derived from transcription read-through/splicing rather than being generated from a fusion gene. Collectively, these findings provide novel insights into the molecular mechanism involved in ESCC and provide a novel potential target for future therapies. The secreted fusion protein translated from GOLM1-MAK10 could also serve as a unique protein signature detectable by standard non-invasive assays. These observations are critical as there is no clinically useful molecular signature available for detecting this deadly disease or monitoring the treatment response. PMID:24243830

Prechemotherapy neutrophil : lymphocyte ratio is superior to the platelet : lymphocyte ratio as a prognostic indicator for locally advanced esophageal squamous cell cancer treated with neoadjuvant chemotherapy.

PubMed

Ji, W H; Jiang, Y H; Ji, Y L; Li, B; Mao, W M

2016-07-01

The study aimed to evaluate the prognostic significance of prechemotherapy neutrophil to lymphocyte ratio and platelet to lymphocyte ratio, and preoperative neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in locally advanced esophageal squamous cell cancer. We analyzed retrospectively locally advanced esophageal squamous cell cancer patients who had received neoadjuvant chemotherapy before undergoing a radical esophagectomy between 2009 and 2012. Neutrophil to lymphocyte ratio and platelet to lymphocyte ratio before chemotherapy and before the surgery were calculated. Univariate analyses showed that prechemotherapy neutrophil to lymphocyte ratio >5 (P = 0.048, hazard ratio = 2.86; 95% confidence interval: 1.01-8.12) and prechemotherapy platelet to lymphocyte ratio >130 (P = 0.025, hazard ratio = 5.50; 95% confidence interval: 1.23-24.55) were associated significantly with overall survival (OS), and prechemotherapy platelet to lymphocyte ratio >130 (P = 0.026, hazard ratio = 3.18; 95% confidence interval: 1.15-8.85) was associated significantly with progression-free survival. However, only prechemotherapy neutrophil to lymphocyte ratio >5 (P = 0.024, hazard ratio = 3.50; 95% confidence interval: 1.18-10.40) remained significantly associated with OS in multivariate analyses. Neither preoperative neutrophil to lymphocyte ratio nor platelet to lymphocyte ratio was associated with OS or progression-free survival. The prechemotherapy neutrophil to lymphocyte ratio >5 to preoperative neutrophil to lymphocyte ratio ≤5 group showed significantly worse OS than the prechemotherapy neutrophil to lymphocyte ratio ≤5 to preoperative neutrophil to lymphocyte ratio ≤5 group (P = 0.050). The prechemotherapy platelet to lymphocyte ratio >130 to preoperative platelet to lymphocyte ratio ≤130 group (P = 0.016) and platelet to lymphocyte ratio >130 to preoperative platelet to lymphocyte ratio >130 group (P = 0.042) showed significantly worse OS than the prechemotherapy platelet to lymphocyte ratio ≤30 to preoperative platelet to lymphocyte ratio ≤130 group. In conclusions, prechemotherapy neutrophil to lymphocyte ratio is an independent prognostic factor for OS in patients with advanced esophageal squamous cell cancer treated with neoadjuvant chemotherapy, and, as an adverse prognostic predictor, increased prechemotherapy neutrophil to lymphocyte ratio is superior to platelet to lymphocyte ratio. Maintaining a low neutrophil to lymphocyte ratio and platelet to lymphocyte ratio throughout treatment is a predictor of better OS. © 2015 International Society for Diseases of the Esophagus.

Long-Term Outcomes and Toxicity of Concurrent Paclitaxel and Radiotherapy for Locally Advanced Head-and-Neck Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Citrin, Deborah; Mansueti, John; Likhacheva, Anna

2009-07-15

Purpose: To report the long-term outcomes and toxicity of a regimen of infusion paclitaxel delivered concurrently with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck. Patients and Methods: Between 1995 and 1999, 35 patients with nonmetastatic, Stage III or IV squamous cell carcinoma of the head and neck were treated with three cycles of paclitaxel as a 120-h continuous infusion beginning on Days 1, 21, and 42, concurrent with radiotherapy. The initial 16 patients received 105 mg/m{sup 2}/cycle, and the subsequent 19 patients received 120 mg/m{sup 2}/cycle. External beam radiotherapy was delivered to amore » dose of 70.2-72 Gy at five fractions weekly. Patients were followed to evaluate the disease outcomes and late toxicity of this regimen. Results: The median follow-up for all patients was 56.5 months. The median survival was 56.5 months, and the median time to local recurrence was not reached. Of the 35 patients, 15 (43%) developed hypothyroidism. Of the 33 patients who underwent percutaneous endoscopic gastrostomy tube placement, 11 were percutaneous endoscopic gastrostomy tube dependent until death or their last follow-up visit. Also, 5 patients (14%) required a tracheostomy until death, and 3 (9%) developed a severe esophageal stricture. All evaluated long-term survivors exhibited salivary hypofunction. Fibrosis in the radiation field occurred in 24 patients (69%). Conclusion: The results of our study have shown that concurrent chemoradiotherapy with a 120-h infusion of paclitaxel provides long-term local control and survival in patients with squamous cell carcinoma of the head and neck. Xerostomia, hypothyroidism, esophageal and pharyngeal complications, and subcutaneous fibrosis were common long-term toxicities; however, the vast majority of toxicities were grade 1 or 2.« less

Esophageal Cancer in Golestan Province, Iran: A Review of Genetic Susceptibility and Environmental Risk Factors

PubMed Central

Gholipour, Mahin; Islami, Farhad; Roshandel, Gholamreza; Khoshnia, Masoud; Badakhshan, Abbas; Moradi, Abdolvahab; Malekzadeh, Reza

2016-01-01

Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor that is typically diagnosed only when the tumor has gained remarkable size, extended to peripheral tissues, and led to dysphagia. Five-year survival of advanced cancer is still very poor (19%), even with improved surgical techniques and adjuvant chemoradiation therapy. Therefore, early detection and prevention are the most important strategies to reduce the burden of ESCC. Our review will focus on the studies conducted in Golestan province, an area with a high prevalence of ESCC in northern Iran. We review three aspects of the research literature on ESCC: epidemiological features, environmental factors (including substance abuse, environmental contaminants, dietary factors, and human papillomavirus [HPV]), and molecular factors (including oncogenes, tumor suppressor genes, cell cycle regulatory proteins, and other relevant biomarkers). Epidemiological and experimental data suggest that some chemicals and lifestyle factors, including polycyclic aromatic hydrocarbons (PAHs), cigarette smoking, opium use, and hot tea drinking are associated with the development of ESCC in Golestan. HPV infects the esophageal epithelium, but so far, no firm evidence of its involvement in esophageal carcinogenesis has been provided. Some of these factors, notably hot tea drinking, may render the esophageal mucosa more susceptible to injury by other carcinogens. There are few studies at molecular level on ESCC in Golestan. Increasing awareness about the known risk factors of ESCC could potentially reduce the burden of ESCC in the region. Further studies on risk factors, identifying high risk populations, and early detection are needed. PMID:27957288

Genetic polymorphisms of alcohol and aldehyde dehydrogenases and glutathione S-transferase M1 and drinking, smoking, and diet in Japanese men with esophageal squamous cell carcinoma.

PubMed

Yokoyama, Akira; Kato, Hoichi; Yokoyama, Tetsuji; Tsujinaka, Toshimasa; Muto, Manabu; Omori, Tai; Haneda, Tatsumasa; Kumagai, Yoshiya; Igaki, Hiroyasu; Yokoyama, Masako; Watanabe, Hiroshi; Fukuda, Haruhiko; Yoshimizu, Haruko

2002-11-01

The genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2), alcohol dehydrogenase-2 (ADH2), ADH3, and glutathione S-transferase M1 (GSTM1) influence the metabolism of alcohol and other carcinogens. The ALDH2*1/2*2 genotype, which encodes inactive ALDH2, and ADH2*1/2*1, which encodes the low-activity form of ADH2, enhance the risk for esophageal cancer in East Asian alcoholics. This case-control study of whether the enzyme-related vulnerability for esophageal cancer can be extended to a general population involved 234 Japanese men with esophageal squamous cell carcinoma and 634 cancer-free Japanese men who received annual health checkups. The GSTM1 genotype was not associated with the risk for this cancer. Light drinkers (1-8.9 units/week) with ALDH2*1/2*2 had an esophageal cancer risk 5.82 times that of light drinkers with ALDH2*1/2*1 (reference category), and their risk was similar to that of moderate drinkers (9-17.9 units/week) with ALDH2*1/2*1 (odds ratio = 5.58). The risk for moderate drinkers with ALDH2*1/2*2 (OR = 55.84) exceeded that for heavy drinkers (18+ units/week) with ALDH2*1/2*1 (OR = 10.38). Similar increased risks were observed for those with ADH2*1/2*1. A multiple logistic model including ALDH2, ADH2, and ADH3 genotypes showed that the ADH3 genotype does not significantly affect the risk for esophageal cancer. For individuals with both ALDH2*1/2*2 and ADH2*1/2*1, the risk of esophageal cancer was enhanced in a multiplicative fashion (OR = 30.12), whereas for those with either ALDH2*1/2*2 or ADH2*1/2*1 alone the ORs were 7.36 and 4.11. In comparison with the estimated population-attributable risks for preference for strong alcoholic beverages (30.7%), smoking (53.6%) and for lower intake of green and yellow vegetables (25.7%) and fruit (37.6%), an extraordinarily high proportion of the excessive risk for esophageal cancer in the Japanese males can be attributed to drinking (90.9%), particularly drinking by persons with inactive heterozygous ALDH2 (68.5%). Education regarding these risky conditions in connection with ALDH2 and ADH2 is vitally important in a new strategic approach aimed at preventing esophageal cancer in East Asians.

Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration

PubMed Central

Giroux, Véronique; Lento, Ashley A.; Islam, Mirazul; Pitarresi, Jason R.; Kharbanda, Akriti; Hamilton, Kathryn E.; Whelan, Kelly A.; Long, Apple; Rhoades, Ben; Tang, Qiaosi; Nakagawa, Hiroshi; Lengner, Christopher J.; Bass, Adam J.; Wileyto, E. Paul; Klein-Szanto, Andres J.; Wang, Timothy C.; Rustgi, Anil K.

2017-01-01

The esophageal lumen is lined by a stratified squamous epithelium comprised of proliferative basal cells that differentiate while migrating toward the luminal surface and eventually desquamate. Rapid epithelial renewal occurs, but the specific cell of origin that supports this high proliferative demand remains unknown. Herein, we have described a long-lived progenitor cell population in the mouse esophageal epithelium that is characterized by expression of keratin 15 (Krt15). Genetic in vivo lineage tracing revealed that the Krt15 promoter marks a long-lived basal cell population able to self-renew, proliferate, and generate differentiated cells, consistent with a progenitor/stem cell population. Transcriptional profiling demonstrated that Krt15+ basal cells are molecularly distinct from Krt15– basal cells. Depletion of Krt15-derived cells resulted in decreased proliferation, thereby leading to atrophy of the esophageal epithelium. Further, Krt15+ cells were radioresistant and contributed to esophageal epithelial regeneration following radiation-induced injury. These results establish the presence of a long-lived and indispensable Krt15+ progenitor cell population that provides additional perspective on esophageal epithelial biology and the widely prevalent diseases that afflict this epithelium. PMID:28481227

Radiation therapy for gastric wall metastasis from esophageal carcinoma.

PubMed

Hashimoto, Naoko; Iwazawa, Jin; Abe, Hisashi; Mitani, Takashi; Kagawa, Kazufumi

2010-04-01

An 86-year-old man with dysphagia underwent gastrointestinal fiberscopy (GIF) and was found to have a circumferential type 3 advanced carcinoma in the upper thoracic esophagus and a type 2 tumor in the posterior wall of the gastric body. Microscopic examination of biopsy specimens of both tumors demonstrated moderately differentiated squamous cell carcinoma. He was diagnosed as having stage IVb (T3N0M1b) esophageal carcinoma with gastric wall metastasis. A total of 60 Gy in 30 fractions of three-dimensional conformal radiation therapy (3D-CRT) was first administered to the esophageal carcinoma, next to the gastric wall metastasis. Concurrent chemotherapy was not given because of the patient's refusal. No subjective morbidity was observed during the treatment. In the GIF study immediately after 3D-CRT, both esophageal and gastric wall tumors had attained a complete response. The dysphagia dissolved as the esophageal tumor shrunk. The patient has been doing well for 17 months after the start of 3D-CRT. No local recurrence was observed in either the esophagus or the stomach during follow-up GIF. Considering the dismal prognosis of esophageal carcinoma patients with intramural metastasis to the stomach, a watchful follow-up is needed.

Clinical and Molecular Characteristics of Squamous Cell Carcinomas From Fanconi Anemia Patients

PubMed Central

van Zeeburg, Hester J. T.; Snijders, Peter J. F.; Wu, Thijs; Gluckman, Eliane; Soulier, Jean; Surralles, Jordi; Castella, Maria; van der Wal, Jacqueline E.; Wennerberg, Johan; Califano, Joseph; Velleuer, Eunike; Dietrich, Ralf; Ebell, Wolfram; Bloemena, Elisabeth; Joenje, Hans; Leemans, C. René

2008-01-01

Fanconi anemia is a recessively inherited disease that is characterized by congenital abnormalities, bone marrow failure, and a predisposition to develop cancer, particularly squamous cell carcinomas (SCCs) in the head and neck and anogenital regions. Previous studies of Fanconi anemia SCCs, mainly from US patients, revealed the presence of high-risk human papillomavirus (HPV) DNA in 21 (84%) of 25 tumors analyzed. We examined a panel of 21 SCCs mainly from European Fanconi anemia patients (n = 19 FA patients; 16 head and neck squamous cell carcinomas [HNSCCs], 2 esophageal SCCs, and 3 anogenital SCCs) for their clinical and molecular characteristics, including patterns of allelic loss, TP53 mutations, and the presence of HPV DNA by GP5+/6+ polymerase chain reaction. HPV DNA was detected in only two (10%) of 21 tumors (both anogenital SCCs) but in none of the 16 HNSCCs. Of the 18 tumors analyzed, 10 contained a TP53 mutation. The patterns of allelic loss were comparable to those generally found in sporadic SCCs. Our data show that HPV does not play a major role in squamous cell carcinogenesis in this cohort of Fanconi anemia patients and that the Fanconi anemia SCCs are genetically similar to sporadic SCCs despite having a different etiology. PMID:19001603

Identification of the layered morphology of the esophageal wall by optical coherence tomography

PubMed Central

Yokosawa, Satoshi; Koike, Tomoyuki; Kitagawa, Yasushi; Hatta, Waku; Uno, Kaname; Abe, Yasuhiko; Iijima, Katsunori; Imatani, Akira; Ohara, Shuichi; Shimosegawa, Tooru

2009-01-01

AIM: To assess each layer of the optical coherence tomography (OCT) image of the esophageal wall with reference to the histological structure. METHODS: Resected specimens of fresh pig esophagus was used as a model for the esophageal wall. We injected cyanoacrylate adhesive into the specimens to create a marker, and scanned them using a miniature OCT probe. The localization of these markers was assessed in the OCT images. Then we compared the OCT-imaged morphology with the corresponding histological section, guided by the cyanoacrylate adhesive markers. We prepared a second set of experiments using nylon sutures as markers. RESULTS: The OCT image of the esophageal specimen has a clear five-layered morphology. First, it consisted of a relatively less reflective layer; second, a more reflective layer; third, a less reflective layer; fourth, a more reflective layer; and fifth, a less reflective layer. Comparing the OCT images with marked histological sections showed that the first layer corresponded to stratified squamous epithelium; the second to lamina propria; the third to muscularis mucosa; fourth, submucosa; and fifth, muscularis propria with deeper structures of the esophageal wall. CONCLUSION: We demonstrated that the OCT image of the normal esophageal wall showed a five-layered morphology, which corresponds to histological esophageal wall components. PMID:19764091

Identification of the layered morphology of the esophageal wall by optical coherence tomography.

PubMed

Yokosawa, Satoshi; Koike, Tomoyuki; Kitagawa, Yasushi; Hatta, Waku; Uno, Kaname; Abe, Yasuhiko; Iijima, Katsunori; Imatani, Akira; Ohara, Shuichi; Shimosegawa, Tooru

2009-09-21

To assess each layer of the optical coherence tomography (OCT) image of the esophageal wall with reference to the histological structure. Resected specimens of fresh pig esophagus was used as a model for the esophageal wall. We injected cyanoacrylate adhesive into the specimens to create a marker, and scanned them using a miniature OCT probe. The localization of these markers was assessed in the OCT images. Then we compared the OCT-imaged morphology with the corresponding histological section, guided by the cyanoacrylate adhesive markers. We prepared a second set of experiments using nylon sutures as markers. The OCT image of the esophageal specimen has a clear five-layered morphology. First, it consisted of a relatively less reflective layer; second, a more reflective layer; third, a less reflective layer; fourth, a more reflective layer; and fifth, a less reflective layer. Comparing the OCT images with marked histological sections showed that the first layer corresponded to stratified squamous epithelium; the second to lamina propria; the third to muscularis mucosa; fourth, submucosa; and fifth, muscularis propria with deeper structures of the esophageal wall. We demonstrated that the OCT image of the normal esophageal wall showed a five-layered morphology, which corresponds to histological esophageal wall components.

Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

PubMed Central

Ahrens, Theresa D; Timme, Sylvia; Hoeppner, Jens; Ostendorp, Jenny; Hembach, Sina; Follo, Marie; Hopt, Ulrich T; Werner, Martin; Busch, Hauke; Boerries, Melanie; Lassmann, Silke

2015-01-01

Esophageal cancers are highly aggressive tumors with poor prognosis despite some recent advances in surgical and radiochemotherapy treatment options. This study addressed the feasibility of drugs targeting epigenetic modifiers in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells. We tested inhibition of histone deacetylases (HDACs) by SAHA, MS-275, and FK228, inhibition of DNA methyltransferases by Azacytidine (AZA) and Decitabine (DAC), and the effect of combination treatment using both types of drugs. The drug targets, HDAC1/2/3 and DNMT1, were expressed in normal esophageal epithelium and tumor cells of ESCC or EAC tissue specimens, as well as in non-neoplastic esophageal epithelial (Het-1A), ESCC (OE21, Kyse-270, Kyse-410), and EAC (OE33, SK-GT-4) cell lines. In vitro, HDAC activity, histone acetylation, and p21 expression were similarly affected in non-neoplastic, ESCC, and EAC cell lines post inhibitor treatment. Combined MS-275/AZA treatment, however, selectively targeted esophageal cancer cell lines by inducing DNA damage, cell viability loss, and apoptosis, and by decreasing cell migration. Non-neoplastic Het-1A cells were protected against HDACi (MS-275)/AZA treatment. RNA transcriptome analyses post MS-275 and/or AZA treatment identified novel regulated candidate genes (up: BCL6, Hes2; down: FAIM, MLKL), which were specifically associated with the treatment responses of esophageal cancer cells. In summary, combined HDACi/AZA treatment is efficient and selective for the targeting of esophageal cancer cells, despite similar target expression of normal and esophageal cancer epithelium, in vitro and in human esophageal carcinomas. The precise mechanisms of action of treatment responses involve novel candidate genes regulated by HDACi/AZA in esophageal cancer cells. Together, targeting of epigenetic modifiers in esophageal cancers may represent a potential future therapeutic approach. PMID:25923331

Etiology and Pathogenesis of Idiopathic Achalasia.

PubMed

Pressman, Amanda; Behar, Jose

2017-03-01

This review examines the etiology and pathogenesis of idiopathic achalasia. This disease is clinically characterized by dysphagia of solids and liquids due to the presence of simultaneous or absent esophageal contractions and impaired or absent relaxation of the lower esophageal sphincter. It includes a review of (a) etiology and pathogenesis of this inflammatory process that damage the ganglion cells of the Auerbach plexus that is limited to the esophagus; (b) genetic abnormalities and polymorphisms associated with this disease that may help explain its heterogeneity expressed by the different motility abnormalities of its phenotypes as well as differences in its clinical progression. These different genetic abnormalities may be responsible for the slow progression of types I or II phenotypes; (c) indirect evidence of viruses present in these patients that may initiate its development; (d) the abnormalities of the muscle layer that may be responsible for the dilation of the body of the esophagus that ultimately causes the sigmoid-like esophagus in the very last phase of this disease. This progression to the end-stage phase tends to occur in about 5% of patients. And, (e) the chronic inflammatory abnormalities in the squamous mucosa that may be the cause of the dysplastic and neoplastic changes that may lead to squamous cell carcinoma whose incidence in this disease is increased. These mucosal abnormalities are usually present in patients with markedly dilated body of the esophagus and severe food stasis.

HPV Infection in Esophageal Squamous Cell Carcinoma and Its Relationship to the Prognosis of Patients in Northern China

PubMed Central

Cao, Fangli; Han, Hui; Zhang, Fang; Wang, Baozhong; Ma, Wei; Wang, Yanwen; Sun, Guiming; Shi, Miao; Ren, Yubo; Cheng, Yufeng

2014-01-01

Purpose. Human papillomavirus (HPV) as a risk factor for esophageal squamous cell carcinoma (ESCC) has previously been studied, but importance of HPV status in ESCC for prognosis is less clear. Methods. A total of 105 specimens with ESCC were tested by in situ hybridization for HPV 16/18 and immunohistochemistry for p16 expression. The 5-year overall survival (OS) and progression-free survival were calculated in relation to these markers and the Cox proportional hazards model was used to determine the hazard ratio (HR) of variables in univariate and multivariate analysis. Results. HPV was detected in 27.6% (29) of the 105 patients with ESCC, and all positive cases were HPV-16. Twenty-five (86.2%) of the 29 HPV-positive tumors were stained positive for p16. HPV infected patients had better 5-year rates of OS (65.9% versus 43.4% among patients with HPV-negative tumors; P = 0.002 by the log-rank test) and had a 63% reduction in the risk of death (adjusted HR = 0.37, 95% CI = 0.16 to 0.82, and P = 0.01). Conclusions. HPV infection may be one of many factors contributing to the development of ESCC and tumor HPV status is an independent prognostic factor for survival among patients with ESCC. PMID:24558329

Inter-institutional survival heterogeneity in chemoradiation therapy for esophageal cancer: exploratory analysis of the JCOG0303 study.

PubMed

Hamamoto, Yasuo; Mizusawa, Junki; Katayama, Hiroshi; Nakamura, Kenichi; Kato, Ken; Tsubosa, Yasuhiro; Ishikura, Satoshi; Igaki, Hiroyasu; Shinoda, Masayuki; Fukuda, Haruhiko; Kitagawa, Yuko; Ando, Nobutoshi

2016-04-01

It is important to examine variation in the treatment effects of patients with esophageal cancer in order to generalize treatment outcomes. We aimed to investigate the range of prognostic differences among hospitals in the treatment of locally advanced esophageal cancer. The JCOG0303 study compared the efficacy of radiotherapy plus low-dose cisplatin and 5-fluorouracil with that of high-dose cisplatin and 5-fluorouracil for unresectable esophageal cancer. Of 32 institutions participating in the JCOG0303 study, the 18 institutions that enrolled three or more patients were included in this study. We predicted the 1-year survival in each institution by using a mixed-effect model. We found that the predicted 1-year survival in the 18 institutions with three or more patients was a median of 60.9%, with a range of 60.9-60.9%. This study is the first to investigated heterogeneity of survival in patients who received definitive chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Fusobacterium nucleatum in gastroenterological cancer: Evaluation of measurement methods using quantitative polymerase chain reaction and a literature review.

PubMed

Yamamura, Kensuke; Baba, Yoshifumi; Miyake, Keisuke; Nakamura, Kenichi; Shigaki, Hironobu; Mima, Kosuke; Kurashige, Junji; Ishimoto, Takatsugu; Iwatsuki, Masaaki; Sakamoto, Yasuo; Yamashita, Yoichi; Yoshida, Naoya; Watanabe, Masayuki; Baba, Hideo

2017-12-01

The human microbiome Fusobacterium nucleatum , which primarily inhabits the oral cavity, causes periodontal disease and has also been implicated in the development of colorectal cancer. However, whether F. nucleatum is present in other gastroenterological cancer tissues remains to be elucidated. The present study evaluated whether quantitative polymerase chain reaction (qPCR) assays were able to detect F. nucleatum DNA and measure the quantity of F. nucleatum DNA in esophageal, gastric, pancreatic and liver cancer tissues. The accuracy of the qPCR assay was determined from a calibration curve using DNA extracted from cells from the oral cavity. Formalin-fixed paraffin-embedded (FFPE) tumor tissues from 20 patients with gastroenterological [esophageal (squamous cell carcinoma), gastric, colorectal, pancreatic and liver] cancer and 20 matched normal tissues were evaluated for F. nucleatum DNA content. The cycle threshold values in the qPCR assay for F. nucleatum and solute carrier organic anion transporter family member 2A1 (reference sample) decreased linearly with the quantity of input DNA ( r 2 >0.99). The F. nucleatum detection rate in esophageal, gastric and colorectal cancer tissues were 20% (4/20), 10% (2/20) and 45% (9/20), respectively. F. nucleatum was not detected in liver and pancreatic cancer tissues. The qPCR results from the frozen and FFPE tissues were consistent. Notably, F. nucleatum was detected at a higher level in superficial areas compared with the invasive areas. F. nucleatum in esophageal, gastric and colorectal cancer tissues was evaluated by qPCR using FFPE tissues. F. nucleatum may be involved in the development of esophageal, gastric and colorectal cancer.

High Resolution Microendoscopy for Quantitative Diagnosis of Esophageal Neoplasia

NASA Astrophysics Data System (ADS)

Shin, Dongsuk

Esophageal cancer is the eighth most common cancer in the world. Cancers of the esophagus account for 3.8% of all cases of cancers, with approximately 482,300 new cases reported in 2008 worldwide. In the United States alone, it is estimated that approximately 18,000 new cases will be diagnosed in 2013, and 15,210 deaths are expected. Despite advances in surgery and chemoradiation therapy, these advances have not led to a significant increase in survival rates, primarily because diagnosis often at an advanced and incurable stage when treatment is more difficult and less successful. Accurate, objective methods for early detection of esophageal neoplasia are needed. Here, quantitative classification algorithms for high resolution miscroendoscopic images were developed to distinguish between esophageal neoplastic and non-neoplastic tissue. A clinical study in 177 patients with esophageal squamous cell carcinoma (ESCC) was performed to evaluate the diagnostic performance of the classification algorithm in collaboration with the Mount Sinai Medical Center in the United States, the First Hospital of Jilin University in China, and the Cancer Institute and Hospital, the Chinese Academy of Medical Science in China. The study reported a sensitivity and specificity of 93% and 92%, respectively, in the training set, 87% and 97%, respectively, in the test set, and 84% and 95%, respectively, in an independent validation set. Another clinical study in 31 patients with Barrett's esophagus resulted in a sensitivity of 84% and a specificity of 85%. Finally, a compact, portable version of the high resolution microendoscopy (HRME) device using a consumer-grade camera was developed and a series of biomedical experimental studies were carried out to assess the capability of the device.

Interleukin-12 and Trastuzumab in Treating Patients With Cancer That Has High Levels of HER2/Neu

ClinicalTrials.gov

2013-02-27

Advanced Adult Primary Liver Cancer; Anaplastic Thyroid Cancer; Bone Metastases; Carcinoma of the Appendix; Distal Urethral Cancer; Fallopian Tube Cancer; Gastrinoma; Glucagonoma; Inflammatory Breast Cancer; Insulinoma; Liver Metastases; Localized Unresectable Adult Primary Liver Cancer; Lung Metastases; Male Breast Cancer; Malignant Pericardial Effusion; Malignant Pleural Effusion; Metastatic Gastrointestinal Carcinoid Tumor; Metastatic Parathyroid Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Newly Diagnosed Carcinoma of Unknown Primary; Occult Non-small Cell Lung Cancer; Pancreatic Polypeptide Tumor; Primary Peritoneal Cavity Cancer; Proximal Urethral Cancer; Pulmonary Carcinoid Tumor; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adrenocortical Carcinoma; Recurrent Adult Primary Liver Cancer; Recurrent Anal Cancer; Recurrent Bladder Cancer; Recurrent Breast Cancer; Recurrent Carcinoma of Unknown Primary; Recurrent Cervical Cancer; Recurrent Colon Cancer; Recurrent Endometrial Carcinoma; Recurrent Esophageal Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Pancreatic Cancer; Recurrent Parathyroid Cancer; Recurrent Prostate Cancer; Recurrent Rectal Cancer; Recurrent Renal Cell Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Intestine Cancer; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Thyroid Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Urethral Cancer; Recurrent Vaginal Cancer; Recurrent Vulvar Cancer; Skin Metastases; Small Intestine Adenocarcinoma; Somatostatinoma; Stage III Adenoid Cystic Carcinoma of the Oral Cavity; Stage III Adrenocortical Carcinoma; Stage III Bladder Cancer; Stage III Cervical Cancer; Stage III Colon Cancer; Stage III Endometrial Carcinoma; Stage III Esophageal Cancer; Stage III Follicular Thyroid Cancer; Stage III Gastric Cancer; Stage III Malignant Testicular Germ Cell Tumor; Stage III Mucoepidermoid Carcinoma of the Oral Cavity; Stage III Ovarian Epithelial Cancer; Stage III Pancreatic Cancer; Stage III Papillary Thyroid Cancer; Stage III Prostate Cancer; Stage III Rectal Cancer; Stage III Renal Cell Cancer; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Vaginal Cancer; Stage III Vulvar Cancer; Stage IIIA Anal Cancer; Stage IIIA Breast Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Anal Cancer; Stage IIIB Breast Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Adrenocortical Carcinoma; Stage IV Anal Cancer; Stage IV Bladder Cancer; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Endometrial Carcinoma; Stage IV Esophageal Cancer; Stage IV Follicular Thyroid Cancer; Stage IV Gastric Cancer; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Pancreatic Cancer; Stage IV Papillary Thyroid Cancer; Stage IV Prostate Cancer; Stage IV Rectal Cancer; Stage IV Renal Cell Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IVA Cervical Cancer; Stage IVA Vaginal Cancer; Stage IVB Cervical Cancer; Stage IVB Vaginal Cancer; Stage IVB Vulvar Cancer; Thyroid Gland Medullary Carcinoma; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer; Urethral Cancer Associated With Invasive Bladder Cancer; WDHA Syndrome

Genome-wide screening of DNA methylation associated with lymph node metastasis in esophageal squamous cell carcinoma.

PubMed

Nagata, Hiroaki; Kozaki, Ken-Ichi; Muramatsu, Tomoki; Hiramoto, Hidekazu; Tanimoto, Kousuke; Fujiwara, Naoto; Imoto, Seiya; Ichikawa, Daisuke; Otsuji, Eigo; Miyano, Satoru; Kawano, Tatsuyuki; Inazawa, Johji

2017-06-06

Lymph node metastasis (LNM) of esophageal squamous cell carcinoma (ESCC) is well-known to be an early event associated with poor prognosis in patients with ESCC. Recently, tumor-specific aberrant DNA methylation of CpG islands around the promoter regions of tumor-related genes has been investigated as a possible biomarker for use in early diagnosis and prediction of prognosis. However, there are few DNA methylation markers able to predict the presence of LNM in ESCC. To identify DNA methylation markers associated with LNM of ESCC, we performed a genome-wide screening of DNA methylation status in a discovery cohort of 67 primary ESCC tissues and their paired normal esophageal tissues using the Illumina Infinium HumanMethylation450 BeadChip. In this screening, we focused on differentially methylated regions (DMRs) that were associated with LNM of ESCC, as prime candidates for DNA methylation markers. We extracted three genes, HOXB2, SLC15A3, and SEPT9, as candidates predicting LNM of ESCC, using pyrosequencing and several statistical analyses in the discovery cohort. We confirmed that HOXB2 and SEPT9 were highly methylated in LNM-positive tumors in 59 ESCC validation samples. These results suggested that HOXB2 and SEPT9 may be useful epigenetic biomarkers for the prediction of the presence of LNM in ESCC.

Genome-wide screening of DNA methylation associated with lymph node metastasis in esophageal squamous cell carcinoma

PubMed Central

Nagata, Hiroaki; Kozaki, Ken-Ichi; Muramatsu, Tomoki; Hiramoto, Hidekazu; Tanimoto, Kousuke; Fujiwara, Naoto; Imoto, Seiya; Ichikawa, Daisuke; Otsuji, Eigo; Miyano, Satoru; Kawano, Tatsuyuki; Inazawa, Johji

2017-01-01

Lymph node metastasis (LNM) of esophageal squamous cell carcinoma (ESCC) is well-known to be an early event associated with poor prognosis in patients with ESCC. Recently, tumor-specific aberrant DNA methylation of CpG islands around the promoter regions of tumor-related genes has been investigated as a possible biomarker for use in early diagnosis and prediction of prognosis. However, there are few DNA methylation markers able to predict the presence of LNM in ESCC. To identify DNA methylation markers associated with LNM of ESCC, we performed a genome-wide screening of DNA methylation status in a discovery cohort of 67 primary ESCC tissues and their paired normal esophageal tissues using the Illumina Infinium HumanMethylation450 BeadChip. In this screening, we focused on differentially methylated regions (DMRs) that were associated with LNM of ESCC, as prime candidates for DNA methylation markers. We extracted three genes, HOXB2, SLC15A3, and SEPT9, as candidates predicting LNM of ESCC, using pyrosequencing and several statistical analyses in the discovery cohort. We confirmed that HOXB2 and SEPT9 were highly methylated in LNM-positive tumors in 59 ESCC validation samples. These results suggested that HOXB2 and SEPT9 may be useful epigenetic biomarkers for the prediction of the presence of LNM in ESCC. PMID:28465481

MicroRNA-548-3p and MicroRNA-576-5p enhance the migration and invasion of esophageal squamous cell carcinoma cells via NRIP1 downregulation.

PubMed

Ni, X F; Zhao, L H; Li, G; Hou, M; Su, M; Zou, C L; Deng, X

2018-06-26

Nuclear receptor interacting protein (NRIP1), also known as RIP140, is a transcriptional coregulator that is required for the maintenance of energy homeostasis and ovulation. Although several studies have identified roles for NRIP1 in various cell processes, the biological functions of NRIP1 in esophageal squamous cell carcinoma (ESCC) remain unknown. In the present study, we demonstrate that NRIP1 inhibited the migration and invasion of ESCC cells. Further mechanistic studies revealed that NRIP1 is directly targeted by miR-548-3p and miR-576-5p. Next, we show that miR-548-3p and miR-576-5p regulated the migration and invasion of ESCC cells via inhibiting NRIP1 expression. Interestingly, in ESCC cell lines and ESCC tissues, expression of miR-548-3p and miR-576-5p was upregulated and NRIP1 was downregulated relative to the control. A statistically significant inverse association was found between the expression level of miR-548-3p/miR-576-5p and NRIP1. Taken together, our results reveal novel functions for miR-548-3p, miR-576-5p, and NRIP1 in regulating ESCC cell migration and invasion, important functions for the metastatic process in esophageal cancer.

Prognostic value of preoperative serum CA 242 in Esophageal squamous cell carcinoma cases.

PubMed

Feng, Ji-Feng; Huang, Ying; Chen, Qi-Xun

2013-01-01

Carbohydrate antigen (CA) 242 is inversely related to prognosis in many cancers. However, few data regarding CA 242 in esophageal cancer (EC) are available. The aim of this study was to determine the prognostic value of CA 242 and propose an optimum cut-off point in predicting survival difference in patients with esophageal squamous cell carcinoma (ESCC). A retrospective analysis was conducted of 192 cases. A receiver operating characteristic (ROC) curve for survival prediction was plotted to verify the optimum cuf- off point. Univariate and multivariate analyses were performed to evaluate prognostic parameters for survival. The positive rate for CA 242 was 7.3% (14/192). The ROC curve for survival prediction gave an optimum cut-off of 2.15 (U/ml). Patients with CA 242 ≤ 2.15 U/ml had significantly better 5-year survival than patients with CA 242 >2.15 U/ml (45.4% versus 22.6%; P=0.003). Multivariate analysis showed that differentiation (P=0.033), CA 242 (P=0.017), T grade (P=0.004) and N staging (P<0.001) were independent prognostic factors. Preoperative CA 242 is a predictive factor for long-term survival in ESCC, especially in nodal-negative patients. We conclude that 2.15 U/ml may be the optimum cuf-off point for CA 242 in predicting survival in ESCC.

Robotic Approach in Benign and Malignant Esophageal Tumors; A Preliminary Seven Case Series.

PubMed

Tomulescu, Victor; Stanescu, Codrut; Blajut, Cristian; Barbulescu, Loredana; Droc, Gabriela; Herlea, Vlad; Popescu, Irinel

2018-01-01

Esophageal surgery has been recognized as very challenging for surgeons and risky for patients. Thoracoscopic approach have proved its benefit in esophageal surgery but has some drawbacks as tremor and limited degrees of freedom, contra-intuitive movements and fulcrum effect of the surgical tools. Robotic technology has been developed with the intent to overcome these limitations of the standard laparoscopy or thoracoscopy. These benefits of robotic procedure are most advantageous when operating in remote areas difficult to reach as in esophageal surgery. The aim of this paper is to present our small experience related with robotic approach in benign and malignant esophageal tumors and critically revise the evidence available about the use of the robotic technology for the treatment of these pathology. Methods: From January 2008 to September 2016 robotic surgery interventions related with benign or malignant esophageal tumors were performed in "Dan Setlacec" Center for General Surgery and Liver Transplantation of Fundeni Clinical Institute in seven patients. This consisted of dissection of the entire esophagus as part of an abdomino-thoracic-cervical procedure for esophageal cancer in 3 patients and the extirpation of an esophageal leiomyoma in 3 cases and a foregut esophageal cyst in one case. Results: All procedures except one were completed entirely using the da Vinci robotic system. The exception was the first case - a 3 cm leiomyoma of the inferior esophagus with ulceration of the superjacent esophageal mucosa. Pathology reports revealed three esophageal leiomyoma, one foregut cyst and three squamous cell carcinomas with free of tumor resection margins. The mean number of retrieved mediastinal nodes was 24 (22 - 27). The postoperative course was uneventful in four cases, in the other three a esophageal fistula occurred in the converted leiomyoma case (closed in the 14th postoperative day), a prolonged drainage in one esophageal cancer case and a temporary right recurrent nerve palsy in an other one. One patient with esophageal cancer and all patients with benign lesions are alive with no signs of recurrence and no symptomatology. Our experience is limited and we cannot conclude for the long term benefits of robotic surgery for esophageal tumors. In our experience the early outcomes were better then using classic open approach, but similar with the cases performed by thoracoscopic approach. We have noticed significant advantages of robotic surgery in relation of lymph node retrieval, leiomyoma dissection safe from esophageal mucosa and suturing. Ergonomics for the surgeon was incomparable better then with the thoracoscopic approach. Celsius.

Dietary habits and esophageal cancer.

PubMed

Palladino-Davis, A G; Mendez, B M; Fisichella, P M; Davis, C S

2015-01-01

Cancer of the esophagus is an underestimated, poorly understood, and changing disease. Its overall 5-year survival is less than 20%, even in the United States, which is largely a function of a delay in diagnosis until its more advanced stages. Additionally, the epidemiologic complexities of esophageal cancer are vast, rendering screening and prevention limited at best. First, the prevalence of esophageal cancer is unevenly distributed throughout the world. Second, the two histological forms (squamous cell and adenocarcinoma) vary in terms of their geographic prevalence and associated risk factors. Third, some populations appear at particular risk for esophageal cancer. And fourth, the incidence of esophageal cancer is in continuous flux among groups. Despite the varied prevalence and risks among populations, some factors have emerged as consistent associations while others are only now becoming more fully recognized. The most prominent, scientifically supported, and long-regarded risk factors for esophageal cancer are tobacco, alcohol, and reflux esophagitis. Inasmuch as the above are regarded as important risk factors for esophageal cancer, they are not the sole contributors. Dietary habits, nutrition, local customs, and the environment may be contributory. Along these lines, vitamins, minerals, fruits, vegetables, meats, fats, salted foods, nitrogen compounds, carcinogens, mycotoxins, and even the temperature of what we consume are increasingly regarded as potential etiologies for this deadly although potentially preventable disease. The goal of this review is to shed light on the less known role of nutrition and dietary habits in esophageal cancer. © 2013 Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.

Three-dimensional conformal radiation for esophageal squamous cell carcinoma with involved-field irradiation may deliver considerable doses of incidental nodal irradiation

PubMed Central

2012-01-01

Background To quantify the incidental irradiation dose to esophageal lymph node stations when irradiating T1-4N0M0 thoracic esophageal squamous cell carcinoma (ESCC) patients with a dose of 60 Gy/30f. Methods Thirty-nine patients with medically inoperable T1–4N0M0 thoracic ESCC were treated with three-dimensional conformal radiation (3DCRT) with involved-field radiation (IFI). The conformal clinical target volume (CTV) was re-created using a 3-cm margin in the proximal and distal direction beyond the barium esophagogram, endoscopic examination and CT scan defined the gross tumor volume (GTV) and a 0.5-cm margin in the lateral and anteroposterior directions of the CT scan-defined GTV. The PTV encompassed 1-cm proximal and distal margins and 0.5-cm radial margin based on the CTV. Nodal regions were delineated using the Japanese Society for Esophageal Diseases (JSED) guidelines and an EORTC-ROG expert opinion. The equivalent uniform dose (EUD) and other dosimetric parameters were calculated for each nodal station. Nodal regions with a metastasis rate greater than 5% were considered a high-risk lymph node subgroup. Results Under a 60 Gy dosage, the median Dmean and EUD was greater than 40 Gy in most high-risk nodal regions except for regions of 104, 106tb-R in upper-thoracic ESCC and 101, 104-R, 105, 106rec-L, 2, 3&7 in middle-thoracic ESCC and 107, 3&7 in lower-thoracic ESCC. In the regions with an EUD less than 40Gy, most incidental irradiation doses were significantly associated with esophageal tumor length and location. Conclusions Lymph node stations near ESCC receive considerable incidental irradiation doses with involved-field irradiation that may contribute to the elimination of subclinical lesions. PMID:23186308

Details of recurrence sites after elective nodal irradiation (ENI) using 3D-conformal radiotherapy (3D-CRT) combined with chemotherapy for thoracic esophageal squamous cell carcinoma--a retrospective analysis.

PubMed

Yamashita, Hideomi; Okuma, Kae; Wakui, Reiko; Kobayashi-Shibata, Shino; Ohtomo, Kuni; Nakagawa, Keiichi

2011-02-01

To describe patterns of recurrence of elective nodal irradiation (ENI) in definitive chemoradiotherapy (CRT) for thoracic esophageal squamous cell carcinoma (SqCC) using 3D-conformal radiotherapy. One hundred and twenty-six consecutive patients with stages I-IVB thoracic esophageal SqCC newly diagnosed between June 2000 and July 2009 and treated with 3D-CRT in our institution were recruited from our database. Definitive CRT consisted of two cycles of nedaplatin/5FU repeated every 4 weeks, with concurrent radiation therapy of 50-50.4 Gy in 25-28 fractions. Until completion, radiotherapy was delivered to the N1 and M1a lymph nodes as ENI in addition to gross tumor volume. All 126 patients were included in this analysis, and their tumors were staged as follows: T1/T2/T3/T4, 28/18/54/26; N0/N1, 50/76; M0/M1a/M1b, 91/5/30. The mean follow-up period for the 63 surviving patients was 28.3 (±22.8) months. Eighty-seven patients (69%) achieved complete response (CR) without any residual tumor at least once after completion of CRT. After achieving CR, each of 40 patients experienced failures (local=20 and distant=20) and no patient experienced elective nodal failure without having any other site of recurrence. The upper thoracic esophageal carcinoma showed significantly more (34%) relapses at the local site than the middle (9%) or lower thoracic (11%) carcinomas. The 2-year and 3-year overall survival was 56% and 43%, respectively. The 1-year, 2-year and 3-year disease-free survival was 46%, 38% and 33%, respectively. In CRT for esophageal SqCC, ENI was effective for preventing regional nodal failure. The upper thoracic esophageal carcinomas had significantly more local recurrences than the middle or lower thoracic sites. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Therapeutics for Equine Gastric Ulcer Syndrome.

PubMed

Zavoshti, Fereydon Rezazadeh; Andrews, Frank M

2017-04-01

Equine gastric ulcer syndrome (EGUS) is an umbrella term used to describe ulcers in the nonglandular squamous and glandular mucosa, terminal esophagus, and proximal duodenum. Gastric ulcers in the squamous and glandular regions occur more often than esophageal or duodenal ulcers and likely have a different pathogenesis. At present, omeprazole is accepted globally as the best pharmacologic therapy for both regions of the stomach; however, the addition of coating agents and synthetic prostaglandins could add to its effectiveness in treatment of EGUS. Dietary and environmental management are necessary for prevention of recurrence. Copyright © 2016 Elsevier Inc. All rights reserved.

Nicotinic cholinergic receptors in esophagus: Early alteration during carcinogenesis and prognostic value

PubMed Central

Chianello Nicolau, Marina; Pinto, Luis Felipe Ribeiro; Nicolau-Neto, Pedro; de Pinho, Paulo Roberto Alves; Rossini, Ana; de Almeida Simão, Tatiana; Soares Lima, Sheila Coelho

2016-01-01

AIM To compare expression of nicotinic cholinergic receptors (CHRNs) in healthy and squamous cell carcinoma-affected esophagus and determine the prognostic value. METHODS We performed RT-qPCR to measure the expression of CHRNs in 44 esophageal samples from healthy individuals and in matched normal surrounding mucosa, and in tumors from 28 patients diagnosed with esophageal squamous cell carcinoma (ESCC). Next, we performed correlation analysis for the detected expression of these receptors with the habits and clinico-pathological characteristics of all study participants. In order to investigate the possible correlations between the expression of the different CHRN subunits in both healthy esophagus and tissues from ESCC patients, correlation matrices were generated. Subsequently, we evaluated whether the detected alterations in expression of the various CHRNs could precede histopathological modifications during the esophageal carcinogenic processes by using receiver operating characteristic curve analysis. Finally, we evaluated the impact of CHRNA5 and CHRNA7 expression on overall survival by using multivariate analysis. RESULTS CHRNA3, CHRNA5, CHRNA7 and CHRNB4, but not CHRNA1, CHRNA4, CHRNA9 or CHRNA10, were found to be expressed in normal (healthy) esophageal mucosa. In ESCC, CHRNA5 and CHRNA7 were overexpressed as compared with patient-matched surrounding non-tumor mucosa (ESCC-adjacent mucosa; P < 0.0001 and P = 0.0091, respectively). Positive correlations were observed between CHRNA3 and CHRNB4 expression in all samples analyzed. Additionally, CHRNB4 was found to be differentially expressed in the healthy esophagus and the normal-appearing ESCC-adjacent mucosa, allowing for distinguishment between these tissues with a sensitivity of 75.86% and a specificity of 78.95% (P = 0.0002). Finally, CHRNA5 expression was identified as an independent prognostic factor in ESCC; patients with high CHRNA5 expression showed an increased overall survival, in comparison with those with low expression. The corresponding age- and tumor stage-adjusted hazard ratio was 0.2684 (95%CI: 0.075-0.97, P = 0.0448). CONCLUSION Expression of CHRNs is homogeneous along healthy esophagus and deregulated in ESCC, suggesting a pathogenic role for these receptors in ESCC development and progression. PMID:27610024

Nicotinic cholinergic receptors in esophagus: Early alteration during carcinogenesis and prognostic value.

PubMed

Chianello Nicolau, Marina; Pinto, Luis Felipe Ribeiro; Nicolau-Neto, Pedro; de Pinho, Paulo Roberto Alves; Rossini, Ana; de Almeida Simão, Tatiana; Soares Lima, Sheila Coelho

2016-08-21

To compare expression of nicotinic cholinergic receptors (CHRNs) in healthy and squamous cell carcinoma-affected esophagus and determine the prognostic value. We performed RT-qPCR to measure the expression of CHRNs in 44 esophageal samples from healthy individuals and in matched normal surrounding mucosa, and in tumors from 28 patients diagnosed with esophageal squamous cell carcinoma (ESCC). Next, we performed correlation analysis for the detected expression of these receptors with the habits and clinico-pathological characteristics of all study participants. In order to investigate the possible correlations between the expression of the different CHRN subunits in both healthy esophagus and tissues from ESCC patients, correlation matrices were generated. Subsequently, we evaluated whether the detected alterations in expression of the various CHRNs could precede histopathological modifications during the esophageal carcinogenic processes by using receiver operating characteristic curve analysis. Finally, we evaluated the impact of CHRNA5 and CHRNA7 expression on overall survival by using multivariate analysis. CHRNA3, CHRNA5, CHRNA7 and CHRNB4, but not CHRNA1, CHRNA4, CHRNA9 or CHRNA10, were found to be expressed in normal (healthy) esophageal mucosa. In ESCC, CHRNA5 and CHRNA7 were overexpressed as compared with patient-matched surrounding non-tumor mucosa (ESCC-adjacent mucosa; P < 0.0001 and P = 0.0091, respectively). Positive correlations were observed between CHRNA3 and CHRNB4 expression in all samples analyzed. Additionally, CHRNB4 was found to be differentially expressed in the healthy esophagus and the normal-appearing ESCC-adjacent mucosa, allowing for distinguishment between these tissues with a sensitivity of 75.86% and a specificity of 78.95% (P = 0.0002). Finally, CHRNA5 expression was identified as an independent prognostic factor in ESCC; patients with high CHRNA5 expression showed an increased overall survival, in comparison with those with low expression. The corresponding age- and tumor stage-adjusted hazard ratio was 0.2684 (95%CI: 0.075-0.97, P = 0.0448). Expression of CHRNs is homogeneous along healthy esophagus and deregulated in ESCC, suggesting a pathogenic role for these receptors in ESCC development and progression.

Prognostic impact of postoperative radiation in patients undergoing radical esophagectomy for pathologic lymph node positive esophageal cancer.

PubMed

Xu, Yaping; Liu, Jinshi; Du, Xianghui; Sun, Xiaojiang; Zheng, Yuanda; Chen, Jianxiang; Li, Bo; Liu, Wei; Jiang, Hao; Mao, Weimin

2013-05-08

Though postoperative radiation for esophageal squamous cell carcinoma is offered in selected cases, there is conflicting evidence as to whether it improves overall survival (OS). A retrospective investigation was performed to analyze the prognostic impact of postoperative radiation therapy (PORT) in a large cohort of patients. From 2001 to 2009, 725 patients underwent radical esophagectomy (R0) with or without PORT were eligible for retrospective analysis. Patients were grouped into surgery alone (n = 467) and surgery plus PORT (n = 258). Median irradiation doses were 50 Gy (range: 40-56 Gy). Radiation fields encompassed the bilateral supraclavicular fossa, mediastinum, subcarinal area, and the tumor bed for the upper/middle-third disease; the bilateral supraclavicular fossa, mediastinum, the tumor bed, subcarinal area, and lower thoracic paraesophageal area for the lower-third disease. Kaplan-Meier and Cox regression analysis were used to compare OS. After median follow-up of 53 months, the median OS was 29 months in the PORT group and 23 months in the surgery alone group. The addition of PORT improved OS at 3 years from 36.6 to 43.6% compared with surgery alone. The use of PORT was associated with significantly improved OS (p = 0.018). For American Joint Committee on Cancer (AJCC) stage III esophageal cancer (T1-2N2M0, T3N1-2M0, T4N1-3M0), there was significant improvement in OS (p = 0.002) in the PORT group, not only for lymph-node metastatic ratio (LNMR) ≥0.25 (p = 0.001), but also for LNMR <0.25 (p = 0.043). However, for stage IIB disease (T1-2N1M0) there was no significant differences. The addition of POCT didn't prolong the OS significantly (Surgery alone group, p = 0.079; PORT group, p = 0.111). This large retrospective analysis supports the use of PORT for pathologic lymph node positive stage III esophageal squamous cell carcinoma. Given the retrospective nature of this study, the results should be confirmed by appropriately powered randomized trials. Further development of adjuvant therapy in EC is warranted.

Hematoporphyrin-mediated photodynamic therapy for treatment of head and neck cancer: clinical update 1996

NASA Astrophysics Data System (ADS)

Schweitzer, Vanessa G.

1996-04-01

From 1983 to 1996 Phase II and III clinical studies at Henry Ford Hospital demonstrated complete or partial responses in 55 of 56 patients treated with hematoporphyrin-derivative or PHOTOFRIN-mediated photodynamic therapy (HPD-PDT) for a variety of benign and malignant upper aerodigestive tract disease: (1) superficial 'condemned mucosa' or 'field cancerization' of the oral cavity and larynx (7 cases); (2) Stage III/IV head and neck cancer (25 cases); (3) mucocutaneous AIDS-associated Kaposi's sarcoma of the upper aerodigestive tract and non AIDS-related Kaposi's sarcoma of the lower extremity (15 cases); (4) recurrent laryngotracheal papillomatosis (3 cases); (5) severe dysplasia/adenocarcinoma or squamous cell carcinoma in situ in Barrett's esophagus (4 cases); (6) partial or completely obstructing terminal esophageal cancer (9 cases). At the time of this report, HPD-PDT produced complete responses in 24 patients (follow up 6 months to 9 years) with 'field cancerization' (CIS, T1N0M0) of the oral cavity and larynx (6 cases), adenocarcinoma in situ in Barrett's esophagus (3 cases), mucocutaneous Kaposi's sarcoma (12 cases), obstructing esophageal carcinoma (1 case), and stage IV squamous cell carcinoma of the nasopharynx (1 case), and radiation therapy or solar-induced basal cell/squamous cell carcinomas (2 cases). PDT treatment protocols, results, complications, and application as adjunct or primary oncologic therapy for head and neck cancer are reviewed in this article.

Ratio of metastatic lymph nodes to total number of nodes resected is prognostic for survival in esophageal carcinoma.

PubMed

Kelty, Clive J; Kennedy, Catherine W; Falk, Gregory L

2010-09-01

The role of the number of metastatic nodes in esophageal cancer surgery is of interest. We assess predictors of survival after oesophagectomy for esophageal and gastroesophageal junction malignancy. Prospective data of consecutive patients undergoing oesophagectomy and systematic lymphadenectomy between 1991 and 2007. Of 224 patients, 148 patients (66%) had adenocarcinoma, 70 (31%) squamous cell carcinoma, and 6 (2.6%) were other tumor types. Five-year survival was 43% with hospital mortality of 3.5%. Locoregional recurrence occurred in 14%. The total number of affected nodes significantly reduced survival (four or more metastatic nodes). Further analysis of the ratio of nodes affected to the total number resected showed a significant decrease in survival as the percentage of positive nodes increased (p < 0.001). Patients undergoing surgery for esophageal cancer should be staged according to a minimum total number of metastatic lymph nodes and ratios because this more accurately predicts survival than current staging systems.

Preoperative serum fibrinogen is an independent prognostic factor in operable esophageal cancer

PubMed Central

Zhang, Shui-Shen; Lei, Yi-Yan; Cai, Xiao-Li; Yang, Hong; Xia, Xin; Luo, Kong-Jia; Su, Chun-Hua; Zou, Jian-Yong; Zeng, Bo; Hu, Yi; Luo, Hong-He

2016-01-01

In order to fully elucidate the association between serum fibrinogen and prognosis of esophageal cancer, we examined serum fibrinogen concentrations in 1512 patients who underwent esophagectomy by the Clauss method. The impact of fibrinogen on overall survival and disease-free survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models. Hyperfibrinogenemia was significantly associated with older age, male gender, smoking, alcohol consumption, weight loss, advanced pathological T stage and lymph node metastasis. Patients with hyperfibrinogenemia exhibited poor OS (HR=1.20, 95%CI: 1.04-1.38, P=0.012) and DFS (HR=1.18, 95%CI: 1.03-1.35, P=0.019). Subgroup analysis further exhibited an significant association between hyperfibrinogenemia and poor OS (P<0.001), DFS (P<0.001) in esophageal squamous cell carcinoma (P<0.001) and early pathological stage (I-II) (P=0.001). Collectively, this study indicates that preoperative serum fibrinogen is an independent prognostic factor for survival in esophageal cancer. PMID:27009857

Esophageal cancer associated with a sarcoid-like reaction and systemic sarcoidosis in lymph nodes: supportive findings of [18F]-fluorodeoxyglucose positron emission tomography-computed tomography during neoadjuvant therapy.

PubMed

Kishino, Takayoshi; Okano, Keiichi; Ando, Yasuhisa; Suto, Hironobu; Asano, Eisuke; Oshima, Minoru; Fujiwara, Masao; Usuki, Hisashi; Kobara, Hideki; Masaki, Tsutomu; Ibuki, Emi; Kushida, Yoshio; Haba, Reiji; Suzuki, Yasuyuki

2018-06-25

In patients with esophageal cancer, differentiation between lymph node metastasis and lymphadenopathies from sarcoidosis or sarcoid-like reactions of lymph nodes is clinically important. Herein, we report two esophageal cancer cases with lymph node involvement of sarcoid-like reaction or sarcoidosis. One patient received chemotherapy and the other chemoradiotherapy as initial treatments. In both cases, [ 18 F]-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) was performed before and after chemo(radio)therapy. After the treatment, FDG uptake was not detected in the primary tumor, but it was slightly reduced in the hilar and mediastinal lymph nodes in both cases. These non-identical responses to chemo(radio)therapy suggest the presence of sarcoid-like reaction of lymph nodes associated with squamous cell carcinoma of the esophagus. Curative surgical resection was performed as treatment. These FDG-PET/CT findings may be helpful to distinguish between metastasis and sarcoidosis-associated lymphadenopathy in esophageal cancer.

Viruses, Other Pathogenic Microorganisms and Esophageal Cancer.

PubMed

Xu, Wenji; Liu, Zhongshu; Bao, Quncha; Qian, Zhikan

2015-05-01

Esophageal cancer (EC) is the eighth most prevalent malignant tumor and the sixth leading cause of cancer mortality throughout the world. Despite the technical developments in diagnosis and treatment, the 5-year survival rate is still low. The etiology of EC remains poorly understood; multiple risk factors may be involved and account for the great variation in EC incidence in different geographic regions. Infection with carcinogenetic pathogens has been proposed as a risk factor for EC. This review explores the recent studies on the association of human papillomavirus (HPV), Epstein-Barr virus (EBV), Helicobacter pylori and esophageal bacterial biota with EC. Among the above-mentioned pathogens, HPV most likely contributes to esophageal squamous cell carcinoma (ESCC) in high-risk populations. New techniques are being applied to studies on the role of infection in EC, which will inevitably bring novel ideas to the field in the near future. Multiple meta-analyses support the finding of a higher HPV detection rate in regions associated with high risk for ESCC compared to low-risk areas. A potential role of HPV in the rise of esophageal adenocarcinoma (EAC) was proposed recently. However, further studies are required before a firm conclusion can be drawn. Less work has been done in studying the association between EBV and ESCC, and the results are quite controversial. H. pylori infection is found to be inversely related to EC, which is probably due to the reduced incidence of gastroesophageal reflux disease. Analysis of the esophageal bacterial biota revealed distinct clusters of bacteria in normal and diseased esophagi. A type II microbiome rich in Gram-negative bacteria potentially contributes to EAC by inducing chronic inflammation. Novel findings from such studies as these may benefit public health by justifying anti-infection measures to prevent EC.

Definitive, Preoperative, and Palliative Radiation Therapy of Esophageal Cancer.

PubMed

Fokas, Emmanouil; Rödel, Claus

2015-10-01

Long-term survival in patients with esophageal cancer remains dismal despite the recent improvements in surgery, the advances in radiotherapy (RT) technology, and the refinement of systemic treatments, including the advent of targeted therapies. Although surgery constitutes the treatment of choice for early-stage disease (stage I), a multimodal approach, including preoperative or definitive chemoradiotherapy (CRT) and perioperative chemotherapy, is commonly pursued in patients with locally advanced disease. A review of the literature was performed to assess the role of RT, alone or in combination with chemotherapy, in the management of esophageal cancer. Evidence from large, randomized phase III trials and meta-analyses supports the application of perioperative chemotherapy alone or preoperative concurrent CRT in patients with lower esophageal and esophagogastric junction adenocarcinomas. Preoperative CRT but not preoperative chemotherapy alone is now routinely used in patients with locally advanced squamous cell carcinoma (SCC). Additionally, definitive CRT without surgery has also emerged as a valuable approach in the management of resectable esophageal SCC to avoid surgery-related morbidity and mortality, whereas salvage surgery is reserved for those with persistent disease. Furthermore, brachytherapy offers a valuable option in the palliative treatment of patients with locally advanced, unresponsive disease. Fluorodeoxyglucose-positron emission tomography (FDG-PET) can facilitate a more accurate treatment response assessment and patient selection. Finally, the development of modern RT techniques, such as intensity-modulated and image-guided RT as well as FDG-PET-based RT planning, could further increase the therapeutic ratio of CRT. Altogether, CRT constitutes an important tool in the treatment armamentarium for esophageal cancer. Further optimization of CRT using modern technology and imaging, targeted therapies, and newer chemotherapeutic agents is a major challenge and should be the goal of future research and clinical trials.

Serotonin disrupts esophageal mucosal integrity: an investigation using a stratified squamous epithelial model.

PubMed

Wu, Liping; Oshima, Tadayuki; Tomita, Toshihiko; Ohda, Yoshio; Fukui, Hirokazu; Watari, Jiro; Miwa, Hiroto

2016-11-01

Serotonin regulates gastrointestinal function, and mast cells are a potential nonneuronal source of serotonin in the esophagus. Tight junction (TJ) proteins in the esophageal epithelium contribute to the barrier function, and the serotonin signaling pathway may contribute to epithelial leakage in gastroesophageal reflux disease. Therefore, the aim of this study was to investigate the role of serotonin on barrier function, TJ proteins, and related signaling pathways. Normal primary human esophageal epithelial cells were cultured with use of an air-liquid interface system. Serotonin was added to the basolateral compartment, and transepithelial electrical resistance (TEER) was measured. The expression of TJ proteins and serotonin receptor 7 (5-HT 7 ) was assessed by Western blotting. The involvement of 5-HT 7 was assessed with use of an antagonist and an agonist. The underlying cellular signaling pathways were examined with use of specific blockers. Serotonin decreased TEER and reduced the expression of TJ proteins ZO-1, occludin, and claudin 1, but not claudin 4. A 5-HT 7 antagonist blocked the serotonin-induced decrease in TEER, and a 5-HT 7 agonist decreased TEER. Inhibition of p38 mitogen-activated protein kinase (MAPK) reduced the serotonin-induced decrease in TEER. Inhibition of p38 MAPK blocked the decrease of ZO-1 levels, whereas extracellular-signal-regulated kinase (ERK) inhibition blocked the decrease in occludin levels. Cell signaling pathway inhibitors had no effect on serotonin-induced alterations in claudin 1 and claudin 4 levels. Serotonin induced phosphorylation of p38 MAPK and ERK, and a 5-HT 7 antagonist partially blocked serotonin-induced phosphorylation of p38 MAPK but not that of ERK. Serotonin disrupted esophageal squamous epithelial barrier function by modulating the levels of TJ proteins. Serotonin signaling pathways may mediate the pathogenesis of gastroesophageal reflux disease.

Potential values of metabolic tumor volume and heterogeneity measured with ¹⁸F-FDG PET/CT pretreatment to evaluate local control for esophageal squamous cell carcinoma treated with nonsurgical therapy.

PubMed

Liu, Qi; Fu, Xiao-Long; Yu, Wen; Zhu, Zheng-Fei; Zhang, Ying-Jian

2015-05-01

The aim of the study was to evaluate the predictive value of fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) pretreatment on local control (LC) and survival after radical radiotherapy or chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma (SCC) and to discuss its potential value for establishing optimal radiation treatment plans. Fifty-eight patients with pathologically proven esophageal SCC who underwent ¹⁸F-FDG PET/CT pretreatment in our center were retrospectively reviewed. We examined the correlation between the PET parameters of primary tumors and LC and overall survival. The coefficient of variation was used to estimate the ¹⁸F-FDG uptake in heterogeneity. The mean duration of follow-up for surviving patients was 38 months, and 36 patients died because of tumor recurrence or other diseases. The rates of 3-year overall survival and LC were 40.4 and 50.4%, respectively. Multivariate analysis of LC revealed that metabolic tumor volume (MTV) greater than 16.08 ml was the only predictor of outcome, with a lower 3-year LC (P=0.017, hazard ratio: 1.608, 95% confidence interval: 1.090-2.371). The coefficient of variations of their primary lesion were higher compared with those of patients who had smaller MTVs. In this study, MTV assessed by PET/CT might be an adverse factor for predicting LC in esophageal SCC. For those with higher MTVs, higher intratumor heterogeneity suggests that irradiation may need to be boosted in stable high-uptake regions to improve LC. These results need to be prospectively validated in larger cohorts.

Definitive chemoradiotherapy versus neoadjuvant chemoradiotherapy followed by surgery for stage II to III esophageal squamous cell carcinoma.

PubMed

Barbetta, Arianna; Hsu, Meier; Tan, Kay See; Stefanova, Dessislava; Herman, Koby; Adusumilli, Prasad S; Bains, Manjit S; Bott, Matthew J; Isbell, James M; Janjigian, Yelena Y; Ku, Geoffrey Y; Park, Bernard J; Wu, Abraham J; Jones, David R; Molena, Daniela

2018-06-01

Definitive chemoradiotherapy (CRT) remains the most commonly used treatment for locally advanced esophageal squamous cell carcinoma (SCC), because of perceptions that esophagectomy offers an unclear survival advantage. We compare recurrence, overall survival (OS), and disease-free survival (DFS) in patients treated with definitive CRT or neoadjuvant CRT followed by surgery (trimodality). This was a retrospective cohort study of patients with stage II and III SCC of the middle and distal esophagus in patients who completed CRT. Treatment groups were matched (1:1) on covariates using a propensity score-matching approach. The effect of trimodality treatment, compared with definitive CRT, on OS, DFS, and site-specific recurrence was evaluated as a time-dependent variable and analyzed using Cox regression with a gamma frailty term for matched units. We included 232 patients treated between 2000 and 2016: 124 (53%) with definitive CRT and 108 (47%) with trimodality. Trimodality was used less frequently over time (61% before 2009 and 29% after 2009; P < .0001). After matching, each group contained 56 patients. Median OS and DFS were 3.1 and 1.8 years for trimodality versus 2.3 and 1.0 years for CRT. Surgery was independently associated with improved OS (hazard ratio, 0.57; 95% confidence interval, 0.34-0.97; P = .039) and DFS (hazard ratio, 0.51; 95% confidence interval, 0.32-0.83; P = .007). CRT followed by surgery might decrease local recurrence and increase DFS and OS in patients with esophageal SCC. Until better tools to select patients with pathological complete response are available, surgery should remain an integral component of the treatment of locally advanced esophageal SCC. Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Ectopic Cdx2 Expression in Murine Esophagus Models an Intermediate Stage in the Emergence of Barrett's Esophagus

PubMed Central

Kong, Jianping; Crissey, Mary Ann; Funakoshi, Shinsuke; Kreindler, James L.; Lynch, John P.

2011-01-01

Barrett's esophagus (BE) is an intestinal metaplasia that occurs in the setting of chronic acid and bile reflux and is associated with a risk for adenocarcinoma. Expression of intestine-specific transcription factors in the esophagus likely contributes to metaplasia development. Our objective was to explore the effects of an intestine-specific transcription factor when expressed in the mouse esophageal epithelium. Transgenic mice were derived in which the transcription factor Cdx2 is expressed in squamous epithelium using the murine Keratin-14 gene promoter. Effects of the transgene upon cell proliferation and differentiation, gene expression, and barrier integrity were explored. K14-Cdx2 mice express the Cdx2 transgene in esophageal squamous tissues. Cdx2 expression was associated with reduced basal epithelial cell proliferation and altered cell morphology. Ultrastructurally two changes were noted. Cdx2 expression was associated with dilated space between the basal cells and diminished cell-cell adhesion caused by reduced Desmocollin-3 mRNA and protein expression. This compromised epithelial barrier function, as the measured trans-epithelial electrical resistance (TEER) of the K14-Cdx2 epithelium was significantly reduced compared to controls (1189 Ohm*cm2 ±343.5 to 508 Ohm*cm2±92.48, p = 0.0532). Secondly, basal cells with features of a transitional cell type, intermediate between keratinocytes and columnar Barrett's epithelial cells, were observed. These cells had reduced keratin bundles and increased endoplasmic reticulum levels, suggesting the adoption of secretory-cell features. Moreover, at the ultrastructural level they resembled “Distinctive” cells associated with multilayered epithelium. Treatment of the K14-Cdx2 mice with 5′-Azacytidine elicited expression of BE-associated genes including Cdx1, Krt18, and Slc26a3/Dra, suggesting the phenotype could be advanced under certain conditions. We conclude that ectopic Cdx2 expression in keratinocytes alters cell proliferation, barrier function, and differentiation. These altered cells represent a transitional cell type between normal squamous and columnar BE cells. The K14-Cdx2 mice represent a useful model to study progression from squamous epithelium to BE. PMID:21494671

Ectopic Cdx2 expression in murine esophagus models an intermediate stage in the emergence of Barrett's esophagus.

PubMed

Kong, Jianping; Crissey, Mary Ann; Funakoshi, Shinsuke; Kreindler, James L; Lynch, John P

2011-04-06

Barrett's esophagus (BE) is an intestinal metaplasia that occurs in the setting of chronic acid and bile reflux and is associated with a risk for adenocarcinoma. Expression of intestine-specific transcription factors in the esophagus likely contributes to metaplasia development. Our objective was to explore the effects of an intestine-specific transcription factor when expressed in the mouse esophageal epithelium. Transgenic mice were derived in which the transcription factor Cdx2 is expressed in squamous epithelium using the murine Keratin-14 gene promoter. Effects of the transgene upon cell proliferation and differentiation, gene expression, and barrier integrity were explored. K14-Cdx2 mice express the Cdx2 transgene in esophageal squamous tissues. Cdx2 expression was associated with reduced basal epithelial cell proliferation and altered cell morphology. Ultrastructurally two changes were noted. Cdx2 expression was associated with dilated space between the basal cells and diminished cell-cell adhesion caused by reduced Desmocollin-3 mRNA and protein expression. This compromised epithelial barrier function, as the measured trans-epithelial electrical resistance (TEER) of the K14-Cdx2 epithelium was significantly reduced compared to controls (1189 Ohm*cm(2) ±343.5 to 508 Ohm*cm(2)±92.48, p = 0.0532). Secondly, basal cells with features of a transitional cell type, intermediate between keratinocytes and columnar Barrett's epithelial cells, were observed. These cells had reduced keratin bundles and increased endoplasmic reticulum levels, suggesting the adoption of secretory-cell features. Moreover, at the ultrastructural level they resembled "Distinctive" cells associated with multilayered epithelium. Treatment of the K14-Cdx2 mice with 5'-Azacytidine elicited expression of BE-associated genes including Cdx1, Krt18, and Slc26a3/Dra, suggesting the phenotype could be advanced under certain conditions. We conclude that ectopic Cdx2 expression in keratinocytes alters cell proliferation, barrier function, and differentiation. These altered cells represent a transitional cell type between normal squamous and columnar BE cells. The K14-Cdx2 mice represent a useful model to study progression from squamous epithelium to BE.

[Neoadjuvant therapy for esophageal cancer - indication and efficacy].

PubMed

Kato, Ken; Hamaguchi, Tetsuya; Yamada, Yasuhide; Shirao, Kuniaki; Shimada, Yasuhiro

2007-10-01

Some approaches such as adjuvant chemotherapy, neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy have been tried to improve the efficacy of treatment for resectable esophageal cancer patients. The usefullness of neoadjuvant chemotherapy, has remained a matter of controversy. However, there is a report from JCOG9907 in Japan that two courses of neoadjuvant 5-FU/CDDP improved the survival of esophageal squamous cell cancer patients. Neoadjuvant chemoradiotherapy has not had a consistent evaluation because of the varying results of each trial. But from the results of meta-analysis and CALGB9781, the neoadjuvant chemoradiotherapy called "trimodality therapy" has been a standard treatment in the United States. We should evaluate whether there would be similar effectiveness in Japan, where the histology and operative approach are different. Some approaches such as DNA microarray and proteomics, which can predict the treatment effect, are being tried.

Towards Tyrosine Metabolism in Esophageal Squamous Cell Carcinoma.

PubMed

Cheng, Jing; Zheng, Guangyong; Jin, Hai; Gao, Xianfu

2017-01-01

Esophageal Squamous Cell Carcinoma (ESCC) is a common malignant tumor in China, which causes about 200,000 deaths each year. Sensitive biomarkers are helpful to diagnose the disease in early stage. To identify biomarkers of ESCC and elucidate underlying mechanism of the disease, a targeted metabolomics strategy based on liquid chromatography-tandem mass spectrometry (LCMS/ MS) has been implemented to explore tyrosine metabolism from 40 ESCC patients and 27 healthy controls. Four metabolites, i.e. phenylalanine, 4-hydroxyphenyllactic acid, 3,4-dihydroxyphenylalanine, and 3,4-dihydroxyphenylacetic acid were identified as diagnostic biomarkers for ESCC patients. Based on these biomarkers, a prediction model was constructed for ESCC diagnosis. The analysis of receiver operating characteristic (ROC) curve confirmed its effectiveness of the model. Our results reveal that tyrosine metabolism is disturbed in ESCC patients and the metabolites involved in tyrosine pathway can be used as diagnostic biomarkers of the disease. Findings of this study can help investigate pathogenesis of ESCC and facilitate understanding mechanism of the disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The therapeutic response of CDDO-Me in the esophageal squamous cell carcinoma (ESCC) cells is mediated by CaMKIIα.

PubMed

Wang, Yan-Yang; Zhou, Shun; Zhao, Ren; Hai, Ping; Zhe, Hong

2016-01-01

CDDO-Me has exhibited a potent anticancer effect in human esophageal squamous cell carcinoma (ESCC) cells in our previous study, but the molecular interactome remains elusive. We applied the approach of stable-isotope labeling by amino acids in cell culture (SILAC) to assess the proteomic responses of CDDO-Me treatment in human ESCC Ec109 cells. The data were subsequently validated using Western blot assay. The results of our study revealed that CDDO-Me increased the expression level of 543 protein molecules, but decreased the expression level of 709 protein molecules in Ec109 cells. Among these modulated protein molecules, calcium/calmodulin-dependent protein kinase type II subunit α (CaMKIIα) was highly expressed in all tested ESCC cell lines, whereas its expression levels were substantially lower in normal control cell line. Its silencing by small interfering RNA inhibited CDDO-Me induced apoptosis and autophagy in ESCC cells. Collectively, these data demonstrate that the therapeutic response of CDDO-Me in the human ESCC cells is mediated by CaMKIIα.

Metastasis-suppressing NID2, an epigenetically-silenced gene, in the pathogenesis of nasopharyngeal carcinoma and esophageal squamous cell carcinoma.

PubMed

Chai, Annie Wai Yeeng; Cheung, Arthur Kwok Leung; Dai, Wei; Ko, Josephine Mun Yee; Ip, Joseph Chok Yan; Chan, Kwok Wah; Kwong, Dora Lai-Wan; Ng, Wai Tong; Lee, Anne Wing Mui; Ngan, Roger Kai Cheong; Yau, Chun Chung; Tung, Stewart Yuk; Lee, Victor Ho Fun; Lam, Alfred King-Yin; Pillai, Suja; Law, Simon; Lung, Maria Li

2016-11-29

Nidogen-2 (NID2) is a key component of the basement membrane that stabilizes the extracellular matrix (ECM) network. The aim of the study is to analyze the functional roles of NID2 in the pathogenesis of nasopharyngeal carcinoma (NPC) and esophageal squamous cell carcinoma (ESCC). We performed genome-wide methylation profiling of NPC and ESCC and validated our findings using the methylation-sensitive high-resolution melting (MS-HRM) assay. Results showed that promoter methylation of NID2 was significantly higher in NPC and ESCC samples than in their adjacent non-cancer counterparts. Consistently, down-regulation of NID2 was observed in the clinical samples and cell lines of both NPC and ESCC. Re-expression of NID2 suppresses clonogenic survival and migration abilities of transduced NPC and ESCC cells. We showed that NID2 significantly inhibits liver metastasis. Mechanistic studies of signaling pathways also confirm that NID2 suppresses the EGFR/Akt and integrin/FAK/PLCγ metastasis-related pathways. This study provides novel insights into the crucial tumor metastasis suppression roles of NID2 in cancers.

Metastasis-suppressing NID2, an epigenetically-silenced gene, in the pathogenesis of nasopharyngeal carcinoma and esophageal squamous cell carcinoma

PubMed Central

Chai, Annie Wai Yeeng; Cheung, Arthur Kwok Leung; Dai, Wei; Ko, Josephine Mun Yee; Ip, Joseph Chok Yan; Chan, Kwok Wah; Kwong, Dora Lai-Wan; Ng, Wai Tong; Lee, Anne Wing Mui; Ngan, Roger Kai Cheong; Yau, Chun Chung; Tung, Stewart Yuk; Lee, Victor Ho Fun; Lam, Alfred King-Yin; Pillai, Suja; Law, Simon; Lung, Maria Li

2016-01-01

Nidogen-2 (NID2) is a key component of the basement membrane that stabilizes the extracellular matrix (ECM) network. The aim of the study is to analyze the functional roles of NID2 in the pathogenesis of nasopharyngeal carcinoma (NPC) and esophageal squamous cell carcinoma (ESCC). We performed genome-wide methylation profiling of NPC and ESCC and validated our findings using the methylation-sensitive high-resolution melting (MS-HRM) assay. Results showed that promoter methylation of NID2 was significantly higher in NPC and ESCC samples than in their adjacent non-cancer counterparts. Consistently, down-regulation of NID2 was observed in the clinical samples and cell lines of both NPC and ESCC. Re-expression of NID2 suppresses clonogenic survival and migration abilities of transduced NPC and ESCC cells. We showed that NID2 significantly inhibits liver metastasis. Mechanistic studies of signaling pathways also confirm that NID2 suppresses the EGFR/Akt and integrin/FAK/PLCγ metastasis-related pathways. This study provides novel insights into the crucial tumor metastasis suppression roles of NID2 in cancers. PMID:27793011

Phosphorylation of ETS-1 is a critical event in DNA polymerase iota-induced invasion and metastasis of esophageal squamous cell carcinoma.

PubMed

He, Chao; Wu, Shuhua; Gao, Aidi; Su, Ye; Min, Han; Shang, Zeng-Fu; Wu, Jinchang; Yang, Li; Ding, Wei-Qun; Zhou, Jundong

2017-12-01

An aberrantly elevated expression of DNA polymerase ι (Pol ι) is significantly associated with poor prognosis of patients with esophageal squamous cell carcinoma (ESCC), yet the mechanisms behind this phenomenon remain obscure. Based on the RNA-Seq transcriptome and real-time PCR analysis, we identified ETS-1 as a candidate gene involved in Pol ι-mediated progression of ESCC. Wound-healing and transwell assay indicated that downregulation of ETS-1 attenuates Pol ι-mediated invasiveness of ESCC. Signaling pathway analysis showed that Pol ι enhances ETS-1 phosphorylation at threonine-38 through the Erk signaling pathway in ESCC cells. Kaplan-Meier analysis, based on 93 clinical tissue samples, revealed that ETS-1 phosphorylation at threonine-38 is associated with poor prognosis of ESCC patients. The present study thus demonstrates that phosphorylation of ETS-1 is a critical event in the Pol ι-induced invasion and metastasis of ESCC. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Novel long noncoding RNA NMR promotes tumor progression via NSUN2 and BPTF in esophageal squamous cell carcinoma.

PubMed

Li, Yuan; Li, Jiagen; Luo, Mei; Zhou, Chengcheng; Shi, Xuejiao; Yang, Wenhui; Lu, Zhiliang; Chen, Zhaoli; Sun, Nan; He, Jie

2018-05-12

Long noncoding RNAs (lncRNA) have been implicated in cancer but most of them remain largely unstudied. Here, we identified a novel NSUN2 methylated lncRNA (NMR), which was significantly upregulated in esophageal squamous cell carcinoma (ESCC), functioned as a key regulator of ESCC tumor metastasis and drug resistance. Upregulation of NMR correlated with tumor metastasis and indicated poor overall survival in ESCC patients. Functionally, NMR could promote tumor cell migration and invasion, inhibit cisplatin-induced apoptosis and increase drug resistance in ESCC cells. Mechanistically, transcription of NMR could be upregulated by NF-κB activation after IL-1β and TNF-α treatment. NMR was methylated by NSUN2 and might competitively inhibit methylation of potential mRNAs. NMR could directly bind to chromatin regulator BPTF, and potentially promote MMP3 and MMP10 expression by ERK1/2 pathway through recruiting BPTF to chromatin. Taken together, NMR functions as an oncogenic gene and may serve as new biomarker and therapeutic target in ESCC. Copyright © 2018 Elsevier B.V. All rights reserved.

Risk factors of electrocoagulation syndrome after esophageal endoscopic submucosal dissection

PubMed Central

Ma, Dae Won; Youn, Young Hoon; Jung, Da Hyun; Park, Jae Jun; Kim, Jie-Hyun; Park, Hyojin

2018-01-01

AIM To investigate post endoscopic submucosal dissection electrocoagulation syndrome (PEECS) of the esophagus. METHODS We analyzed 55 consecutive cases with esophageal endoscopic submucosal dissection for superficial esophageal squamous neoplasms at a tertiary referral hospital in South Korea. Esophageal PEECS was defined as “mild” meeting one of the following criteria without any obvious perforation: fever (≥ 37.8 °C), leukocytosis (> 10800 cells/μL), or regional chest pain more than 5/10 points as rated on a numeric pain intensity scale. The grade of PEECS was determined as “severe” when meet two or more of above criteria. RESULTS We included 51 cases without obvious complications in the analysis. The incidence of mild and severe esophageal PEECS was 47.1% and 17.6%, respectively. Risk factor analysis revealed that resected area, procedure time, and muscle layer exposure were significantly associated with PEECS. In multivariate analysis, a resected area larger than 6.0 cm2 (OR = 4.995, 95%CI: 1.110-22.489, P = 0.036) and muscle layer exposure (OR = 5.661, 95%CI: 1.422-22.534, P = 0.014) were independent predictors of esophageal PEECS. All patients with PEECS had favorable outcomes with conservative management approaches, such as intravenous hydration or antibiotics. CONCLUSION Clinicians should consider the possibility of esophageal PEECS when the resected area exceeds 6.0 cm2 or when the muscle layer exposure is noted. PMID:29563758

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts.

PubMed

Kretschmer, Inga; Freudenberger, Till; Twarock, Sören; Yamaguchi, Yu; Grandoch, Maria; Fischer, Jens W

2016-02-19

The aim of this study was to characterize the interaction of KYSE-410, an esophageal squamous cell carcinoma cell line, and fibroblasts with respect to the extracellular matrix component hyaluronan (HA) and chemokine expression. KYSE-410 cells induced the mRNA expression of HA synthase 2 (Has2) in normal skin fibroblasts (SF) only in direct co-cultures. Parallel to Has2 mRNA, Has2 antisense RNA (Has2os2) was up-regulated in co-cultures. Knockdown of LEF1, a downstream target of Wnt signaling, abrogated Has2 and Has2os2 induction. After knockdown of Has2 in SF, significantly less α-smooth muscle actin expression was detected in co-cultures. Moreover, it was investigated whether the phenotype of KYSE-410 was affected in co-culture with SF and whether Has2 knockdown in SF had an impact on KYSE-410 cells in co-culture. However, no effects on epithelial-mesenchymal transition markers, proliferation, and migration were detected. In addition to Has2 mRNA, the chemokine CCL5 was up-regulated and CCL11 was down-regulated in SF in co-culture. Furthermore, co-cultures of KYSE-410 cells and cancer-associated fibroblasts (CAF) were investigated. Similar to SF, Has2 and Ccl5 were up-regulated and Ccl11 was down-regulated in CAF in co-culture. Importantly and in contrast to SF, inhibiting HA synthesis by 4-methylumbelliferone abrogated the effect of co-culture on Ccl5 in CAF. Moreover, HA was found to promote adhesion of CD4(+) but not CD8(+) cells to xenogaft tumor tissues. In conclusion, direct co-culture of esophageal squamous cell carcinoma and fibroblasts induced stromal HA synthesis via Wnt/LEF1 and altered the chemokine profile of stromal fibroblasts, which in turn may affect the tumor immune response. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts*

PubMed Central

Kretschmer, Inga; Freudenberger, Till; Twarock, Sören; Yamaguchi, Yu; Grandoch, Maria; Fischer, Jens W.

2016-01-01

The aim of this study was to characterize the interaction of KYSE-410, an esophageal squamous cell carcinoma cell line, and fibroblasts with respect to the extracellular matrix component hyaluronan (HA) and chemokine expression. KYSE-410 cells induced the mRNA expression of HA synthase 2 (Has2) in normal skin fibroblasts (SF) only in direct co-cultures. Parallel to Has2 mRNA, Has2 antisense RNA (Has2os2) was up-regulated in co-cultures. Knockdown of LEF1, a downstream target of Wnt signaling, abrogated Has2 and Has2os2 induction. After knockdown of Has2 in SF, significantly less α-smooth muscle actin expression was detected in co-cultures. Moreover, it was investigated whether the phenotype of KYSE-410 was affected in co-culture with SF and whether Has2 knockdown in SF had an impact on KYSE-410 cells in co-culture. However, no effects on epithelial-mesenchymal transition markers, proliferation, and migration were detected. In addition to Has2 mRNA, the chemokine CCL5 was up-regulated and CCL11 was down-regulated in SF in co-culture. Furthermore, co-cultures of KYSE-410 cells and cancer-associated fibroblasts (CAF) were investigated. Similar to SF, Has2 and Ccl5 were up-regulated and Ccl11 was down-regulated in CAF in co-culture. Importantly and in contrast to SF, inhibiting HA synthesis by 4-methylumbelliferone abrogated the effect of co-culture on Ccl5 in CAF. Moreover, HA was found to promote adhesion of CD4+ but not CD8+ cells to xenogaft tumor tissues. In conclusion, direct co-culture of esophageal squamous cell carcinoma and fibroblasts induced stromal HA synthesis via Wnt/LEF1 and altered the chemokine profile of stromal fibroblasts, which in turn may affect the tumor immune response. PMID:26699196

Krüppel-Like Factor 4 Enhances Sensitivity of Cisplatin to Esophageal Squamous Cell Carcinoma (ESCC) Cells

PubMed Central

Chen, Chuangui; Ma, Zhao; Zhang, Hongdian; Liu, Xiaoqiong; Yu, Zhentao

2017-01-01

Background The aim of this study was to elucidate the role of Krüppel-Like factor 4 (KLF4) in cisplatin resistance in esophageal squamous cell carcinoma (ESCC) cells, which may eventually help to improve the treatment efficacy. Material/Methods Human esophageal squamous cell carcinoma (ESCC) cell line CaEs-17, TE-1, EC109, KYSE510, KYSE140, KYSE70, and KYSE30 were selected to detect their sensitivity to cisplatin. 5-Azacytidine-2′-deoxycytidine (5′-Aza-CdR) treatment and methylation-specific PCR (MS-PCR) were used to detect the methylation status for KLF4. Cell viability, apoptosis, and cell cycle were measured using methyl thiazolyl tetrazolium (MTT) assay, Annexin V affinity assay, and flow cytometry, respectively. Results The sensitivity to cisplatin was different in the seven ESCC cell lines, with TE-1 having the lowest sensitivity and KYSE140 having the highest sensitivity. Interestingly, the level of KLF4 was relatively low in TE-1 cells; while it was high in KYSE140 cells. These results suggested that KLF4 may be involved in cisplatin resistance. The promoter region was mostly unmethylated in KYSE140 cells; while it was hypermethylated in TE-1 cells. After treatment with demethylation reagent 5-Aza-CdR, cisplatin sensitivities were significantly increased after upregulation of KLF4, as the IC50 values were significantly decreased in the TE-1 cell treated with 5-Aza-CdR. Furthermore, upregulation of KLF4 induced cell apoptosis and cell cycle arrest at S phase. Conclusions KLF4 enhances the sensitivity of cisplatin to ESCC cells through apoptosis induction and cell cycle arrest. Our data provided a novel insight to the mechanism of cisplatin resistance; overexpression of KLF4 may be a potential therapeutic strategy for cisplatin resistance in human ESCC. PMID:28694421

Krüppel-Like Factor 4 Enhances Sensitivity of Cisplatin to Esophageal Squamous Cell Carcinoma (ESCC) Cells.

PubMed

Chen, Chuangui; Ma, Zhao; Zhang, Hongdian; Liu, Xiaoqiong; Yu, Zhentao

2017-07-11

BACKGROUND The aim of this study was to elucidate the role of Krüppel-Like factor 4 (KLF4) in cisplatin resistance in esophageal squamous cell carcinoma (ESCC) cells, which may eventually help to improve the treatment efficacy. MATERIAL AND METHODS Human esophageal squamous cell carcinoma (ESCC) cell line CaEs-17, TE-1, EC109, KYSE510, KYSE140, KYSE70, and KYSE30 were selected to detect their sensitivity to cisplatin. 5-Azacytidine-2'-deoxycytidine (5'-Aza-CdR) treatment and methylation-specific PCR (MS-PCR) were used to detect the methylation status for KLF4. Cell viability, apoptosis, and cell cycle were measured using methyl thiazolyl tetrazolium (MTT) assay, Annexin V affinity assay, and flow cytometry, respectively. RESULTS The sensitivity to cisplatin was different in the seven ESCC cell lines, with TE-1 having the lowest sensitivity and KYSE140 having the highest sensitivity. Interestingly, the level of KLF4 was relatively low in TE-1 cells; while it was high in KYSE140 cells. These results suggested that KLF4 may be involved in cisplatin resistance. The promoter region was mostly unmethylated in KYSE140 cells; while it was hypermethylated in TE-1 cells. After treatment with demethylation reagent 5-Aza-CdR, cisplatin sensitivities were significantly increased after upregulation of KLF4, as the IC50 values were significantly decreased in the TE-1 cell treated with 5-Aza-CdR. Furthermore, upregulation of KLF4 induced cell apoptosis and cell cycle arrest at S phase. CONCLUSIONS KLF4 enhances the sensitivity of cisplatin to ESCC cells through apoptosis induction and cell cycle arrest. Our data provided a novel insight to the mechanism of cisplatin resistance; overexpression of KLF4 may be a potential therapeutic strategy for cisplatin resistance in human ESCC.

Novel poly (ADP-ribose) polymerase inhibitor, AZD2281, enhances radiosensitivity of both normoxic and hypoxic esophageal squamous cancer cells.

PubMed

Zhan, L; Qin, Q; Lu, J; Liu, J; Zhu, H; Yang, X; Zhang, C; Xu, L; Liu, Z; Cai, J; Ma, J; Dai, S; Tao, G; Cheng, H; Sun, X

2016-04-01

Radiotherapy plays an important role in the treatment of esophageal squamous cell carcinoma (ESCC). However, the outcome of radiotherapy in ESCC remains unsatisfactory because esophageal squamous cancer cells, particularly those under hypoxic condition, exhibit radioresistance. The aim of this study was to determine whether or not AZD2281, a potent poly (ADP-ribose) polymerase (PARP) inhibitor, could enhance the radiation sensitivity of two ESCC cell lines, namely ECA109 and TE13. The radiosensitizing effect of AZD2281 was evaluated on the basis of cell death, clonogenic survival and tumor xenograft progression. AZD2281 alone was slightly toxic to ESCC cell lines. Apoptosis was increased and clonogenic survival was decreased in both cell lines when AZD2281 was combined with ionizing radiation (IR) under normoxic condition. AZD2281 enhanced IR-induced apoptosis to a more significant level under chronic hypoxic condition (0.2% O(2), 48 hour) than under normoxic condition. AZD2281 also slightly enhanced clonogenic cell death under chronic hypoxic condition compared with that under normoxic condition. This result could be associated with increased radiation-induced DNA double-strand breaks (DSB), decreased DSB repair and increased apoptosis of ESCC cells. Furthermore, homologous recombination (HR) protein Rad51 expression and focus formation were decreased in ESCC cells exposed to moderate chronic hypoxic condition (0.2% O(2), 48 hour); this result indicated that chronic hypoxic ESCC cells were HR deficient, possibly causing contextual synthetic lethality with PARP inhibitor in radiation sensitization. AZD2281 was also a radiation sensitizer in ESCC tumor xenograft models. Hence, in vitro and in vivo findings provide evidence that AZD2281 potently sensitizes ESCC cells to X-ray irradiation. The selective cell killing of HR-defective hypoxic cells contributes to radiosensitization by PARP inhibitor in ESCC cells under hypoxic condition. © 2015 International Society for Diseases of the Esophagus.

Hot Food and Beverage Consumption and the Risk of Esophageal Cancer: A Meta-Analysis.

PubMed

Andrici, Juliana; Eslick, Guy D

2015-12-01

Esophageal cancer is a neoplasm with a poor prognosis. Its two histologic subtypes, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), have been associated with different risk factors. The possibility of an association between the consumption of hot food and beverages and esophageal cancer, especially ESCC, has long been suspected, presenting a potentially modifiable risk factor. A meta-analysis of existing observational studies was performed to provide a quantitative estimate of the risk of esophageal cancer associated with the consumption of hot food and drink. A search was conducted through MEDLINE, PubMed, EMBASE, and Current Contents Connect to November 11, 2014. Pooled ORs and 95% CIs were calculated using a random effects model for the risk of esophageal cancer associated with the consumption of hot food and drink. Subgroup analyses were conducted for ESCC and EAC, as well as for studies that adjusted for tobacco smoking and alcohol consumption, two well-recognized risk factors for ESCC. Consumption of hot food and drink was associated with an increased risk of any esophageal cancer (OR=1.90, 95% CI=1.46, 2.48). Heterogeneity was observed. There was an increased risk of ESCC (OR=2.29, 95% CI=1.79, 2.93), which remained even after adjusting for significant confounding variables (OR=2.39, 95% CI=1.71, 3.33). The relationship was not significant for EAC. The consumption of hot food and beverages was associated with an increased risk of esophageal cancer, particularly ESCC. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

Evaluation of the value of ENI in radiotherapy for cervical and upper thoracic esophageal cancer: a retrospective analysis.

PubMed

Liu, Mina; Zhao, Kuaile; Chen, Yun; Jiang, Guo-Liang

2014-10-25

A retrospective study to compare the failure patterns and effects of elective nodal irradiation (ENI) or involved field irradiation (IFI) for cervical and upper thoracic esophageal squamous cell carcinoma (SCC) patients. One hundred and sixty nine patients with the cervical and upper thoracic esophageal SCC were analyzed retrospectively; 99 patients (59%) underwent IFI and 70 patients (41%) received ENI. We defined "Out-PTVifi in-PTVeni metastasis" as lymph node metastasis occurring in the cervical prophylactic field of PTVeni thus out of PTVifi. Out-PTVifi in-PTVeni cervical node metastasis occurred in 8% of patients in the IFI group, all within 2 years after treatment. However, it occurred in 10% of patients in the ENI group, and these failures happened gradually since one year after treatments. No difference was found in OS and the incidences of Grade ≥ 3 treatment-related esophageal and lung toxicities between the two groups. ENI for cervical and upper thoracic esophageal SCC patients did not bring longer OS and better long-term control of cervical lymph nodes. Although ENI might delay cervical nodes progression in elective field; it could not decrease the incidence of these failures.

NRAGE is involved in homologous recombination repair to resist the DNA-damaging chemotherapy and composes a ternary complex with RNF8-BARD1 to promote cell survival in squamous esophageal tumorigenesis.

PubMed

Yang, Q; Pan, Q; Li, C; Xu, Y; Wen, C; Sun, F

2016-08-01

NRAGE, a neurotrophin receptor-interacting melanoma antigen-encoding gene homolog, is significantly increased in the nucleus of radioresistant esophageal tumor cell lines and is highly upregulated to promote cell proliferation in esophageal carcinomas (ECs). However, whether the overexpressed NRAGE promotes cell growth by participating in DNA-damage response (DDR) is still unclear. Here we show that NRAGE is required for efficient double-strand breaks (DSBs) repair via homologous recombination repair (HRR) and downregulation of NRAGE greatly sensitizes EC cells to DNA-damaging agents both in vitro and in vivo. Moreover, NRAGE not only regulates the stability of DDR factors, RNF8 and BARD1, in a ubiquitin-proteolytic pathway, but also chaperons the interaction between BARD1 and RNF8 via their RING domains to form a novel ternary complex. Additionally, the expression of NRAGE is closely correlated with RNF8 and BARD1 in esophageal tumor tissues. In summary, our findings reveal a novel function of NRAGE that will help to guide personalized esophageal cancer treatments by targeting NRAGE to increase cell sensitivity to DNA-damaging therapeutics in the long run.

Quantification of plasma exosome is a potential prognostic marker for esophageal squamous cell carcinoma.

PubMed

Matsumoto, Yasunori; Kano, Masayuki; Akutsu, Yasunori; Hanari, Naoyuki; Hoshino, Isamu; Murakami, Kentaro; Usui, Akihiro; Suito, Hiroshi; Takahashi, Masahiko; Otsuka, Ryota; Xin, Hu; Komatsu, Aki; Iida, Keiko; Matsubara, Hisahiro

2016-11-01

Exosomes play important roles in cancer progression. Although its contents (e.g., proteins and microRNAs) have been focused on in cancer research, particularly as potential diagnostic markers, the exosome behavior and methods for exosome quantification remain unclear. In the present study, we analyzed the tumor-derived exosome behavior and assessed the quantification of exosomes in patient plasma as a biomarker for esophageal squamous cell carcinoma (ESCC). A CD63-GFP expressing human ESCC cell line (TE2-CD63-GFP) was made by transfection, and mouse subcutaneous tumor models were established. Fluorescence imaging was performed on tumors and plasma exosomes harvested from mice. GFP-positive small vesicles were confirmed in the plasma obtained from TE2-CD63-GFP tumor-bearing mice. Patient plasma was collected in Chiba University Hospital (n=86). Exosomes were extracted from 100 µl of the plasma and quantified by acetylcholinesterase (AChE) activity. The relationship between exosome quantification and the patient clinical characteristics was assessed. The quantification of exosomes isolated from the patient plasma revealed that esophageal cancer patients (n=66) expressed higher exosome levels than non-malignant patients (n=20) (P=0.0002). Although there was no correlation between the tumor progression and the exosome levels, exosome number was the independent prognostic marker and low levels of exosome predicted a poor prognosis (P=0.03). In conclusion, exosome levels may be useful as an independent prognostic factor for ESCC patients.

The AXL receptor tyrosine kinase is associated with adverse prognosis and distant metastasis in esophageal squamous cell carcinoma

PubMed Central

Wong, Li-Fan; Lee, Jang-Ming

2016-01-01

Esophageal squamous cell carcinoma (ESCC) is a frequently recurrent deadly cancer for which no efficient targeted drug exists. AXL is an adverse prognostic factor in some cancers. Strong clinical evidence to support the prognostic role of AXL in ESCC is lacking. A total of 116 patients diagnosed with operable primary ESCC were enrolled. Both AXL and HER2 expression were detected by immunohistochemistry (IHC) in esophageal tissue and were correlated with the clinical outcome of patients. The efficacy of the AXL targeted drug foretinib was also evaluated in ESCC cells. Expression of AXL was found in about 80 % of ESCC tissue, and was significantly correlated with progression of tumor (P<0.001), increased risk of death (Hazard ratio HR [95 % CI=2.09[1.09-4.04], P=0.028], and distant metastasis (odds ratio OR [95 %CI]=3.96 (1.16-13.60), P=0.029). The adverse clinical impact of AXL was more evident when cumulatively expressed with HER2. In cell model, ESCC cells were more sensitive to AXL inhibitor foretinib than to the HER2 inhibitor lapatinib. Meanwhile, the AXL inhibitor foretinib showed a synergistic effect with HER2 inhibitors and the potential to overcome drug resistance to lapatinib. We thus concluded that AXL is a strong adverse prognostic factor for ESCC. Therapeutic agents targeting AXL have great potential to improve prognosis of ESCC patients. PMID:27172793

Derlin-1 is a target to improve radiotherapy effect of esophageal squamous cell carcinoma

PubMed Central

Zhao, Yue; Liu, Yang; Li, Qingchang; Qiu, Xueshan; Wang, Enhua

2017-01-01

Radiotherapy is widely used for treatment of esophageal squamous cell carcinoma (ESCC). This study aimed to explore the role of Derlin-1 on the sensitivity of ESCC to radiotherapy and its underlying mechanism. We examined the clinical significance of Derlin-1 in 125 ESCC tissues. We found that Derlin-1 protein was higher in ESCC tissues than that in normal esophageal epithelial tissues. Derlin-1 overexpression was correlated with chemoradiotherapy resistance in ESCC patients and served an independent predictor for short overall survival. siRNA knockdown and plasmid transfection were carried out in ESCC cell lines. Derlin-1 depletion inhibited cell growth while its overexpression facilitated cell growth. Derlin-1 overexpression in Eca-109 cells dramatically enhanced its resistance to radiotherapy with decreased apoptosis rate. On the contrary, Derlin-1 depletion in TE-1 cell line showed the opposite effects. In addition, radioresistance conferred by Derlin-1 was attributed to its role of activating AKT/Bcl-2 signaling pathway and reducing caspase3 cleavage. Blockage of AKT signaling attenuated the role of Derlin-1 on radioresistance. Furthermore, Derlin-1 could interact with PI3K p110α in ESCC cell lines. Taken together, Our data demonstrate that Derlin-1 overexpression predicts poor prognosis and protects ESCC from irradiation induced apoptosis through PI3K/AKT/Bcl-2 signaling pathway. Derlin-1 may serve as a novel predictor for radiosentivity and a molecular target for ESCC. PMID:28903408

Expression of kallikrein-related peptidase 13 is associated with poor prognosis in esophageal squamous cell carcinoma.

PubMed

Nohara, Kyoko; Yamada, Kazuhiko; Yamada, Leo; Hagiwara, Teruki; Igari, Toru; Yokoi, Chizu; Soma, Daisuke; Yamashita, Satoshi; Dohi, Taeko; Kawamura, Yuki I

2018-06-01

Our previous differential transcriptome analysis between a paired specimen of normal and esophageal squamous cell carcinoma (ESCC) tissues found aberrant expression of kallikrein-related peptidase 13 (KLK13) in tumors. In this study, we evaluated the expression of KLK13 in many ESCC cases in relation with clinical features, and the prognosis. Eighty-eight ESCC cases were subjected to immunohistological staining for KLK13 and classified into KLK13-negative and KLK13-positive groups. Difference of clinical features and the prognosis between the groups was analyzed. In normal esophageal mucosa, KLK13 expression was evident but limited in the stratum granulosum in all cases. By contrast, only 27 of 88 ESCC samples showed KLK13 expression, whereas the remaining 61 tumors showed no KLK13 expression. The KLK13-positive group was significantly associated with pT classification (deeper tumor invasions; P = 0.0282), pN classification (lymph node metastasis; P = 0.0163), and advanced TNM stage (P = 0.0198). In KLK13-positive samples, KLK13-expressing cells often expressed Ki67, a proliferation marker, unlike normal mucosa, in which Ki67-expressing cells were limited to the basal layer and did not express KLK13. Compared with patients with KLK13-negative group, KLK13-positive group showed poorer postoperative prognosis. Relatively high levels of KLK13 expression in ESCC were associated with cell proliferation and correlated with tumor progression, advanced cancer stage, and poor prognosis.

Radiation therapy and esophageal cancer.

PubMed

Shridhar, Ravi; Almhanna, Khaldoun; Meredith, Kenneth L; Biagioli, Matthew C; Chuong, Michael D; Cruz, Alex; Hoffe, Sarah E

2013-04-01

Squamous cell carcinoma and adenocarcinoma account for more than 90% of all esophageal cancer cases. Although the incidence of squamous cell carcinoma has declined, the incidence of adenocarcinoma has risen due to increases in obesity and gastroesophageal reflux disease. The authors examine the role of radiation therapy alone (external beam and brachytherapy) for the management of esophageal cancer or combined with other modalities. The impact on staging and appropriate stratification of patients referred for curative vs palliative intent with modalities is reviewed. The authors also explore the role of emerging radiation technologies. Current data show that neoadjuvant chemoradiotherapy followed by surgical resection is the accepted standard of care, with 3-year overall survival rates ranging from 30% to 60%. The benefit of adjuvant radiation therapy is limited to patients with node-positive cancer. The survival benefit of surgical resection after chemoradiotherapy remains controversial. External beam radiation therapy alone results in few long-term survivors and is considered palliative at best. Radiation dose-escalation has failed to improve local control or survival. Brachytherapy can provide better long-term palliation of dysphagia than metal stent placement. Although three-dimensional conformal treatment planning is the accepted standard, the roles of IMRT and proton therapy are evolving and potentially reduce adverse events due to better sparing of normal tissue. Future directions will evaluate the benefit of induction chemotherapy followed by chemoradiotherapy, the role of surgery in locally advanced disease, and the identification of responders prior to treatment based on microarray analysis.

Esophageal cancer stem cells are suppressed by tranilast, a TRPV2 channel inhibitor.

PubMed

Shiozaki, Atsushi; Kudou, Michihiro; Ichikawa, Daisuke; Fujiwara, Hitoshi; Shimizu, Hiroki; Ishimoto, Takeshi; Arita, Tomohiro; Kosuga, Toshiyuki; Konishi, Hirotaka; Komatsu, Shuhei; Okamoto, Kazuma; Marunaka, Yoshinori; Otsuji, Eigo

2018-02-01

Recent evidence suggests that the targeting of membrane proteins specifically activated in cancer stem cells (CSCs) is an important strategy for cancer therapy. The objectives of the present study were to investigate the expression and activity of ion-transport-related molecules in the CSCs of esophageal squamous cell carcinoma. Cells exhibiting strong aldehyde dehydrogenase 1 family member A1 (ALDH1A1) activity were isolated from TE8 cells by fluorescence-activated cell sorting, and CSCs were then generated with the sphere formation assay. The gene expression profiles of CSCs were examined by microarray analysis. Among TE8 cells, ALDH1A1 messenger RNA and protein levels were higher in CSCs than in non-CSCs. The CSCs obtained were resistant to cisplatin and had the ability to redifferentiate. The results of the microarray analysis revealed that the expression of 50 genes encoding plasma membrane proteins was altered in CSCs, whereas that of several genes related to ion channels, including transient receptor potential vanilloid 2 (TRPV2), was upregulated. The TRPV2 inhibitor tranilast was more cytotoxic at a lower concentration in CSCs than in non-CSCs, and effectively decreased the number of tumorspheres. Furthermore, tranilast significantly decreased the cell population that strongly expressed ALDH1A1 among TE8 cells. The results of the present study suggest that TRPV2 is involved in the maintenance of CSCs, and that its specific inhibitor, tranilast, has potential as a targeted therapeutic agent against esophageal squamous cell carcinoma.

Dietary patterns and the risk of esophageal squamous cell carcinoma: A population-based case-control study in a rural population.

PubMed

Liu, Xudong; Wang, Xiaorong; Lin, Sihao; Lao, Xiangqian; Zhao, Jin; Song, Qingkun; Su, Xuefen; Tak-Sun Yu, Ignatius

2017-02-01

Few studies were available in exploring the roles of dietary patterns in the development of esophageal cancer, especially in China. This study aimed to investigate the roles of dietary patterns in the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese rural population. A population-based cases-control study was designed and conducted in Yanting County, Sichuan Province of China during two years (between June 2011 and May 2013). A total of 942 pairs of ESCC cases and controls were recruited. A food frequency questionnaire was adopted to collect information of dietary consumption. Dietary patterns were extracted by using principle component and factor analysis based on 24 dietary groups. Odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated by using logistic regression model, with adjustment for possible confounding variables. Four major dietary patterns were identified, which were labeled as "prudent", "vegetable and fruits", "processed food" and "alcohol drinking". In comparison of the highest with the lowest quartiles of pattern scores, the processed food pattern (OR: 2.84, 95% CI: 2.13-3.80) and alcohol drinking pattern (OR: 2.69, 95% CI: 1.95-3.71) were significantly associated with an increased risk of ESCC, while the vegetable and fruit pattern (OR: 0.70, 95% CI: 0.53-0.92) was associated with reduced risk by 30%. The prudent pattern was associated with a reduced risk by 33% (OR: 0.67, 95% CI: 0.50-0.88) in a multivariate logistic regression model, but no statistical significance was reached in a composite model. The results suggest an important role of dietary patterns in ESCC. Diets rich in vegetables and fruits may decrease the risk of ESCC, whereas diets rich in processed food and drinking alcohol may increase the risk. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Progress in digestive endoscopy: Flexible Spectral Imaging Colour Enhancement (FICE)-technical review.

PubMed

Negreanu, L; Preda, C M; Ionescu, D; Ferechide, D

2015-01-01

Background. A substantial advance in digestive endoscopy that has been made during the last decade is represented by digital chromoendoscopy, which was developed as a quicker and sometimes better alternative to the gold standard of dye spraying. Fujifilm developed a virtual coloration technique called Flexible spectral Imaging Color Enhancement (FICE). FICE provides a better detection of lesions of "minimal" esophagitis, of dysplasia in Barrett's esophagus and of squamous cell esophageal cancer. The use of FICE resulted in an improvement in the visualization of the early gastric cancer, being less invasive, and time consuming than the classic dye methods. Current evidence does not support FICE for screening purposes in colon cancer but it definitely improves characterization of colonic lesions. Its use in inflammatory bowel disease is still controversial and in video capsule endoscopy is considered a substantial progress. Conclusions. The use of FICE endoscopy in routine clinical practice can increase the diagnostic yield and can provide a better characterization of lesions. Future studies to validate its use, the good choice of channels, and the "perfect indications" and to provide common definitions and classifications are necessary.

Endoscopic methods in the treatment of early-stage esophageal cancer

PubMed Central

2014-01-01

Most patients with early esophageal cancer restricted to the mucosa may be offered endoscopic therapy, which is similarly effective, less invasive and less expensive than esophagectomy. Selection of appropriate relevant treatment and therapy methods should be performed at a specialized center with adequate facilities. The selection of an endoscopic treatment method for high-grade dysplasia and early-stage esophageal adenocarcinoma requires that tumor infiltration is restricted to the mucosa and that there is no neighboring lymph node metastasis. In squamous cell carcinoma, this treatment method is accepted in cases of tumors invading only up to the lamina propria of mucosa (m2). Tumors treated with the endoscopic method should be well or moderately differentiated and should not invade lymphatic or blood vessels. When selecting endoscopic treatments for these lesions, a combination of endoscopic resection and endoscopic ablation methods should be considered. PMID:25097676

Definitive chemoradiation for locoregional recurrences of esophageal cancer after primary curative treatment.

PubMed

Jeene, P M; Versteijne, E; van Berge Henegouwen, M I; Bergmann, J J G H M; Geijsen, E D; Muller, K; van Laarhoven, H W M; Hulshof, M C C M

2017-02-01

The aim of this study was to determine the outcome of salvage definitive chemoradiation (dCRT) for a locoregional recurrence after any prior curative treatment outside previously irradiated areas. Thirty-nine patients treated between January 2005 and December 2014 were reviewed for locoregional recurrent esophageal cancer outside previously irradiated areas. All patients received salvage treatment with external beam radiotherapy (50.4 Gy in 28 fractions) combined with weekly concurrent paclitaxel and carboplatin. The median follow-up period was 15 months (range 1.7-120). The median overall survival (OS) for all patients after salvage dCRT was 22 months (95% CI 6.2-37.6). The 1-, 3-, and 5-year OS was 72%, 31%, and 28%, respectively. Median survival after salvage dCRT for a regional lymph node recurrence was 33 months (95% CI 5.8-60.3) versus 14 months (95% CI 6.8-21.6) for a recurrence at the anastomosis (P = 0.022, logrank). Median OS was 35 months for the squamous cell carcinoma group and 19 months for the adenocarcinoma group (P = 0.67). Sixteen of 39 patients developed a locoregional recurrence after salvaged dCRT. The median locoregional recurrence-free survival (LRFS) was 24 months. The 1-, 3-, and 5-year LRFS was 79%, 36%, and 36%, respectively. Median disease-free survival (DFS) was 15 months. The 1-, 3-, and 5-year DFS was 66%, 27%, and 27%, respectively. Of 16 patients, 8 (50%) with a primary failure at the site of the anastomosis developed a local recurrence after salvaged dCRT compared to 7 of 22 patients (32%) with a primary recurrence in a lymph node. Definitive chemoradiation is a feasible and effective treatment for locoregional recurrent esophageal cancer outside a previously irradiated area, and should be given with a curative intent. This holds true for recurrence of both squamous cell carcinoma and adenocarcinoma. Lymph node recurrences have a markedly better prognosis than recurrences at the site of the anastomosis. © 2016 International Society for Diseases of the Esophagus.

Evidence for a functional role of epigenetically regulated midcluster HOXB genes in the development of Barrett esophagus

PubMed Central

di Pietro, Massimiliano; Lao-Sirieix, Pierre; Boyle, Shelagh; Cassidy, Andy; Castillo, Dani; Saadi, Amel; Eskeland, Ragnhild; Fitzgerald, Rebecca C.

2012-01-01

Barrett esophagus (BE) is a human metaplastic condition that is the only known precursor to esophageal adenocarcinoma. BE is characterized by a posterior intestinal-like phenotype in an anterior organ and therefore it is reminiscent of homeotic transformations, which can occur in transgenic animal models during embryonic development as a consequence of mutations in HOX genes. In humans, acquired deregulation of HOX genes during adulthood has been linked to carcinogenesis; however, little is known about their role in the pathogenesis of premalignant conditions. We hypothesized that HOX genes may be implicated in the development of BE. We demonstrated that three midcluster HOXB genes (HOXB5, HOXB6, and HOXB7) are overexpressed in BE, compared with the anatomically adjacent normal esophagus and gastric cardia. The midcluster HOXB gene signature in BE is identical to that seen in normal colonic epithelium. Ectopic expression of these three genes in normal squamous esophageal cells in vitro induces markers of intestinal differentiation, such as KRT20, MUC2, and VILLIN. In BE-associated adenocarcinoma, the activation midcluster HOXB gene is associated with loss of H3K27me3 and gain of AcH3, compared with normal esophagus. These changes in histone posttranslational modifications correlate with specific chromatin decompaction at the HOXB locus. We suggest that epigenetically regulated alterations of HOX gene expression can trigger changes in the transcriptional program of adult esophageal cells, with implications for the early stages of carcinogenesis. PMID:22603795

Effect of Remote Internet Follow-Up on Postradiotherapy Compliance Among Patients with Esophageal Cancer: A Randomized Controlled Study.

PubMed

Wang, Ping; Yang, Lin; Hua, Zhongsheng

2015-11-01

To explore the effects of using remote Internet follow-up on postradiotherapy compliance with medical advice provided to patients with esophageal cancer. Between January 1 and August 1, 2013, in total, 128 patients with esophageal squamous cell cancer treated with radiotherapy were randomly assigned to either an observation group (n=64) or a control group (n=64). The control group received routine outpatient follow-up, whereas the observation group received additional remote Internet follow-up for 6 months after discharge from the hospital. The treatment effects and compliance were investigated using a questionnaire. At 3 months and 6 months after discharge, patients in the observation group had sought significantly more consultations and undergone more periodic re-examinations than patients in the control group (all p<0.001). Furthermore, both the disease-free survival rate and the symptom reduction rate were significantly higher in the observation group compared with the control group (all p<0.001). Remote Internet follow-up is an easy and fast method for improving postradiotherapy compliance with medical instructions and promoting normalization among patients with esophageal cancer.

Laparoscopic transhiatal esophagectomy: outcomes.

PubMed

Tinoco, Renam; El-Kadre, Luciana; Tinoco, Augusto; Rios, Rodrigo; Sueth, Daniela; Pena, Felipe

2007-08-01

Laparoscopic transhiatal esophagectomy, indicated for benign and malignant esophageal diseases, is a complex operation, often associated with a high rate of morbidity and mortality. During the past decade this technique has became well accepted among specialized surgeons for the treatment of esophageal cancer, avoiding thoracotomy and reducing open access complications. The aim of the present study was to retrospectively analyze patients with esophageal cancer who underwent laparoscopic transhiatal esophagectomy. From November 1993 to August 2006, 78 patients underwent laparoscopic transhiatal esophagectomy. There were 68 cases of esophageal cancer (57 males and 21 females, age range = 28-73 years) with a predominant rate of squamous cell carcinoma (60.2%). The conversion rate was 6.4%. The mean operative time was 153 min with a 12.8% rate of cervical leak and a postoperative (30-day) mortality rate of 5.1%. The four-year survival rate was 19% as determined within a subgroup of 21 patients whose followup during the period was possible. Laparoscopic transhiatal esophagectomy is a safe alternative for experienced professionals. This access can improve mortality, hospital stay, and other outcomes when compared with open methods.

Clinical significance of preoperative and postoperative cytokeratin 19 messenger RNA level in peripheral blood of esophageal cancer patients.

PubMed

Qiao, Y-F; Chen, C-G; Yue, J; Ma, Z; Yu, Z-T

2016-11-01

The purpose of this study is to analyze the correlation between preoperative/postoperative Cytokeratin 19 (CK19) messenger RNA (mRNA) level in peripheral blood (PB) and the clinical significance in esophageal cancer patients with different clinicopathological factors. We detected the preoperative and postoperative CK19 mRNA level in the PB of 139 esophageal cancer patients who underwent complete resection and evaluated its clinical significance. We found that both the preoperative and postoperative CK19 mRNA level increased in the esophageal cancer patients with lymph node metastasis, relapse or distant metastasis compared with that in cancers without lymph node metastasis, relapse or distant metastasis. High postoperative CK19 mRNA levels indicate a short disease-free survival (DFS) for the whole cohort esophageal cancer patients, whereas the high preoperative CK19 mRNA levels only indicate a short DFS for the esophageal cancer patients with squamous cell carcinoma, TNM III stage, and lymph node metastasis. The dynamic change of CK19 mRNA levels could indicate the prognosis of esophageal cancer patients. The patients with decreasing CK19 mRNA level after surgery had good prognosis, and the patients with changeless CK19 mRNA level had poor prognosis. Taken together, CK19 mRNA levels could be a promising marker in assessing prognosis or assigning treatment for the esophageal cancer patients according to different clinicopathological factors. © 2015 International Society for Diseases of the Esophagus.

The usefulness of three-dimensional cell culture in induction of cancer stem cells from esophageal squamous cell carcinoma cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fujiwara, Daisuke; Kato, Kazunori, E-mail: kzkatou@juntendo.ac.jp; Department of Atopy Research Center, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421

2013-05-17

Highlights: •Spheroids were created from esophageal carcinoma cells using NanoCulture® Plates. •The proportion of strongly ALDH-positive cells increased in 3-D culture. •Expression of cancer stem cell-related genes was enhanced in 3-D culture. •CA-9 expression was enhanced, suggesting hypoxia had been induced in 3-D culture. •Drug resistance was increased. 3-D culture is useful for inducing cancer stem cells. -- Abstract: In recent years, research on resistance to chemotherapy and radiotherapy in cancer treatment has come under the spotlight, and researchers have also begun investigating the relationship between resistance and cancer stem cells. Cancer stem cells are assumed to be present inmore » esophageal cancer, but experimental methods for identification and culture of these cells have not yet been established. To solve this problem, we created spheroids using a NanoCulture® Plate (NCP) for 3-dimensional (3-D) cell culture, which was designed as a means for experimentally reproducing the 3-D structures found in the body. We investigated the potential for induction of cancer stem cells from esophageal cancer cells. Using flow cytometry we analyzed the expression of surface antigen markers CD44, CD133, CD338 (ABCG2), CD318 (CDCP1), and CD326 (EpCAM), which are known cancer stem cell markers. None of these surface antigen markers showed enhanced expression in 3-D cultured cells. We then analyzed aldehyde dehydrogenase (ALDH) enzymatic activity using the ALDEFLUOR reagent, which can identify immature cells such as stem cells and precursor cells. 3-D-cultured cells were strongly positive for ALDH enzyme activity. We also analyzed the expression of the stem cell-related genes Sox-2, Nanog, Oct3/4, and Lin28 using RT-PCR. Expression of Sox-2, Nanog, and Lin28 was enhanced. Analysis of expression of the hypoxic surface antigen marker carbonic anhydrase-9 (CA-9), which is an indicator of cancer stem cell induction and maintenance, revealed that CA-9 expression was enhanced, suggesting that hypoxia had been induced. Comparison of cancer drug resistance using cisplatin and doxorubicin in 3-D-cultured esophageal cancer cells showed that cancer drug resistance had increased. These results indicate that 3-D culture of esophageal squamous cell carcinoma lines is a useful method for inducing cancer stem cells.« less

7-Hydroxystaurosporine and Irinotecan Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors or Triple Negative Breast Cancer (Currently Accruing Only Triple-negative Breast Cancer Patients Since 6/8/2007)

ClinicalTrials.gov

2013-09-27

Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Estrogen Receptor-negative Breast Cancer; Extensive Stage Small Cell Lung Cancer; Gastrointestinal Stromal Tumor; HER2-negative Breast Cancer; Metastatic Gastrointestinal Carcinoid Tumor; Ovarian Sarcoma; Ovarian Stromal Cancer; Progesterone Receptor-negative Breast Cancer; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adult Primary Liver Cancer; Recurrent Anal Cancer; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Borderline Ovarian Surface Epithelial-stromal Tumor; Recurrent Breast Cancer; Recurrent Cervical Cancer; Recurrent Colon Cancer; Recurrent Endometrial Carcinoma; Recurrent Esophageal Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Recurrent Prostate Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Cell Lung Cancer; Recurrent Small Intestine Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Small Intestine Adenocarcinoma; Small Intestine Leiomyosarcoma; Small Intestine Lymphoma; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Anal Cancer; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Borderline Ovarian Surface Epithelial-stromal Tumor; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Endometrial Carcinoma; Stage IV Esophageal Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Gastric Cancer; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Pancreatic Cancer; Stage IV Prostate Cancer; Stage IV Rectal Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Stage IVA Cervical Cancer; Stage IVB Cervical Cancer; Triple-negative Breast Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer; Unspecified Adult Solid Tumor, Protocol Specific; Untreated Metastatic Squamous Neck Cancer With Occult Primary

Physical activity is associated with reduced risk of esophageal cancer, particularly esophageal adenocarcinoma: a systematic review and meta-analysis

PubMed Central

2014-01-01

Background Physical activity has been inversely associated with risk of several cancers. We performed a systematic review and meta-analysis to evaluate the association between physical activity and risk of esophageal cancer (esophageal adenocarcinoma [EAC] and/or esophageal squamous cell carcinoma [ESCC]). Methods We conducted a comprehensive search of bibliographic databases and conference proceedings from inception through February 2013 for observational studies that examined associations between recreational and/or occupational physical activity and esophageal cancer risk. Summary adjusted odds ratio (OR) estimates with 95% confidence intervals (CI) were estimated using the random-effects model. Results The analysis included 9 studies (4 cohort, 5 case–control) reporting 1,871 cases of esophageal cancer among 1,381,844 patients. Meta-analysis demonstrated that the risk of esophageal cancer was 29% lower among the most physically active compared to the least physically active subjects (OR, 0.71; 95% CI, 0.57-0.89), with moderate heterogeneity (I2 = 47%). On histology-specific analysis, physical activity was associated with a 32% decreased risk of EAC (4 studies, 503 cases of EAC; OR, 0.68; 95% CI, 0.55-0.85) with minimal heterogeneity (I2 = 0%). There were only 3 studies reporting the association between physical activity and risk of ESCC with conflicting results, and the meta-analysis demonstrated a null association (OR, 1.10; 95% CI, 0.21-5.64). The results were consistent across study design, geographic location and study quality, with a non-significant trend towards a dose–response relationship. Conclusions Meta-analysis of published observational studies indicates that physical activity may be associated with reduced risk of esophageal adenocarcinoma. Lifestyle interventions focusing on increasing physical activity may decrease the global burden of EAC. PMID:24886123

Analysis of thermal effects in endoscopic nanocarriers-based photodynamic therapy applied to esophageal diseases

NASA Astrophysics Data System (ADS)

Salas-García, I.; Fanjul-Vélez, F.; Ortega-Quijano, N.; Wilfert, O.; Hudcova, L.; Poliak, J.; Barcik, P.; Arce-Diego, J. L.

2014-02-01

In this work we propose a predictive model that allows the study of thermal effects produced when the optical radiation interacts with an esophageal or stomach disease with gold nanoparticles embedded. The model takes into account light distribution in the tumor tissue by means of a Monte Carlo method. Mie theory is used to obtain the gold nanoparticles optical properties and the thermal model employed is based on the bio-heat equation. The complete model was applied to two types of tumoral tissue (squamous cell carcinoma located in the esophagus and adenocarcinoma in the stomach) in order to study the thermal effects induced by the inclusion of gold nanoparticles.

Cigarette smoking and hOGG1 Ser326Cys polymorphism are associated with 8-OHdG accumulation on mitochondrial DNA in thoracic esophageal squamous cell carcinoma.

PubMed

Lin, Chen-Sung; Wang, Liang-Shun; Chou, Teh-Ying; Hsu, Wen-Hu; Lin, Hui-Chen; Lee, Shu-Yu; Lee, Mau-Hua; Chang, Shi-Chuan; Wei, Yau-Huei

2013-12-01

We examined whether cigarette smoking affects the degrees of oxidative damage (8-hydroxyl-2'-deoxyguanosine [8-OHdG]) on mitochondrial DNA (mtDNA), whether the degree of 8-OHdG accumulation on mtDNA is related to the increased total mtDNA copy number, and whether human 8-oxoguanine DNA glycosylase 1 (hOGG1) Ser326Cys polymorphisms affect the degrees of 8-OHdG accumulation on mtDNA in thoracic esophageal squamous cell carcinoma (TESCC). DNA extracted from microdissected tissues of paired noncancerous esophageal muscles, noncancerous esophageal mucosa, and cancerous TESCC nests (n = 74) along with metastatic lymph nodes (n = 38) of 74 TESCC patients was analyzed. Both the mtDNA copy number and mtDNA integrity were analyzed by quantitative real-time polymerase chain reaction (PCR). The hOGG1 Ser326Cys polymorphisms were identified by restriction fragment length polymorphism PCR and PCR-based direct sequencing. Among noncancerous esophageal mucosa, cancerous TESCC nests, and metastatic lymph nodes, the mtDNA integrity decreased (95.2 to 47.9 to 18.6 %; P < 0.001) and the mtDNA copy number disproportionally increased (0.163 to 0.204 to 0.207; P = 0.026). In TESCC, higher indexes of cigarette smoking (0, 0-20, 20-40, and >40 pack-years) were related to an advanced pathologic N category (P = 0.038), elevated mtDNA copy number (P = 0.013), higher mtDNA copy ratio (P = 0.028), and increased mtDNA integrity (P = 0.069). The TESCC mtDNA integrity in patients with Ser/Ser, Ser/Cys, and Cys/Cys hOGG1 variants decreased stepwise from 65.2 to 52.1 to 41.3 % (P = 0.051). Elevated 8-OHdG accumulations on mtDNA in TESCC were observed. Such accumulations were associated with a compensatory increase in total mtDNA copy number, indexes of cigarette smoking, and hOGG1 Ser326Cys polymorphisms.

Statin use is associated with reduced risk of histologic subtypes of esophageal cancer: a nested case-control analysis.

PubMed

Alexandre, Leo; Clark, Allan B; Bhutta, Hina Y; Holt, Sean; Lewis, Michael P N; Hart, Andrew R

2014-03-01

Most patients with esophageal adenocarcinoma (EAC) or squamous cell cancer (ESCC) present with advanced, incurable disease. Statins have reported anti-carcinogenic effects and may be chemoprotective. We investigated the association between regular use of statins and the main histologic subtypes of esophageal malignancy (EAC, esophagogastric junctional adenocarcinoma, and ESCC) in the UK general population. We identified all individuals in the UK General Practice Research Database diagnosed with esophageal cancer from 2000 through 2009. Patients were linked to the National Cancer Registry to confirm histologic subtypes. Each patient was matched with up to 4 controls for age, sex, and practice. We performed a nested case-control analysis using conditional logistic regression to estimate the risk of each subtype with regular statin use, adjusted for body mass index, smoking, alcohol intake, and concomitant use of medications. In total, 581 participants with EAC, 213 with esophagogastric junctional adenocarcinoma, and 332 with ESCC were matched to 2167, 783, and 1242 controls, respectively. Regular statin use was inversely associated with development of EAC (odds ratio = 0.58; 95% confidence interval: 0.39-0.87) (with significant dose and duration responses) and esophagogastric junctional adenocarcinoma (odds ratio = 0.29; 95% confidence interval: 0.09-0.92) (with high-dose use only). Statin use for 1-4 years was inversely associated with ESCC (odds ratio = 0.51; 95% confidence interval: 0.27-0.98). In a nested case-control analysis of a UK population-based cohort, statin use was inversely associated with histologic subtypes of esophageal cancer. Randomized controlled trials are warranted to determine whether statins have chemopreventive effects in high-risk groups. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Genomic profiling of 766 cancer-related genes in archived esophageal normal and carcinoma tissues.

PubMed

Chen, Jing; Guo, Liping; Peiffer, Daniel A; Zhou, Lixin; Chan, Owen Tsan Mo; Bibikova, Marina; Wickham-Garcia, Eliza; Lu, Shih-Hsin; Zhan, Qimin; Wang-Rodriguez, Jessica; Jiang, Wei; Fan, Jian-Bing

2008-05-15

We employed the BeadArraytrade mark technology to perform a genetic analysis in 33 formalin-fixed, paraffin-embedded (FFPE) human esophageal carcinomas, mostly squamous-cell-carcinoma (ESCC), and their adjacent normal tissues. A total of 1,432 single nucleotide polymorphisms (SNPs) derived from 766 cancer-related genes were genotyped with partially degraded genomic DNAs isolated from these samples. This directly targeted genomic profiling identified not only previously reported somatic gene amplifications (e.g., CCND1) and deletions (e.g., CDKN2A and CDKN2B) but also novel genomic aberrations. Among these novel targets, the most frequently deleted genomic regions were chromosome 3p (including tumor suppressor genes FANCD2 and CTNNB1) and chromosome 5 (including tumor suppressor gene APC). The most frequently amplified genomic region was chromosome 3q (containing DVL3, MLF1, ABCC5, BCL6, AGTR1 and known oncogenes TNK2, TNFSF10, FGF12). The chromosome 3p deletion and 3q amplification occurred coincidently in nearly all of the affected cases, suggesting a molecular mechanism for the generation of somatic chromosomal aberrations. We also detected significant differences in germline allele frequency between the esophageal cohort of our study and normal control samples from the International HapMap Project for 10 genes (CSF1, KIAA1804, IL2, PMS2, IRF7, FLT3, NTRK2, MAP3K9, ERBB2 and PRKAR1A), suggesting that they might play roles in esophageal cancer susceptibility and/or development. Taken together, our results demonstrated the utility of the BeadArray technology for high-throughput genetic analysis in FFPE tumor tissues and provided a detailed genetic profiling of cancer-related genes in human esophageal cancer. (c) 2008 Wiley-Liss, Inc.

Useful strategies to prevent severe stricture after endoscopic submucosal dissection for superficial esophageal neoplasm.

PubMed

Uno, Kaname; Iijima, Katsunori; Koike, Tomoyuki; Shimosegawa, Tooru

2015-06-21

The minimal invasiveness of endoscopic submucosal dissection (ESD) prompted us to apply this technique to large-size early esophageal squamous cell carcinoma and Barrett's adenocarcinoma, despite the limitations in the study population and surveillance duration. A post-ESD ulceration of greater than three-fourths of esophageal circumference was advocated as an important risk factor for refractory strictures that require several sessions of dilation therapy. Most of the preoperative conditions are asymptomatic, but dilatation treatment for dysphagia associated with the stricture has potential risks of severe complications and a worsening of quality of life. Possible mechanisms of dysphasia were demonstrated based on dysmotility and pathological abnormalities at the site: (1) delayed mucosal healing; (2) severe inflammation and disorganized fibrosis with abundant extracellular matrices in the submucosa; and (3) atrophy in the muscularis proper. However, reports on the administration of anti-scarring agents, preventive dilation therapies, and regenerative medicine demonstrated limited success in stricture prevention, and there were discrepancies in the study designs and protocols of these reports. The development and consequent long-term assessments of new prophylactic technologies on the promotion of wound healing and control of the inflammatory/tumor microenvironment will require collaboration among various research fields because of the limited accuracy of preoperative staging and high-risk of local recurrence.

Outcomes of Radiofrequency Ablation for Dysplastic Barrett's Esophagus: A Comprehensive Review

PubMed Central

Iabichino, Giuseppe; Arena, Monica; Consolo, Pierluigi; Morace, Carmela; Opocher, Enrico; Mangiavillano, Benedetto

2016-01-01

Barrett's esophagus is a condition in which the normal squamous lining of the esophagus has been replaced by columnar epithelium containing intestinal metaplasia induced by recurrent mucosal injury related to gastroesophageal reflux disease. Barrett's esophagus is a premalignant condition that can progress through a dysplasia-carcinoma sequence to esophageal adenocarcinoma. Multiple endoscopic ablative techniques have been developed with the goal of eradicating Barrett's esophagus and preventing neoplastic progression to esophageal adenocarcinoma. For patients with high-grade dysplasia or intramucosal neoplasia, radiofrequency ablation with or without endoscopic resection for visible lesions is currently the most effective and safe treatment available. Recent data demonstrate that, in patients with Barrett's esophagus and low-grade dysplasia confirmed by a second pathologist, ablative therapy results in a statistically significant reduction in progression to high-grade dysplasia and esophageal adenocarcinoma. Treatment of dysplastic Barrett's esophagus with radiofrequency ablation results in complete eradication of both dysplasia and of intestinal metaplasia in a high proportion of patients with a low incidence of adverse events. A high proportion of treated patients maintain the neosquamous epithelium after successful treatment without recurrence of intestinal metaplasia. Following successful endoscopic treatment, endoscopic surveillance should be continued to detect any recurrent intestinal metaplasia and/or dysplasia. This paper reviews all relevant publications on the endoscopic management of Barrett's esophagus using radiofrequency ablation. PMID:28070182

Useful strategies to prevent severe stricture after endoscopic submucosal dissection for superficial esophageal neoplasm

PubMed Central

Uno, Kaname; Iijima, Katsunori; Koike, Tomoyuki; Shimosegawa, Tooru

2015-01-01

The minimal invasiveness of endoscopic submucosal dissection (ESD) prompted us to apply this technique to large-size early esophageal squamous cell carcinoma and Barrett’s adenocarcinoma, despite the limitations in the study population and surveillance duration. A post-ESD ulceration of greater than three-fourths of esophageal circumference was advocated as an important risk factor for refractory strictures that require several sessions of dilation therapy. Most of the preoperative conditions are asymptomatic, but dilatation treatment for dysphagia associated with the stricture has potential risks of severe complications and a worsening of quality of life. Possible mechanisms of dysphasia were demonstrated based on dysmotility and pathological abnormalities at the site: (1) delayed mucosal healing; (2) severe inflammation and disorganized fibrosis with abundant extracellular matrices in the submucosa; and (3) atrophy in the muscularis proper. However, reports on the administration of anti-scarring agents, preventive dilation therapies, and regenerative medicine demonstrated limited success in stricture prevention, and there were discrepancies in the study designs and protocols of these reports. The development and consequent long-term assessments of new prophylactic technologies on the promotion of wound healing and control of the inflammatory/tumor microenvironment will require collaboration among various research fields because of the limited accuracy of preoperative staging and high-risk of local recurrence. PMID:26109798

Phase I/II Study of IMMU-132 in Patients With Epithelial Cancers

ClinicalTrials.gov

2018-04-23

Colorectal Cancer; Gastric Adenocarcinoma; Esophageal Cancer; Hepatocellular Carcinoma; Non-small Cell Lung Cancer; Small Cell Lung Cancer; Ovarian Epithelial Cancer; Carcinoma Breast Stage IV; Hormone-refractory Prostate Cancer; Pancreatic Ductal Adenocarcinoma; Head and Neck Cancers- Squamous Cell; Renal Cell Cancer; Urinary Bladder Neoplasms; Cervical Cancer; Endometrial Cancer; Follicular Thyroid Cancer; Glioblastoma Multiforme; Triple Negative Breast Cancer

PIK3CA gene mutations in Northwest Chinese esophageal squamous cell carcinoma

PubMed Central

Liu, Shi-Yuan; Chen, Wei; Chughtai, Ehtesham Annait; Qiao, Zhe; Jiang, Jian-Tao; Li, Shao-Min; Zhang, Wei; Zhang, Jin

2017-01-01

AIM To evaluate PIK3CA gene mutational status in Northwest Chinese esophageal squamous cell carcinoma (ESCC) patients, and examine the associations of PIK3CA gene mutations with clinicopathological characteristics and clinical outcome. METHODS A total of 210 patients with ESCC who underwent curative resection were enrolled in this study. Pyrosequencing was applied to investigate mutations in exons 9 and 20 of PIK3CA gene in 210 Northwest Chinese ESCCs. The associations of PIK3CA gene mutations with clinicopathological characteristics and clinical outcome were examined. RESULTS PIK3CA gene mutations in exon 9 were detected in 48 cases (22.9%) of a non-biased database of 210 curatively resected Northwest Chinese ESCCs. PIK3CA gene mutations were not associated with sex, tobacco use, alcohol use, tumor location, stage, or local recurrence. When compared with wild-type PIK3CA gene cases, patients with PIK3CA gene mutations in exons 9 experienced significantly better disease-free survival and overall survival rates. CONCLUSION The results of this study suggest that PIK3CA gene mutations could act as a prognostic biomarker in Northwest Chinese ESCC patients. PMID:28465643

Etiology and Prevention of Esophageal Cancer

PubMed Central

Yang, Chung S.; Chen, Xiaoxin; Tu, Shuiping

2016-01-01

Background Esophageal cancer (EC) occurs commonly, especially in Asia, and is the sixth leading cause of cancer deaths worldwide. Recently, great progress has been made in research on the etiology and prevention of EC. Summary The major risk factors for esophageal squamous cell carcinoma (ESCC) are tobacco smoking and alcohol drinking, which act synergistically. Dietary parameters, including dietary carcinogens and insufficiency of micronutrients, could also be important risk factors in certain areas. A common etiological factor for both EC and some other cancers are low levels of intake of fruits and vegetables. With improvements in diet and drinking water in developing countries, the incidence of ESCC decreased. However, in economically well-developed countries, the incidence of esophageal adenocarcinoma (EAC) has markedly increased in the past 40 years. The major etiological factor for EAC is gastroesophageal reflux, which is also an etiological factor for gastric cardia adenocarcinoma (GCA). In certain areas of China, the occurrence of GCA is closely related to ESCC. Susceptibility genes for EC are starting to be discovered, and this may help to identify high-risk groups that have more need for preventive measures. Mitigation of the risk factors, early detection and treatment of precancerous lesions are effective approaches for prevention. Smoking cessation, avoidance of excessive alcohol, meat and caloric consumption, increasing physical activity and frequent consumption of vegetables and fruits are prudent lifestyle modifications for the prevention of EC as well as other diseases. Key Message The etiology of EC includes tobacco smoking, alcohol drinking, low levels of intake of fruits and vegetables as well as gastroesophageal reflux and susceptibility genes. Practical Implications A healthy lifestyle including smoking cessation, increasing physical activity, consumption of vegetables as well as reduction of alcohol intake and caloric consumption are major approaches to the prevention of EC. PMID:27722152

[Incidence and survival of esophageal cancer with different histological types in Linzhou between 2003 and 2012].

PubMed

Liu, S Z; Yu, L; Chen, Q; Quan, P L; Cao, X Q; Sun, X B

2017-05-06

Objective: To investigate the incidence and survival of esophageal cancer with different histological types and to understand the incidence trend and burden of esophageal cancer in Linzhou during 2003-2012. Methods: All incidence records of esophageal cancer and population reported were collected from Linzhou Cancer Registry during 2003-2012. Incidence rate was calculated using gender and histological types. Age standardized incidence rate was calculated according to world Segi's population and Chinese census data in 2000. Age standardized incidence rate by world population between 2003 and 2012 was analyzed with JoinPoint regression model and estimated annual percentage change (EAPC) was calculated. 5-year survival rate was calculated with Kaplan-Meier model. Results: There were 8 229 esophageal cancer cases in Linzhou during 2003-2012. The average annual incidence rate was 80.08/100 000 (8 229/10 276 481). Among all esophageal cancer cases, 7 019 (85.3%) were diagnosed as esophageal squamous cell carcinoma (ESCC). In Linzhou, the age standardized incidence rate by Chinese standard population and by world standard population was 80.92/100 000 and 81.85/100 000 in 2003, 67.97/100 000 and 68.63/100 000 in 2012. JoinPoint regression model showed that EAPC was-12.9% (95 %CI: -16.4%--9.1%) for other and unspecified histological type between 2003 and 2012. The EAPC was-5.5% (95 %CI: -9.2%--1.6%) for esophageal cancer between 2007 and 2012,-5.4% (95 %CI: -7.0%--3.9%) for esophageal cancer in female between 2006 and 2012,-4.9% (95 %CI: -9.5%--0.1%) for ESCC between 2007 and 2012. The 5-year prevalence of esophageal cancer was 215.49 per 100 000 (2 337/1 084 493), and 5 489 died within 5 years after incidence. 5-year survival rate of esophageal cancer was 34.6% (95 %CI: 33.5%-35.6%). Conclusion: Esophageal cancer had a decreasing trend in Linzhou. The survival rate was increasing. But, esophageal cancer was still a major burden in Linzhou. The major histological type was ESCC. ESCC had a similar decreasing trend with esophageal cancer.

Increased risk of stomach and esophageal malignancies in people with AIDS.

PubMed

Persson, E Christina; Shiels, Meredith S; Dawsey, Sanford M; Bhatia, Kishor; Anderson, Lesley A; Engels, Eric A

2012-10-01

People infected with human immunodeficiency virus (HIV) have an increased risk of some malignancies, but little is known about the effects of infection on risk of cancers of the upper gastrointestinal tract. We evaluated the risks of different histologic and anatomic subtypes of carcinomas and non-Hodgkin lymphomas (NHLs) of the stomach and esophagus in people with acquired immunodeficiency syndrome (AIDS). We analyzed data from the HIV/AIDS Cancer Match Study, which links data collected from 1980 to 2007 for 16 US population-based HIV and AIDS and cancer registries. We compared risks of stomach and esophageal malignancies in people with AIDS (N = 596,955) with those of the general population using standardized incidence ratios (SIRs). We assessed calendar trends using Poisson regression. People with AIDS had increased risks of carcinomas of the esophagus (SIR, 1.69; 95% confidence interval [CI], 1.37-2.07; n = 95) and stomach (SIR, 1.44; 95% CI, 1.17-1.76; n = 96). Risk was increased for esophageal adenocarcinoma (SIR, 1.91; 95% CI, 1.31-2.70) and squamous cell carcinoma (SIR, 1.47; 95% CI, 1.10-1.92). People with AIDS had greater risks of carcinomas of the gastric cardia (SIR, 1.36; 95% CI, 0.83-2.11) and noncardia (SIR, 1.53; 95% CI, 1.12-2.05) than the general population. Although most stomach and esophageal NHLs that developed in people with AIDS were diffuse large B-cell lymphomas, these individuals also had an increased risk of stomach mucosa-associated lymphoid tissue lymphoma (SIR, 5.99; 95% CI, 3.19-10.2; n = 13). The incidence of carcinomas remained fairly constant over time, but rates of NHL decreased from 1980 to 2007 (P(trend) < .0001). People with AIDS are at increased risk for developing esophageal and stomach carcinomas and NHLs. Although the incidence of NHL decreased from 1980 to 2007 as treatments for HIV infection improved, HIV-infected individuals face continued risks of esophageal and stomach carcinomas. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

Increased Risk of Stomach and Esophageal Malignancies in People With AIDS

PubMed Central

Persson, E. Christina; Shiels, Meredith S.; Dawsey, Sanford M.; Bhatia, Kishor; Anderson, Lesley A.; Engels, Eric A.

2013-01-01

BACKGROUND & AIMS People infected with human immunodeficiency virus (HIV) have an increased risk of some malignancies, but little is known about the effects of infection on risk of cancers of the upper gastrointestinal tract. We evaluated the risks of different histologic and anatomic subtypes of carcinomas and non-Hodgkin lymphomas (NHLs) of the stomach and esophagus in people with acquired immunodeficiency syndrome (AIDS). METHODS We analyzed data from the HIV/AIDS Cancer Match Study, which links data collected from 1980 to 2007 for 16 US population-based HIV and AIDS and cancer registries. We compared risks of stomach and esophageal malignancies in people with AIDS (N = 596,955) with those of the general population using standardized incidence ratios (SIRs). We assessed calendar trends using Poisson regression. RESULTS People with AIDS had increased risks of carcinomas of the esophagus (SIR, 1.69; 95% confidence interval [CI], 1.37–2.07; n = 95) and stomach (SIR, 1.44; 95% CI, 1.17–1.76; n = 96). Risk was increased for esophageal adenocarcinoma (SIR, 1.91; 95% CI, 1.31–2.70) and squamous cell carcinoma (SIR, 1.47; 95% CI, 1.10 –1.92). People with AIDS had greater risks of carcinomas of the gastric cardia (SIR, 1.36; 95% CI, 0.83–2.11) and noncardia (SIR, 1.53; 95% CI, 1.12–2.05) than the general population. Although most stomach and esophageal NHLs that developed in people with AIDS were diffuse large B-cell lymphomas, these individuals also had an increased risk of stomach mucosa–associated lymphoid tissue lymphoma (SIR, 5.99; 95% CI, 3.19 –10.2; n = 13). The incidence of carcinomas remained fairly constant over time, but rates of NHL decreased from 1980 to 2007 (Ptrend < .0001). CONCLUSIONS People with AIDS are at increased risk for developing esophageal and stomach carcinomas and NHLs. Although the incidence of NHL decreased from 1980 to 2007 as treatments for HIV infection improved, HIV-infected individuals face continued risks of esophageal and stomach carcinomas. PMID:22796240

Esophageal cancer diagnosed by high-resolution manometry of the esophagus: A case report

PubMed Central

LIU, RONGBEI; CHU, HUA; XU, FEI; CHEN, SHUJIE

2016-01-01

A 48-year-old female who presented with a history of dysphagia for 5 months and regurgitation for 1 week was referred to the Sir Run Run Shaw Hospital (Hangzhou, China) for further evaluation, since the gastroscopy and endoscopic ultrasound performed in local hospitals did not reveal the presence of cancer. High-resolution manometry (HRM) of the esophagus was performed to determine the patient's condition, and revealed an abnormal high-pressure zone that was located 33 cm from the incisor and did not relax upon swallowing. Synchronous waves were observed, and the pressure of the esophageal lumen was found to increase with secondary synchronous peristaltic waves. The lower esophageal sphincter was 39 cm from the incisor and relaxed upon swallowing. The abnormal high-pressure zone could have been caused by an obstruction, and therefore an upper gastrointestinal series (barium swallow) test and gastroscopy were recommended to further pinpoint the cause. Following the two examinations, mid-esophageal cancer was considered as a possible diagnosis. A biopsy was performed and the final diagnosis was that of basaloid squamous cell carcinoma. The findings of the present study suggest that, for patients with evident symptoms of esophageal motor dysfunction without significant gastroscopy findings, HRM is recommended. PMID:27123076

Foretinib Enhances the Radiosensitivity in Esophageal Squamous Cell Carcinoma by Inhibiting Phosphorylation of c-Met

PubMed Central

Chen, Guang-Zong; Dai, Wang-Shu; Zhu, Hong-Cheng; Song, Hong-Mei; Yang, Xi; Wang, Yuan-Dong; Min, Hua; Lu, Qian; Liu, Shu; Sun, Xin-Chen; Zeng, Xiao-Ning

2017-01-01

As a crucial event involved in the metastasis and relapse of esophageal cancer, c-Met overexpression has been considered as one of the culprits responsible for the failure in patients who received radiochemotherapy. Since c-Met has been confirmed to be pivotal for cell survival, proliferation and migration, little is known about its impact on the regulation of radiosensitivity in esophageal cancer. The present study investigated the radiosensitization effects of c-Met inhibitor foretinib in ECA-109 and TE-13 cell lines. Foretinib inhibited c-Met signaling in a dose-dependent manner resulting in decreases in the cell viability of ECA-109 and TE-13. Pretreatment with foretinib synergistically prompted cell apoptosis and G2/M arrest induced by irradiation. Moreover, decreases ability of DNA damage repair was also observed. In vivo studies confirmed that the combinatorial use of foretinib with irradiation significantly diminishes tumor burden compared to either treatment alone. The present findings implied a crucial role of c-Met in the modulation of radiosensitization in esophageal cancer, and foretinib increased the radiosensitivity in ECA-109 and TE-13 cells mainly via c-Met signaling, highlighting a novel profile of foretinib as a potential radiosensitizer for the treatment of esophageal cancer. PMID:28529610

Aberrant methylation of DACT1 and DACT2 are associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma.

PubMed

Guo, Yan-Li; Shan, Bao-En; Guo, Wei; Dong, Zhi-Ming; Zhou, Zhen; Shen, Su-Peng; Guo, Xin; Liang, Jia; Kuang, Gang

2017-01-11

The DACT (Dishevelled-associated antagonist of β-catenin) family of scaffold proteins may play important roles in tumorigenesis. However, the epigenetic changes of DACT1, 2, 3 and their effect on esophageal squamous cell carcinoma (ESCC) have not been investigated so far. The aim of this study was to investigate the promoter methylation and expression of DACT family, in order to elucidate more information on the role of DACT with regard to the progression and prognosis of ESCC. MSP and BGS methods were respectively applied to examine the methylation status of DACT; RT-PCR, Western blot and immunohistochemistry methods were respectively used to determine the mRNA and protein expression of DACT; MTT, Colony-formation and Wound-healing assay were performed to assess the effect of DACT1 and DACT2 on proliferation and migration of esophageal cancer cells. Frequent reduced expression of DACT1, DACT2 and DACT3 were found in esophageal cancer cell lines and the expression levels of DACT1 and DACT2 were reversed by 5-Aza-Dc. Decreased mRNA and protein expression of DACT1 and DACT2 were observed in ESCC tumor tissues and were associated with the methylation status of transcription start site (TSS) region. The hypermethylation of CpG islands (CGI) shore region in DACT1 was observed both in tumor and corresponding adjacent tissues but wasn't related to the transcriptional inhibition of DACT1. The methylation status of TSS region in DACT1 and DACT2 and the protein expression of DACT2 were independently associated with ESCC patients' prognosis. The TSS region hypermethylation may be one of the main mechanisms for reduced expression of DACT1 and DACT2 in ESCC. The simultaneous methylation of DACT1 and DACT2 may play important roles in progression of ESCC and may serve as prognostic methylation biomarkers for ESCC patients.

Macrophage Migration Inhibitory Factor Stimulates Angiogenic Factor Expression and Correlates With Differentiation and Lymph Node Status in Patients With Esophageal Squamous Cell Carcinoma

PubMed Central

Ren, Yi; Law, Simon; Huang, Xin; Lee, Ping Yin; Bacher, Michael; Srivastava, Gopesh; Wong, John

2005-01-01

Objective: The objectives of this study were: 1) to examine the expression of macrophage migration inhibitory factor (MIF) in esophageal squamous cell carcinoma (ESCC); 2) to see if a relationship exists between MIF expression, clinicopathologic features, and long-term prognosis; and 3) to ascertain the possible biologic function of MIF in angiogenesis. Summary Background Data: MIF has been linked to fundamental processes such as those controlling cell proliferation, cell survival, angiogenesis, and tumor progression. Its role in ESCC, and the correlation of MIF expression and tumor pathologic features in patients, has not been elucidated. Methods: The expression of MIF in tumor and nontumor tissues was examined by immunohistochemical staining. Concentrations of MIF, vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) in patients’ sera and in the supernatant of tumor cells culture were examined by ELISA. Correlations with clinicopathologic factors were made. Results: In 72 patients with ESCC, intracellular MIF was overexpressed in esophagectomy specimens. The expression of MIF correlated with both tumor differentiation and lymph node status. The median survival in the low-MIF expression group (<50% positively stained cancer cells on immunohistochemistry) and high expression group (≥50% positively stained cancer cells) was 28.3 months and 15.8 months, respectively (P = 0.03). The 3-year survival rates for the 2 groups were 37.7% and 12.1%, respectively. MIF expression was related to microvessel density; increased MIF serum levels also correlated with higher serum levels of VEGF. In addition, in vitro MIF stimulation of esophageal cancer cell lines induced a dose-dependent increase in VEGF and IL-8 secretion. Conclusions: These results demonstrate, for the first time, that human esophageal carcinomas express and secrete large amounts of MIF. Through its effects on VEGF and IL-8, MIF may serve as an autocrine factor in angiogenesis and thus play an important role in the pathogenesis of ESCC. PMID:15973102

Three-dimensional conformal radiotherapy with concurrent chemotherapy for postoperative recurrence of esophageal squamous cell carcinoma: clinical efficacy and failure pattern

PubMed Central

2013-01-01

Background To assess the therapeutic outcome and failure pattern of three-dimensional conformal radiotherapy (3D-CRT)-based concurrent chemoradiotherapy (CCRT) for recurrence of esophageal squamous cell carcinoma (SCC) after radical surgery. Methods Treatment outcome and failure pattern were retrospectively evaluated in 83 patients with localized cervical and thoracic recurrences after radical surgery for thoracic esophageal SCC. All patients were treated with 3DCRT-based CCRT (median radiation dose 60 Gy), in which 39 received concurrent cisplatin plus 5-fluorouracil (PF), and 44 received concurrent docetaxel plus cisplatin (TP). Treatment response was evaluated at 1–3 months after CCRT. Results With a median follow-up of 34 months (range, 2–116 months), the 3-year overall survival (OS) of all the patients was 51.8% and the median OS time was 43.0 months. The overall tumor response rate was 75.9% (63/83), with a complete remission (CR) rate of 44.6% (37/83). In univariate analysis, tumor response after CCRT (p = 0.000), recurrence site (p = 0.028) and concurrent chemotherapy (p = 0.090) showed a trend favoring better OS. Multivariate analysis revealed that tumor response after CCRT (p = 0.000) and concurrent chemotherapy (p = 0.010) were independent predictors of OS. Forty-seven patients had progressive diseases after CCRT, 27 had local failure (27/47, 57.4%), 18 had distant metastasis (18/47, 38.3%) and 2 had both local and distant failures (2/47, 4.3%). Conclusions 3DCRT-based CCRT is effective in postoperatively recurrent esophageal SCC. Patients that obtained complete remission after CCRT appeared to achieve long-term OS and might benefit from concurrent TP regimen. Local and distant failures remained high and prospective studies are needed to validate these factors. PMID:24139225

Three-dimensional conformal radiotherapy with concurrent chemotherapy for postoperative recurrence of esophageal squamous cell carcinoma: clinical efficacy and failure pattern.

PubMed

Bao, Yong; Liu, ShiLiang; Zhou, QiChao; Cai, PeiQiang; Anfossi, Simone; Li, QiaoQiao; Hu, YongHong; Liu, MengZhong; Fu, JianHua; Rong, TieHua; Li, Qun; Liu, Hui

2013-10-18

To assess the therapeutic outcome and failure pattern of three-dimensional conformal radiotherapy (3D-CRT)-based concurrent chemoradiotherapy (CCRT) for recurrence of esophageal squamous cell carcinoma (SCC) after radical surgery. Treatment outcome and failure pattern were retrospectively evaluated in 83 patients with localized cervical and thoracic recurrences after radical surgery for thoracic esophageal SCC. All patients were treated with 3DCRT-based CCRT (median radiation dose 60 Gy), in which 39 received concurrent cisplatin plus 5-fluorouracil (PF), and 44 received concurrent docetaxel plus cisplatin (TP). Treatment response was evaluated at 1-3 months after CCRT. With a median follow-up of 34 months (range, 2-116 months), the 3-year overall survival (OS) of all the patients was 51.8% and the median OS time was 43.0 months. The overall tumor response rate was 75.9% (63/83), with a complete remission (CR) rate of 44.6% (37/83). In univariate analysis, tumor response after CCRT (p = 0.000), recurrence site (p = 0.028) and concurrent chemotherapy (p = 0.090) showed a trend favoring better OS. Multivariate analysis revealed that tumor response after CCRT (p = 0.000) and concurrent chemotherapy (p = 0.010) were independent predictors of OS. Forty-seven patients had progressive diseases after CCRT, 27 had local failure (27/47, 57.4%), 18 had distant metastasis (18/47, 38.3%) and 2 had both local and distant failures (2/47, 4.3%). 3DCRT-based CCRT is effective in postoperatively recurrent esophageal SCC. Patients that obtained complete remission after CCRT appeared to achieve long-term OS and might benefit from concurrent TP regimen. Local and distant failures remained high and prospective studies are needed to validate these factors.

Phase II Study of Chemoradiotherapy With 5-Fluorouracil and Cisplatin for Stage II-III Esophageal Squamous Cell Carcinoma: JCOG Trial (JCOG 9906)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kato, Ken, E-mail: kenkato@ncc.go.jp; Muro, Kei; Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi

Purpose: In this Phase II study, we evaluated the efficacy and toxicity of chemoradiotherapy (CRT) with cisplatin (CDDP) and 5-fluorouracil (5-FU) for Stage II-III esophageal squamous cell carcinoma (ESCC). Patients and Methods: Patients with clinical Stage II-III (T1N1M0 or T2-3N0-1M0) thoracic ESCC were enrolled between April 2000 and March 2002. Chemotherapy comprised two courses of protracted infusion of 5-FU (400 mg/m{sup 2}/day) on Days 1-5 and 8-12, and 2-h infusion of CDDP (40 mg/m{sup 2}) on Days 1 and 8; this regimen was repeated every 5 weeks. Concurrent radiotherapy involved 60-Gy irradiation (30 fractions) for 8 weeks with a 2-weekmore » break. Responders received two courses of 5-FU (800 mg/m{sup 2}/day) on Days 1-5 and CDDP (80 mg/m{sup 2}) on Day 1. Final analysis was conducted in March 2007. Survival and late toxicities were monitored for 5 years. Results: The characteristics of the 76 patients enrolled were as follows: median age, 61 years; male/female, 68/8; performance status 0/1, 59/17 patients; Stage IIA/IIB/III, 26/12/38 patients. Of the 74 eligible patients, 46 (62.2%) achieved complete response. Median survival time was 29 months, with 3- and 5-year survival rates of 44.7% and 36.8%, respectively. Acute toxicities included Grade 3/4 esophagitis (17%), nausea (17%), hyponatremia (16%), and infection without neutropenia (12%). Late toxicities comprised Grade 3/4 esophagitis (13%), pericardial (16%) and pleural (9%) effusion, and radiation pneumonitis (4%), causing 4 deaths. Conclusions: CRT is effective for Stage II-III ESCC with manageable acute toxicities and can provide a nonsurgical treatment option. However, further improvement is required for reduction in late toxicity.« less

Prognostic significance of Glasgow prognostic score in patients undergoing esophagectomy for esophageal squamous cell carcinoma.

PubMed

Feng, Ji-Feng; Zhao, Qiang; Chen, Qi-Xun

2014-01-01

Recent studies have revealed that Glasgow prognostic score (GPS), an inflammation-based prognostic score, is inversely related to prognosis in a variety of cancers; high levels of GPS is associated with poor prognosis. However, few studies regarding GPS in esophageal cancer (EC) are available. The aim of this study was to determine whether the GPS is useful for predicting cancer-specific survival (CSS) of patients for esophageal squamous cell carcinoma (ESCC). The GPS was calculated on the basis of admission data as follows: Patients with elevated C-reactive protein (CRP) level (>10 mg/L) and hypoalbuminemia (<35 g/L) were assigned to GPS2. Patients with one or no abnormal value were assigned to GPS1 or GPS0, respectively. Our study showed that GPS was associated with tumor size, depth of invasion, and nodal metastasis (P<0.001). In addition, there was a negative correlation between the serum CRP and albumin (r=-0.412, P<0.001). The 5-year CSS in patients with GPS0, GPS1, and GPS2 were 60.8%, 34.7% and 10.7%, respectively (P<0.001). Multivariate analysis showed that GPS was a significant predictor of CSS. GPS1-2 had a hazard ratio (HR) of 2.399 [95% confidence interval (CI): 1.805-3.190] for 1-year CSS (P<0.001) and 1.907 (95% CI: 1.608-2.262) for 5-year CSS (P<0.001). High levels of GPS is associated with tumor progression. GPS can be considered as an independent prognostic factor in patients who underwent esophagectomy for ESCC.

Risks and Benefits of Multimodal Esophageal Cancer Treatments: A Meta-Analysis.

PubMed

Sun, Lei; Zhao, Fen; Zeng, Yan; Yi, Cheng

2017-02-19

BACKGROUND Esophageal cancer has traditionally been associated with very poor outcomes. A number of therapies are available for the treatment and palliation of esophageal cancer, but little systematic evidence compares the efficacy of different treatment strategies. This meta-analysis aimed to investigate whether treatments in addition to radiotherapy could provide better efficacy and safety. MATERIAL AND METHODS We identified a total of 12 eligible studies with 18 study arms by searching PubMed, the Cochrane Library, EMBASE, and Clinical Trials.gov without time or language restrictions. The final search was conducted on 17 August 2016. We calculated mean differences (MD) and risk ratios (RR) with 95% confidence intervals (CI) for continuous and dichotomous data, respectively. Heterogeneity was calculated and reported using Tau², Chi², and I² analyses. RESULTS Twelve studies with 18 study arms were included in the analysis. Addition of surgery to chemo-radiotherapy resulted in improved median survival time (p=0.009) compared with chemo-radiotherapy alone, but all other outcomes were unaffected. Strikingly, and in contrast with patients with squamous cell carcinomas, the subset of patients with adenocarcinoma who received therapies in addition to radiotherapy showed a significant improvement in median survival time (p<0.0001), disease-free survival (p=0.007), 2-year survival rates (p=0.002), and 3-year survival rates (p=0.01). The incidence of adverse effects increased substantially with additional therapies. CONCLUSIONS This meta-analysis reveals stark differences in outcomes in patients depending on the type of carcinoma. Patients with squamous cell carcinoma should be educated about the risks and benefits of undergoing multiple therapies.

High expression of glucose-regulated protein 78 (GRP78) is associated with metastasis and poor prognosis in patients with esophageal squamous cell carcinoma.

PubMed

Ren, Peng; Chen, Chuangui; Yue, Jie; Zhang, Jianguo; Yu, Zhentao

2017-01-01

Glucose-regulated protein 78 (GRP78) plays an important role in the invasion and metastasis of many human cancers. However, the role of this protein in the progression of invasion and metastasis in esophageal squamous cell carcinoma (ESCC) remains elusive. Immunohistochemistry and Western blot were performed to analyze GRP78 expression in 92 patients with primary ESCC. The correlation of GRP78 expression with clinicopathological factors was analyzed. In vitro, the expression levels of GRP78 were downregulated by small interfering RNA transfection in TE-1 and CaEs-17 ESCC lines. Cell invasion and migration assays were applied to determine the invasion and migratory abilities of ESCC cells. Compared with GRP78 in adjacent normal esophageal tissues, GRP78 was overexpressed in ESCC tissues. High GRP78 expression was significantly correlated with positive lymph node metastasis ( P =0.035) and advanced tumor stage ( P =0.017). Survival analysis revealed that high GRP78 expression was significantly associated with shorter overall survival ( P =0.037). In multivariate analysis, GRP78 overexpression was identified as an independent prognostic factor for overall survival ( P =0.011). si-GRP78 can significantly decrease the GRP78 expression level and reverse the invasion and migratory abilities of ESCC cells in TE-1 and CaEs-17 cell lines. These findings demonstrated that high expression of GRP78 was associated with disease progression and metastasis in ESCC and might serve as a novel prognostic marker for patients with ESCC.

High expression of glucose-regulated protein 78 (GRP78) is associated with metastasis and poor prognosis in patients with esophageal squamous cell carcinoma

PubMed Central

Ren, Peng; Chen, Chuangui; Yue, Jie; Zhang, Jianguo; Yu, Zhentao

2017-01-01

Background Glucose-regulated protein 78 (GRP78) plays an important role in the invasion and metastasis of many human cancers. However, the role of this protein in the progression of invasion and metastasis in esophageal squamous cell carcinoma (ESCC) remains elusive. Patients and methods Immunohistochemistry and Western blot were performed to analyze GRP78 expression in 92 patients with primary ESCC. The correlation of GRP78 expression with clinicopathological factors was analyzed. In vitro, the expression levels of GRP78 were downregulated by small interfering RNA transfection in TE-1 and CaEs-17 ESCC lines. Cell invasion and migration assays were applied to determine the invasion and migratory abilities of ESCC cells. Results Compared with GRP78 in adjacent normal esophageal tissues, GRP78 was overexpressed in ESCC tissues. High GRP78 expression was significantly correlated with positive lymph node metastasis (P=0.035) and advanced tumor stage (P=0.017). Survival analysis revealed that high GRP78 expression was significantly associated with shorter overall survival (P=0.037). In multivariate analysis, GRP78 overexpression was identified as an independent prognostic factor for overall survival (P=0.011). si-GRP78 can significantly decrease the GRP78 expression level and reverse the invasion and migratory abilities of ESCC cells in TE-1 and CaEs-17 cell lines. Conclusion These findings demonstrated that high expression of GRP78 was associated with disease progression and metastasis in ESCC and might serve as a novel prognostic marker for patients with ESCC. PMID:28228658

MiRNA Expression Analysis of Pretreatment Biopsies Predicts the Pathological Response of Esophageal Squamous Cell Carcinomas to Neoadjuvant Chemoradiotherapy.

PubMed

Wen, Jing; Luo, Kongjia; Liu, Hui; Liu, Shiliang; Lin, Guangrong; Hu, Yi; Zhang, Xu; Wang, Geng; Chen, Yuping; Chen, Zhijian; Li, Yi; Lin, Ting; Xie, Xiuying; Liu, Mengzhong; Wang, Huiyun; Yang, Hong; Fu, Jianhua

2016-05-01

To identify miRNA markers useful for esophageal squamous cell carcinoma (ESCC) neoadjuvant chemoradiotherapy (neo-CRT) response prediction. Neo-CRT followed by surgery improves ESCC patients' survival compared with surgery alone. However, CRT outcomes are heterogeneous, and no current methods can predict CRT responses. Differentially expressed miRNAs between ESCC pathological responders and nonresponders after neo-CRT were identified by miRNA profiling and verified by real-time quantitative polymerase chain reaction (qPCR) of 27 ESCCs in the training set. Several class prediction algorithms were used to build the response-classifying models with the qPCR data. Predictive powers of the models were further assessed with a second set of 79 ESCCs. Ten miRNAs with greater than a 1.5-fold change between pathological responders and nonresponders were identified and verified, respectively. A support vector machine (SVM) prediction model, composed of 4 miRNAs (miR-145-5p, miR-152, miR-193b-3p, and miR-376a-3p), were developed. It provided overall accuracies of 100% and 87.3% for discriminating pathological responders and nonresponders in the training and external validation sets, respectively. In multivariate analysis, the subgroup determined by the SVM model was the only independent factor significantly associated with neo-CRT response in the external validation sets. Combined qPCR of the 4 miRNAs provides the possibility of ESCC neo-CRT response prediction, which may facilitate individualized ESCC treatment. Further prospective validation in larger independent cohorts is necessary to fully assess its predictive power.

Current status of superficial pharyngeal squamous cell carcinoma in Japan.

PubMed

Rikitake, Ryoko; Ando, Mizuo; Saito, Yuki; Yoshimoto, Seiichi; Yamasoba, Tatsuya; Higashi, Takahiro

2017-10-01

To investigate the status and treatment of superficial pharyngeal squamous cell carcinoma in Japan. We analyzed all cases diagnosed between 2011 and 2013, as recorded in the national database of hospital-based cancer registries. We extracted data on patient sex, age, tumor locations, histology, presentation routes, initial treatments, and TNM stages. Additionally, we compared the characteristics of pharyngeal carcinoma to those of esophageal cancer. A total of 16,521 oropharyngeal and hypopharyngeal cancers from 409 institutions were included. Diagnosis of Tis tumors was infrequent, and both cancers were likely to be diagnosed at an advanced stage (n = 866, 5.3%). Tis diseases were the most commonly detected during follow-up examinations for other diseases (n = 608, 70%). While more oropharyngeal Tis patients were men compared to T1-4 patients (88 vs 82%, respectively), hypopharyngeal cancer patients comprised an equally high proportion of men (94 vs 92%, respectively). The most common location of oropharyngeal Tis tumors was the posterior wall (32%), whereas T1-4 tumors were most commonly found on the lateral wall (36%). In hypopharyngeal cancer, both Tis and T1-4 were most commonly located in the pyriform sinus (62%). The proportion of Tis tumors diagnosed at individual institutions showed a positive correlation with the number of endoscopic treatments (r = 0.32, P < 0.001) and the number of esophageal cancer cases (r = 0.37, P < 0.001). Our national database study elucidated the current characteristics of superficial pharyngeal squamous cell carcinoma patients in Japan. Further improvements in early diagnosis and standardized treatments are warranted.

Clinical impact of surveillance for head and neck cancer in patients with esophageal squamous cell carcinoma.

PubMed

Morimoto, Hiroyuki; Yano, Tomonori; Yoda, Yusuke; Oono, Yasuhiro; Ikematsu, Hiroaki; Hayashi, Ryuichi; Ohtsu, Atsushi; Kaneko, Kazuhiro

2017-02-14

To evaluate the clinical impact of surveillance for head and neck (HN) region with narrow band imaging (NBI) in patients with esophageal squamous cell carcinoma (ESCC). Since 2006, we introduced the surveillance for HN region using NBI for all patients with ESCC before treatment, and each follow-up. The patients with newly diagnosed stage I to III ESCC were enrolled and classified into two groups as follows: Group A (no surveillance for HN region); between 1992 and 2000), and Group B (surveillance for HN region with NBI; between 2006 and 2008). We comparatively evaluated the detection rate of superficial head and neck squamous cell carcinoma (HNSCC), and the serious events due to metachronous advanced HNSCC during the follow-up. A total 561 patients (group A: 254, group B: 307) were enrolled. Synchronous superficial HNSCC was detected in 1 patient (0.3%) in group A, and in 12 (3.9%) in group B ( P = 0.008). During the follow up period, metachronous HNSCC were detected in 10 patients (3.9%) in group A and in 30 patients (9.8%) in group B ( P = 0.008). All metachronous lesions in group B were early stage, and 26 patients underwent local resection, however, 6 of 10 patients (60%) in group A lost their laryngeal function and died with metachronous HNSCC. Surveillance for the HN region by using NBI endoscopy increase the detection rate of early HNSCC in patients with ESCC, and led to decrease serious events related to advanced metachronous HNSCC.

Autophagy levels are elevated in Barrett’s esophagus and promote cell survival from acid and oxidative stress

PubMed Central

Kong, Jianping; Whelan, Kelly A.; Laczkó, Dorottya; Dang, Brendan; Monroig, Angeliz Caro; Soroush, Ali; Falcone, John; Amaravadi, Ravi K.; Rustgi, Anil K.; Ginsberg, Gregory G; Falk, Gary W; Nakagawa, Hiroshi; Lynch, John P.

2015-01-01

Autophagy is a highly conserved mechanism that is activated during cellular stress. We hypothesized that autophagy may be induced by acid reflux, which causes injury and inflammation, and therefore contributes to the pathogenesis of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). Currently, the role of autophagy in BE and EAC is poorly studied. We quantitatively define autophagy levels in human BE cell lines, a transgenic mouse model of BE, and human BE and EAC biopsies. Human non-dysplastic BE had the highest basal number of autophagic vesicles (AVs), while AVs were reduced in normal squamous cells and dysplastic BE cells, and nearly absent in EAC. To demonstrate a functional role for autophagy in BE pathogenesis, normal squamous (STR), non-dysplastic BE (CPA), dysplastic BE (CPD), and esophageal adenocarcinoma (OE19) cell lines were exposed to an acid pulse (pH3.5) followed by incubation in the presence or absence of chloroquine, an autophagy inhibitor. Acid exposure increased reactive oxygen species (ROS) levels in STR and CPA cells. Chloroquine alone had a small impact on intracellular ROS or cell survival. However, combination of chloroquine with the acid pulse resulted in a significant increase in ROS levels at 6 hours in STR and CPA cells, and increased cell death in all cell lines. These findings establish increased numbers of AVs in human BE compared to normal squamous or EAC, and suggest that autophagy functions to improve cell survival after acid reflux injury. Autophagy may thus play a critical role in BE pathogenesis and progression. PMID:26373456

GPR84 and TREM-1 Signaling Contribute to the Pathogenesis of Reflux Esophagitis

PubMed Central

Abdel-Aziz, Heba; Schneider, Mathias; Neuhuber, Winfried; Kassem, Abdel Meguid; Khailah, Saleem; Müller, Jürgen; Eldeen, Hadeel Gamal; Khairy, Ahmed; Khayyal, Mohamed T; Shcherbakova, Anastasiia; Efferth, Thomas; Ulrich-Merzenich, Gudrun

2015-01-01

Gastro-esophageal reflux disease (GERD) is one of the most common disorders in gastroenterology. Patients present with or without increased acid exposure indicating a nonuniform etiology. Thus, the common treatment with proton pump inhibitors (PPIs) fails to control symptoms in up to 40% of patients. To further elucidate the pathophysiology of the condition and explore new treatment targets, transcriptomics, proteomics and histological methods were applied to a surgically induced subchronic reflux esophagitis model in Wistar rats after treatment with either omeprazole (PPI) or STW5, a herbal preparation shown to ameliorate esophagitis without affecting refluxate pH. The normal human esophageal squamous cell line HET-1A and human endoscopic biopsies were used to confirm our findings to the G-protein–coupled receptor (GPR) 84 in human tissue. Both treatments reduced reflux-induced macroscopic and microscopic lesions of the esophagi as well as known proinflammatory cytokines. Proteomic and transcriptomic analyses identified CINC1–3, MIP-1/3α, MIG, RANTES and interleukin (IL)-1β as prominent mediators in GERD. Most regulated cyto-/chemokines are linked to the TREM-1 signaling pathway. The fatty acid receptor GPR84 was upregulated in esophagitis but significantly decreased in treated groups, a finding supported by Western blot and immunohistochemistry in both rat tissue and HET-1A cells. GPR84 was also found to be significantly upregulated in patients with grade B reflux esophagitis. The expression of GPR84 in esophageal tissue and its potential involvement in GERD are reported for the first time. IL-8 (CINC1–3) and the TREM-1 signaling pathway are proposed, besides GPR84, to play an important role in the pathogenesis of GERD.org PMID:26650186

GPR84 and TREM-1 signaling contribute to the pathogenesis of reflux esophagitis.

PubMed

Abdel-Aziz, Heba; Schneider, Mathias; Neuhuber, Winfried; Kassem, Abdel Meguid; Khailah, Saleem; Müller, Jürgen; Gamaleldeen, Hadeel; Khairy, Ahmed; Khayyal, Mohamed T; Shcherbakova, Anastasiia; Efferth, Thomas; Ulrich-Merzenich, Gudrun

2015-11-24

Gastro-esophageal reflux disease (GERD) is one of the most common disorders in gastroenterology. Patients present with or without increased acid exposure indicating a non-uniform etiology. Thus the common treatment with proton pump inhibitors (PPIs) fails to control symptoms in up to 40% of patients.To further elucidate the pathophysiology of the condition and explore new treatment targets, transcriptomics, proteomics and histological methods were applied to a surgically induced sub-chronic reflux esophagitis model in Wistar rats after treatment with either omeprazole (PPI) or STW5, a herbal preparation shown to ameliorate esophagitis without affecting refluxate pH. The normal human esophageal squamous cellline HET-1A and human endoscopic biopsies were used to confirm our findings to the G-protein coupled receptor (GPR) 84 in human tissue.Both treatments reduced reflux-induced macroscopic and microscopic lesions of the esophagi as well as known pro-inflammatory cytokines. Proteomic and transcriptomic analyses identified CINC1-3, MIP-1/3α, MIG, RANTES and IL-1β as prominent mediators in GERD. Most regulated cyto-/chemokines are linked to the TREM-1 signaling pathway. The fatty acid receptor GPR84 was up-regulated in esophagitis but significantly decreased in treated groups, a finding supported by Western blot and immunohistochemistry in both rat tissue and HET-1A cells. GPR84 was also found to be significantly up-regulated in patients with grade B reflux esophagitis.The expression of GPR84 in esophageal tissue and its potential involvement in GERD are reported for the first time. IL-8 (CINC1-3) and the TREM-1 signaling pathway are proposed, besides GPR84, to play an important role in the pathogenesis of GERD.

Preoperative chemoradiation with paclitaxel-carboplatin or with fluorouracil-oxaliplatin-folinic acid (FOLFOX) for resectable esophageal and junctional cancer: the PROTECT-1402, randomized phase 2 trial.

PubMed

Messager, Mathieu; Mirabel, Xavier; Tresch, Emmanuelle; Paumier, Amaury; Vendrely, Véronique; Dahan, Laetitia; Glehen, Olivier; Vasseur, Frederique; Lacornerie, Thomas; Piessen, Guillaume; El Hajbi, Farid; Robb, William B; Clisant, Stéphanie; Kramar, Andrew; Mariette, Christophe; Adenis, Antoine

2016-05-18

Often curative treatment for locally advanced resectable esophageal or gastro-esophageal junctional cancer consists of concurrent neoadjuvant radiotherapy and chemotherapy followed by surgery. Currently, one of the most commonly used chemotherapy regimens in this setting is a combination of a fluoropyrimidin and of a platinum analogue. Due to the promising results of the recent CROSS trial, another regimen combining paclitaxel and carboplatin is also widely used by European and American centers. No clinical study has shown the superiority of one treatment over the other. The objective of this Phase II study is to clarify clinical practice by comparing these two chemotherapy treatments. Our aim is to evaluate, in operable esophageal and gastro-esophageal junctional cancer, the complete resection rate and severe postoperative morbidity rate associated with these two neoadjuvant chemotherapeutic regimens (carboplatin-paclitaxel or fluorouracil-oxaliplatin-folinic acid) when each is combined with the radiation regime utilized in the CROSS trial. PROTECT is a prospective, randomized, multicenter, open arms, phase II trial. Eligible patients will have a histologically confirmed adenocarcinoma or squamous cell carcinoma and be treated with neoadjuvant radiochemotherapy followed by surgery for stage IIB or stage III resectable esophageal cancer. A total of 106 patients will be randomized to receive either 3 cycles of FOLFOX combined to concurrent radiotherapy (41.4 Grays) or carboplatin and paclitaxel with the same radiation regimen, using a 1:1 allocation ratio. This ongoing trial offers the unique opportunity to compare two standards of chemotherapy delivered with a common regimen of preoperative radiation, in the setting of operable locally advanced esophageal or gastro-esophageal junctional tumors. NCT02359968 (ClinicalTrials.gov) (registration date: 9 FEB 2015), EudraCT: 2014-000649-62 (registration date: 10 FEB 2014).

The OGG1 Ser326Cys polymorphism and the risk of esophageal cancer: a meta-analysis.

PubMed

Wang, Zhan; Gan, Lu; Nie, Wei; Geng, Yan

2013-10-01

The oxoguanine DNA glycosylase (OGG1) Ser326Cys polymorphism has been implicated in susceptibility to esophageal cancer. Several studies investigated the association of this polymorphism with esophageal cancer in different populations. However, the results were contradictory. A meta-analysis was conducted to assess the association between the OGG1 Ser326Cys polymorphism and esophageal cancer susceptibility. Databases, including PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and Weipu Database were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. A random-effects model was used. Twelve studies involving 2363 cases and 3621 controls were included. Overall, a significant association between the OGG1 Ser326Cys polymorphism and esophageal cancer was observed for Cys/Cys versus Cys/Ser+Ser/Ser (OR=1.40; 95% CI 1.12-1.74; p=0.003; Pheterogeneity=0.18). In the subgroup analysis by ethnicity, a significant association was found among Asians (OR=1.51; 95% CI 1.15-1.96; p=0.002; Pheterogeneity=0.22), but not among Caucasians (OR=1.21; 95% CI 0.81-1.81; p=0.35; Pheterogeneity=0.21). In the subgroup analysis by pathologic type, we found that the Cys/Cys genotype was associated with increased esophageal squamous cell carcinoma risk (OR=1.86; 95% CI 1.36-2.53; p<0.0001; Pheterogeneity=0.73). This meta-analysis suggested that the OGG1 Ser326Cys polymorphism was a risk factor of esophageal cancer.

Prognostic and clinicopathological significance of platelet to lymphocyte ratio in esophageal cancer: a meta-analysis.

PubMed

Deng, Juhong; Zhang, Peng; Sun, Yue; Peng, Ping; Huang, Yu

2018-03-01

The prognostic and clinicopathological significance of the platelet to lymphocyte ratio (PLR) has been studied in various cancers. However, studies examining the role of PLR in esophageal cancer have not yielded consistent results. The purpose of this meta-analysis was to study the prognostic and clinicopathological significance of PLR in esophageal cancer patients. We performed a literature search in three major databases: PubMed, Web of Science and Embase (up until May 1, 2017). The clinicopathologic significance of PLR and its prognostic significance were analyzed. Our meta-analysis consisted of 13 studies with 4,621 patients. The pooled hazard ratios (HRs) showed that a high PLR was associated with poor survival of esophageal cancer [HR =1.283; 95% confidence interval (CI): 1.173-1.404; P<0.001]. Subgroup analysis revealed that elevated PLR was associated with poor survival in esophageal squamous cell carcinoma (HR =1.281; 95% CI: 1.098-1.493; P=0.002). The pooled odds ratio (OR) indicated that high PLR was also associated with the depth of tumor invasion (OR =1.543, 95% CI: 1.269-1.876, P<0.001), lymph node metastasis (OR =1.427, 95% CI: 1.195-1.705, P<0.001), tumor length (OR =1.81, 95% CI: 1.331-2.461, P<0.001), and Tumor stage (OR =1.459, 95% CI: 1.235-1.724, P<0.001). Our results demonstrate that elevated PLR was significantly associated with poor prognosis of esophageal cancer. Furthermore, the high PLR might predict worse clinicopathological features of esophageal cancer patients.

Association between ambient ultraviolet radiation and risk of esophageal cancer.

PubMed

Tran, Bich; Lucas, Robyn; Kimlin, Michael; Whiteman, David; Neale, Rachel

2012-12-01

Ecological studies have suggested an inverse relationship between latitude and risks of some cancers. However, associations between solar ultraviolet radiation (UVR) exposure and esophageal cancer risk have not been fully explored. We therefore investigated the association between nevi, freckles, and measures of ambient UVR over the life-course with risks of esophageal cancers. We compared estimated lifetime residential ambient UVR among Australian patients with esophageal cancer (330 esophageal adenocarcinoma (EAC), 386 esophago-gastric junction adenocarcinoma (EGJAC), and 279 esophageal squamous cell carcinoma (ESCC)), and 1471 population controls. We asked people where they had lived at different periods of their life, and assigned ambient UVR to each location based on measurements from NASA's Total Ozone Mapping Spectrometer database. Freckling and nevus burden were self-reported. We used multivariable logistic regression models to estimate the magnitude of associations between phenotype, ambient UVR, and esophageal cancer risk. Compared with population controls, patients with EAC and EGJAC were less likely to have high levels of estimated cumulative lifetime ambient UVR (EAC odds ratio (OR) 0.59, 95% confidence interval (CI) 0.35-0.99, EGJAC OR 0.55, 0.34-0.90). We found no association between UVR and risk of ESCC (OR 0.91, 0.51-1.64). The associations were independent of age, sex, body mass index, education, state of recruitment, frequency of reflux, smoking status, alcohol consumption, and H. pylori serostatus. Cases with EAC were also significantly less likely to report high levels of nevi than controls. These data show an inverse association between ambient solar UVR at residential locations and risk of EAC and EGJAC, but not ESCC.

Upregulation of mucin glycoprotein MUC1 in the progression to esophageal adenocarcinoma and therapeutic potential with a targeted photoactive antibody-drug conjugate

PubMed Central

Haidry, Rehan J.; Oukrif, Dahmane; Khan, Saif-U-Rehman; Puccio, Ignazio; Gandy, Michael; Reinert, Halla W.; Bloom, Ellie; Rashid, Mohammed; Yahioglu, Gokhan; Deonarain, Mahendra P.; Hamoudi, Rifat; Rodriguez-Justo, Manuel; Novelli, Marco R.; Lovat, Laurence B.

2017-01-01

Background Mucin glycoprotein 1 (MUC1) is a glycosylated transmembrane protein on epithelial cells. We investigate MUC1 as a therapeutic target in Barrett’s epithelium (BE) and esophageal adenocarcinoma (EA) and provide proof of concept for a light based therapy targeting MUC1. RESULTS MUC1 was present in 21% and 30% of significantly enriched pathways comparing BE and EA to squamous epithelium respectively. MUC1 gene expression was x2.3 and x2.2 higher in BE (p=<0.001) and EA (p=0.03). MUC1 immunohistochemical expression increased during progression to EA and followed tumor invasion. HuHMFG1 based photosensitive antibody drug conjugates (ADC) showed cell internalization, MUC1 selective and light-dependent cytotoxicity (p=0.0006) and superior toxicity over photosensitizer alone (p=0.0022). Methods Gene set enrichment analysis (GSEA) evaluated pathways during BE and EA development and quantified MUC1 gene expression. Immunohistochemistry and flow cytometry evaluated the anti-MUC1 antibody HuHMFG1 in esophageal cells of varying pathological grade. Confocal microscopy examined HuHMFG1 internalization and HuHMFG1 ADCs were created to deliver a MUC1 targeted phototoxic payload. Conclusions MUC1 is a promising target in EA. Molecular and light based targeting of MUC1 with a photosensitive ADC is effective in vitro and after development may enable treatment of locoregional tumors endoscopically. PMID:28212575

Using typical endoscopic features to diagnose esophageal squamous papilloma.

PubMed

Wong, Ming-Wun; Bair, Ming-Joug; Shih, Shou-Chuan; Chu, Cheng-Hsin; Wang, Horng-Yuan; Wang, Tsang-En; Chang, Chen-Wang; Chen, Ming-Jen

2016-02-21

To better understand some of the superficial tiny lesions that are recognized as squamous papilloma of the esophagus (SPE) and receive a different pathological diagnosis. All consecutive patients with esophageal polypoid lesions detected by routine endoscopy at our Endoscopy Centre between October 2009 and June 2014 were retrospectively analysed. We enrolled patients with SPE or other superficial lesions to investigate four key endoscopic appearances (whitish color, exophytic growth, wart-like shape, and surface vessels) and used narrow band imaging (NBI) to distinguish their differences. These series endoscopic images of each patient were retrospectively reviewed by three experienced endoscopists with no prior access to the images. All lesion specimens obtained by forceps biopsy were fixed in formalin and processed for pathological examination. The following data were collected from patient medical records: gender, age, indications for esophagogastroduodenoscopy, and endoscopic characteristics including lesion location, number, color, size, surface morphology, surrounding mucosa, and surface vessels under NBI. Clinicopathological features were also compared. During the study period, 41 esophageal polypoid lesions from 5698 endoscopic examinations were identified retrospectively. These included 24 patients with pathologically confirmed SPE, 11 patients with squamous hyperplasia, three patients with glycogenic acanthosis, two patients with ectopic sebaceous glands, and one patient with a xanthoma. In the χ (2) test, exophytic growth (P = 0.003), a wart-like shape (P < 0.001), and crossing surface vessels under NBI (P = 0.001) were more frequently observed in SPE than in other lesion types. By contrast, there was no significant difference regarding the appearance of a whitish color between SPE and other lesion types (P = 0.872). The most sensitive characteristic was wart-like projections (81.3%) and the most specific was exophytic growth (87.5%). Promising positive predictive values of 84.2%, 80.8%, and 82.6% were noted for exophytic growth, wart-like projections, and surface vessel crossing on NBI, respectively. The use of three key typical endoscopic appearances--exophytic growth, a wart-like shape, and vessel crossing on the lesion surface under NBI--has a promising positive predictive value of 88.2%. This diagnostic triad is useful for the endoscopic diagnosis of SPE.

Using typical endoscopic features to diagnose esophageal squamous papilloma

PubMed Central

Wong, Ming-Wun; Bair, Ming-Joug; Shih, Shou-Chuan; Chu, Cheng-Hsin; Wang, Horng-Yuan; Wang, Tsang-En; Chang, Chen-Wang; Chen, Ming-Jen

2016-01-01

AIM: To better understand some of the superficial tiny lesions that are recognized as squamous papilloma of the esophagus (SPE) and receive a different pathological diagnosis. METHODS: All consecutive patients with esophageal polypoid lesions detected by routine endoscopy at our Endoscopy Centre between October 2009 and June 2014 were retrospectively analysed. We enrolled patients with SPE or other superficial lesions to investigate four key endoscopic appearances (whitish color, exophytic growth, wart-like shape, and surface vessels) and used narrow band imaging (NBI) to distinguish their differences. These series endoscopic images of each patient were retrospectively reviewed by three experienced endoscopists with no prior access to the images. All lesion specimens obtained by forceps biopsy were fixed in formalin and processed for pathological examination. The following data were collected from patient medical records: gender, age, indications for esophagogastroduodenoscopy, and endoscopic characteristics including lesion location, number, color, size, surface morphology, surrounding mucosa, and surface vessels under NBI. Clinicopathological features were also compared. RESULTS: During the study period, 41 esophageal polypoid lesions from 5698 endoscopic examinations were identified retrospectively. These included 24 patients with pathologically confirmed SPE, 11 patients with squamous hyperplasia, three patients with glycogenic acanthosis, two patients with ectopic sebaceous glands, and one patient with a xanthoma. In the χ2 test, exophytic growth (P = 0.003), a wart-like shape (P < 0.001), and crossing surface vessels under NBI (P = 0.001) were more frequently observed in SPE than in other lesion types. By contrast, there was no significant difference regarding the appearance of a whitish color between SPE and other lesion types (P = 0.872). The most sensitive characteristic was wart-like projections (81.3%) and the most specific was exophytic growth (87.5%). Promising positive predictive values of 84.2%, 80.8%, and 82.6% were noted for exophytic growth, wart-like projections, and surface vessel crossing on NBI, respectively. CONCLUSION: The use of three key typical endoscopic appearances - exophytic growth, a wart-like shape, and vessel crossing on the lesion surface under NBI - has a promising positive predictive value of 88.2%. This diagnostic triad is useful for the endoscopic diagnosis of SPE. PMID:26900297

Association between radiation dose and pathological complete response after preoperative radiochemotherapy in esophageal squamous cell cancer.

PubMed

Ordu, Arif Deniz; Nieder, Carsten; Geinitz, Hans; Scherer, Vera; Kup, Philipp Günther; Schuster, Tibor; Combs, Stephanie E; Fakhrian, Khashayar

2014-12-01

This study was undertaken to examine the impact of radiation dose on pathological complete response (pCR) rates following neoadjuvant radiochemotherapy (N-RCT) for squamous cell esophageal cancer (ESCC). From 1988 to 2011, 218 patients were treated with 30-30.6 Gy (1.8-2 Gy per fraction), 39.6-40 Gy (1.8-2 Gy per fraction) or 44-45 Gy (1.8-2 Gy per fraction) and concomitant cisplatin ± 5-fluorouracil (5-FU), oxaliplatin + 5-FU or 5-FU alone. The most commonly used concomitant chemotherapy was continuous infusion of 5-FU-alone with a dose of 300 mg/m(2)/day during the whole course of treatment (n=111). To eliminate the dispersing effect of potentially different efficacy levels of these drug regimens on pCR, we excluded patients with regimens other than 5-FU-alone. Histomorphological regression grade 1a (0% residual tumor), 1b (<10% residual tumor), 2 (10-50% residual tumor) and 3 (>50% residual tumor) was observed in 26 (23%), 24 (22%), 36 (32%) and 25 (23%) patients, respectively. pCR was observed in 9 out of 71 (13%) patients treated with 30 Gy-30.6 Gy, 13 of 34 (38%) patients treated with 39.6-40 Gy and 4 of 6 (67%) patients treated with 44-45 Gy (p=0.001). Median follow-up time from the start of N-RCT was 191 months (range=2-262 months). The estimated 5-year overall survival (OS) was 33% for the whole cohort. OS at 5 years was 58% for patients with pCR compared to 25% for patients with less favorable response to N-RCT (p=0.009), respectively. The dose of radiation correlates significantly with the likelihood of achieving a pCR in stage II/III squamous cell esophageal cancer patients. Prospective randomized trials are required to definitively evaluate the impact of application of higher radiation doses on efficacy and safety/tolerability in the context of N-RCT on the clinical outcomes. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Alcohol Consumption and Multiple Dysplastic Lesions Increase Risk of Squamous Cell Carcinoma in the Esophagus, Head, and Neck.

PubMed

Katada, Chikatoshi; Yokoyama, Tetsuji; Yano, Tomonori; Kaneko, Kazuhiro; Oda, Ichiro; Shimizu, Yuichi; Doyama, Hisashi; Koike, Tomoyuki; Takizawa, Kohei; Hirao, Motohiro; Okada, Hiroyuki; Yoshii, Takako; Konishi, Kazuo; Yamanouchi, Takenori; Tsuda, Takashi; Omori, Tai; Kobayashi, Nozomu; Shimoda, Tadakazu; Ochiai, Atsushi; Amanuma, Yusuke; Ohashi, Shinya; Matsuda, Tomonari; Ishikawa, Hideki; Yokoyama, Akira; Muto, Manabu

2016-11-01

Some patients develop multiple squamous cell carcinomas (SCCs) in the upper aerodigestive tract, attributed to field cancerization; alcohol consumption has been associated with this process. We examined the association between multiple areas of dysplastic squamous epithelium with the development of SCC of the esophagus or head and neck cancer, as well as alcohol consumption and smoking. We examined 331 patients with early stage esophageal SCC using Lugol chromoendoscopy to evaluate the dysplastic squamous epithelium in the esophagus. Patients then were assigned to 3 groups, based on the number of Lugol-voiding lesions: A, no lesion; B, 1-9 lesions; or C, 10 or more lesions. Participants completed lifestyle surveys on their history of drinking, smoking, and diet. All participants were evaluated by laryngopharyngoscopy before registration; only those without head and neck cancer were included, except for patients with superficial SCC limited to the subepithelial layer. Lesions detected in the esophagus and head and neck by surveillance were considered to be metachronous. The study end point was the cumulative incidence of metachronous SCCs in the esophagus and head and neck after endoscopic resection of esophageal SCC, according to the grade of Lugol-voiding lesions. At study entry, all patients were instructed to abstain from alcohol and smoking. Over the 2-year study period, metachronous SCCs of the esophagus were detected in 4% of patients in group A, in 9.4% of patients in group B, and in 24.7% of patients in group C (P < .0001 for patients in group A vs B or B vs C). Head and neck SCCs were detected in none of the patients in group A, in 1.7% of the patients in group B, and in 8.6% of the patients in group C (P = .016 for patients in group A vs C and P = .008 for patients in group B vs C). SCC of the esophagus or head and neck developed in 4.0% of patients in group A, in 10.0% of patients in group B, and in 31.4% of patients in group C (P < .0001 for group A vs B or A vs C). Alcohol abstinence decreased the risk of multiple SCCs of the esophagus (adjusted hazard ratio, 0.47, 95% confidence interval, 0.25-0.91; P = .025), whereas smoking abstinence did not. Multiple dysplastic lesions in the esophagus increase the risk of multiple SCCs. Alcohol abstinence reduces the risk of metachronous SCCs. Clinical Trials registry: UMIN000001676 and UMIN000005466. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Sex difference in survival of patients treated by surgical resection for esophageal cancer.

PubMed

Hidaka, Hideki; Hotokezaka, Masayuki; Nakashima, Shinya; Uchiyama, Shuichiro; Maehara, Naoki; Chijiiwa, Kazuo

2007-10-01

Squamous cell carcinoma accounts for most of the esophageal cancers in Japan and is often related to excessive smoking and drinking. Although esophageal cancer occurs far more frequently in men than in women, it is not certain whether there are sex-specific differences in morbidity and mortality after surgical resection of the esophagus. We conducted a study to determine the influence of sex on the short- and long-term results of surgical resection in patients with esophageal cancer. There were 295 patients with a newly diagnosed primary malignant neoplasm of the esophagus treated at our University hospital between January 1978 and December 2005. There were 185 patients (166 men, 19 women; age range 39-86 years) who underwent surgical resection for primary esophageal malignant neoplasms. Survival rates were calculated according to the Kaplan-Meier method and tested with the log-rank test. Cox proportional hazards model was used to assess independent predictors of survival. The cumulative amount of alcohol consumed and number of cigarettes smoked were significantly higher in men than in women. Postoperative complications occurred in 101 men (60.8%) and 9 women (47.4%), but significant sex differences in postoperative morbidity and mortality were not observed. Overall survival was significantly better for women than for men. Postoperative morbidity and mortality do not appear to differ between men and women with esophageal cancer treated by surgical resection. Long-term survival after surgical resection of the esophagus appears to be significantly better for women than for men.

Black esophagus: Acute esophageal necrosis syndrome

PubMed Central

Gurvits, Grigoriy E

2010-01-01

Acute esophageal necrosis (AEN), commonly referred to as “black esophagus”, is a rare clinical entity arising from a combination of ischemic insult seen in hemodynamic compromise and low-flow states, corrosive injury from gastric contents in the setting of esophago-gastroparesis and gastric outlet obstruction, and decreased function of mucosal barrier systems and reparative mechanisms present in malnourished and debilitated physical states. AEN may arise in the setting of multiorgan dysfunction, hypoperfusion, vasculopathy, sepsis, diabetic ketoacidosis, alcohol intoxication, gastric volvulus, traumatic transection of the thoracic aorta, thromboembolic phenomena, and malignancy. Clinical presentation is remarkable for upper gastrointestinal bleeding. Notable symptoms may include epigastric/abdominal pain, vomiting, dysphagia, fever, nausea, and syncope. Associated laboratory findings may reflect anemia and leukocytosis. The hallmark of this syndrome is the development of diffuse circumferential black mucosal discoloration in the distal esophagus that may extend proximally to involve variable length of the organ. Classic “black esophagus” abruptly stops at the gastroesophageal junction. Biopsy is recommended but not required for the diagnosis. Histologically, necrotic debris, absence of viable squamous epithelium, and necrosis of esophageal mucosa, with possible involvement of submucosa and muscularis propria, are present. Classification of the disease spectrum is best described by a staging system. Treatment is directed at correcting coexisting clinical conditions, restoring hemodynamic stability, nil-per-os restriction, supportive red blood cell transfusion, and intravenous acid suppression with proton pump inhibitors. Complications include perforation with mediastinal infection/abscess, esophageal stricture and stenosis, superinfection, and death. A high mortality of 32% seen in the setting of AEN syndrome is usually related to the underlying medical co-morbidities and diseases. PMID:20614476

A Model To Identify Individuals at High Risk for Esophageal Squamous Cell Carcinoma and Precancerous Lesions in Regions of High Prevalence in China.

PubMed

Liu, Mengfei; Liu, Zhen; Cai, Hong; Guo, Chuanhai; Li, Xiang; Zhang, Chaoting; Wang, Hui; Hang, Dong; Liu, Fangfang; Deng, Qiuju; Yang, Xin; Yuan, Wenqing; Pan, Yaqi; Li, Jingjing; Zhang, Chanyuan; Shen, Na; He, Zhonghu; Ke, Yang

2017-10-01

We aimed to develop a population-based model to identify individuals at high risk for esophageal squamous cell carcinoma (ESCC) in regions of China with a high prevalence of this cancer. We collected findings from 15,073 permanent residents (45-69 years old) of 334 randomly selected villages in Hua County, Henan Province, China who underwent endoscopic screening (with iodine staining) for ESCC from January 2012 through September 2015. The entire esophagus and stomach were examined; biopsies were collected from all focal lesions (or from standard sites in the esophagus if no abnormalities were found) and analyzed histologically. Squamous dysplasia, carcinoma in situ, and ESCC were independently confirmed by 2 pathologists. Before endoscopy, subjects completed a questionnaire on ESCC risk factors. Variables were evaluated with unconditional univariate logistic regression analysis; variables found to be significantly associated with ESCC were then analyzed by multivariate logistic regression modeling. We used the Akaike information criterion to develop our final model structure and the coding form of variables with multiple measures. We developed 2 groups of models, separately defining severe dysplasia and above (SDA) (lesions including severe dysplasia and higher-grade lesions) and moderate dysplasia and above (lesions including moderate dysplasia and higher-grade lesions) as outcome events. Age-stratified and whole-age models were developed; their discriminative ability in the full multivariate model and the simple age model was compared. We performed area under the receiver operating characteristic curve (AUC) and the DeLong test to evaluate model performance. Our age-stratified prediction models identified individuals 60 years of age or younger with SDA with an AUC value of 0.795 (95% confidence interval, 0.736-0.854) and individuals older than 60 years with SDA with an AUC value of 0.681 (95% confidence interval, 0.618-0.743). Factors associated with SDA in individuals 60 years or younger included age closer to 60 years, use of coal or wood as a main source of cooking fuel, body mass index of 22 kg/m 2 or less, unexplained epigastric pain, and rapid ingestion of meals. In subjects older than 60 years, SDA associated with age, family history of ESCC, cigarette smoking, body mass index of 22 kg/m 2 or less, pesticide exposure, irregular eating habits, intake of high temperature foods, rapid ingestion of meals, and ingestion of leftover food in summer months. Use of our model in screening could have allowed 27% of subjects 60 years or younger and 9% of subjects older than 60 years to avoid endoscopy without missing SDAs. This means that approximately 2500 of endoscopies in total (16.6%) could have been avoided. We developed a low-cost, easy-to-use model to identify individuals at risk for severe dysplasia or cancer of the esophagus living in a region of China with a high risk of ESCC. This model might be used to select individuals and groups of persons who should undergo endoscopy analysis for esophageal cancer. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Weighted gene co-expression network analysis of gene modules for the prognosis of esophageal cancer.

PubMed

Zhang, Cong; Sun, Qian

2017-06-01

Esophageal cancer is a common malignant tumor, whose pathogenesis and prognosis factors are not fully understood. This study aimed to discover the gene clusters that have similar functions and can be used to predict the prognosis of esophageal cancer. The matched microarray and RNA sequencing data of 185 patients with esophageal cancer were downloaded from The Cancer Genome Atlas (TCGA), and gene co-expression networks were built without distinguishing between squamous carcinoma and adenocarcinoma. The result showed that 12 modules were associated with one or more survival data such as recurrence status, recurrence time, vital status or vital time. Furthermore, survival analysis showed that 5 out of the 12 modules were related to progression-free survival (PFS) or overall survival (OS). As the most important module, the midnight blue module with 82 genes was related to PFS, apart from the patient age, tumor grade, primary treatment success, and duration of smoking and tumor histological type. Gene ontology enrichment analysis revealed that "glycoprotein binding" was the top enriched function of midnight blue module genes. Additionally, the blue module was the exclusive gene clusters related to OS. Platelet activating factor receptor (PTAFR) and feline Gardner-Rasheed (FGR) were the top hub genes in both modeling datasets and the STRING protein interaction database. In conclusion, our study provides novel insights into the prognosis-associated genes and screens out candidate biomarkers for esophageal cancer.

Single nucleotide polymorphisms in obesity-related genes and the risk of esophageal cancers.

PubMed

Doecke, James D; Zhao, Zhen Zhen; Stark, Mitchell S; Green, Adèle C; Hayward, Nicholas K; Montgomery, Grant W; Webb, Penelope M; Whiteman, David C

2008-04-01

Rates of adenocarcinoma of the esophagus (EAC) and esophagogastric junction (EGJAC) have been rising rapidly in recent decades, in contrast to the declining rates of esophageal squamous cell carcinomas (ESCC). Obesity is a major risk factor for both EAC and EGJAC, but not ESCC, and there is speculation that obesity promotes adenocarcinoma development through endocrine and related pathways. We therefore compared the prevalence of 12 single nucleotide polymorphisms (SNPs) in nine candidate genes previously implicated in obesity pathways (LEP, LEPR, ADIPOQ, POMC, PPARalpha, PPARgamma, RXRgamma, GHRL, and INSIG2) in a large Australian case-control study comprising DNA samples from 260 EAC cases, 301 EGJAC cases, 213 ESCC cases, and 1,352 population controls. No SNPs were associated with EGJAC or ESCC. Although several SNPs seemed to be associated with EAC on crude analysis [ADIPOQ (rs1501299), LEP (5'-untranslated region), PPARgamma (H447H), and GHRL (M72L)], effect sizes were modest and none of the associations was significant after correcting for multiple comparisons. Further, we found no consistent evidence that any of the genotypes were associated with risk of EAC or EGJAC within strata of body mass index (<25.0 kg/m(2), 25.0-29.9 kg/m(2), >30 kg/m(2)). In conclusion, our data suggest that these SNPs do not play a major role in esophageal carcinogenesis.

Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma.

PubMed

Natsuizaka, Mitsuteru; Whelan, Kelly A; Kagawa, Shingo; Tanaka, Koji; Giroux, Veronique; Chandramouleeswaran, Prasanna M; Long, Apple; Sahu, Varun; Darling, Douglas S; Que, Jianwen; Yang, Yizeng; Katz, Jonathan P; Wileyto, E Paul; Basu, Devraj; Kita, Yoshiaki; Natsugoe, Shoji; Naganuma, Seiji; Klein-Szanto, Andres J; Diehl, J Alan; Bass, Adam J; Wong, Kwok-Kin; Rustgi, Anil K; Nakagawa, Hiroshi

2017-11-24

Notch1 transactivates Notch3 to drive terminal differentiation in stratified squamous epithelia. Notch1 and other Notch receptor paralogs cooperate to act as a tumor suppressor in squamous cell carcinomas (SCCs). However, Notch1 can be stochastically activated to promote carcinogenesis in murine models of SCC. Activated form of Notch1 promotes xenograft tumor growth when expressed ectopically. Here, we demonstrate that Notch1 activation and epithelial-mesenchymal transition (EMT) are coupled to promote SCC tumor initiation in concert with transforming growth factor (TGF)-β present in the tumor microenvironment. We find that TGFβ activates the transcription factor ZEB1 to repress Notch3, thereby limiting terminal differentiation. Concurrently, TGFβ drives Notch1-mediated EMT to generate tumor initiating cells characterized by high CD44 expression. Moreover, Notch1 is activated in a small subset of SCC cells at the invasive tumor front and predicts for poor prognosis of esophageal SCC, shedding light upon the tumor promoting oncogenic aspect of Notch1 in SCC.

Osthole inhibits the PI3K/AKT signaling pathway via activation of PTEN and induces cell cycle arrest and apoptosis in esophageal squamous cell carcinoma.

PubMed

Zhu, Xinbing; Li, Zhengzheng; Li, Tongtong; Long, Fei; Lv, Yuesheng; Liu, Lei; Liu, Xuefeng; Zhan, Qimin

2018-06-01

Esophageal squamous cell carcinoma (ESCC) is one of the most common lethal tumors and is known to be lack of effective therapy. Thus, novel therapeutic strategies are greatly needed for treatment of ESCC. Osthole, a natural active extract, has been documented to have anti-tumor activity. However, the effect of osthole on ESCC cells has not been elucidated. In this study, we demonstrated that osthole could inhibit the ESCC cell proliferation in dose- and time-dependent manner. Osthole treatment also induced G2/M phase arrest and apoptosis of ESCC cells. Furthermore, upon exposure to osthole, the expression of Cyclin B1, Cdc2, Bcl-2, PARP1 and Survivin was decreased, while the expression of BAX, cleaved PARP1, cleaved Caspase3 and cleaved Caspase9 was increased. In addition, osthole treatment elicited upregulation of PTEN and downregulation of PI3K and phosphorylated AKT (p-AKT). Taken together, our study demonstrates that osthole could suppress ESCC proliferation through inducing cell cycle arrest and apoptosis. Moreover, PTEN-PI3K/AKT signaling pathway can be regulated by osthole. Our results indicate that osthole may find therapeutic application in the treatment of ESCC patients. Copyright © 2018. Published by Elsevier Masson SAS.

Prognostic significance of NFIA and NFIB in esophageal squamous carcinoma and esophagogastric junction adenocarcinoma.

PubMed

Yang, Bo; Zhou, Zhi-Hang; Chen, Li; Cui, Xiang; Hou, Jun-Yan; Fan, Kai-Jie; Han, Si-Hao; Li, Peng; Yi, Shao-Qiong; Liu, Yang

2018-05-01

The nuclear factor I (NFI) family members, especially NFIA and NFIB, play essential roles in cancers. The roles of NFIA and NFIB in esophageal squamous cell carcinoma (ESCC) and esophagogastric junction adenocarcinoma (EJA) remain poorly known. This study aimed to determine the expression of NFIA and NFIB in ESCC and EJA and elucidate their prognostic significance. The expression of NFIA and NFIB was examined in 163 ESCC samples and 26 EJA samples by immunohistochemistry. The results showed that high NFIA expression correlated significantly with poor differentiation, lymph node metastasis, and advanced TNM stage in patients with ESCC. High NFIB expression only correlated with poor differentiation in patients with ESCC. Survival analysis showed that NFIA but not NFIB associated with short overall survival (OS) and disease-free survival (DFS) of patients with ESCC. On the other hand, high NFIB expression correlated with lymph node metastasis, advanced TNM stage, and short OS and DFS in patients with EJA. Finally, multivariate analysis demonstrated that high NFIA expression was an independent prognostic factor for ESCC. Taken together, these results demonstrated that NFIA and NFIB could serve as prognostic indicators for ESCC and EJA, respectively. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Overexpression of stathmin plays a pivotal role in the metastasis of esophageal squamous cell carcinoma

PubMed Central

Han, Gaijing; Wu, Zongyong; Zhao, Nan; Zhou, Lanping; Liu, Fang; Niu, Fangfei; Xu, Yang; Zhao, Xiaohang

2017-01-01

Purpose Esophageal squamous cell carcinoma (ESCC) is a serious malignant tumor that affects human health. We analyzed the correlation between serum stathmin level and ESCC and elucidated the molecular mechanisms of stathmin's promotion of ESCC cell invasion and metastasis. Methods Stathmin level in ESCC and healthy control serum were detected by enzyme-linked immunosorbent assay (ELISA), and the clinical parameters were analyzed. We established ESCC cells with stathmin overexpression or knockdown and then evaluated the effects of stathmin on invasion and metastasis in ESCC. Differentially expressed genes were analyzed by Human Transcriptome Array and confirmed by RT-PCR. The expression levels of the integrin family, focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK) were detected by immunoblotting. Results Serum levels of stathmin were significantly higher in ESCC than in control serum and associated with lymph node metastasis, tumor stage and size. Furthermore, we found that stathmin promoted migration and invasion of ESCC cells in vitro and in vivo. In addition, we confirmed that the activation of the integrinα5β1/FAK/ERK pathway is increased in stathmin-overexpression cells and accelerates cell motility by enhancing cell adhesion ability. Conclusion Stathmin may predict a potential metastasis biomarker for ESCC. PMID:28977901

Targeting c-Myc: JQ1 as a promising option for c-Myc-amplified esophageal squamous cell carcinoma.

PubMed

Wang, Jingyuan; Liu, Zhentao; Wang, Ziqi; Wang, Shubin; Chen, Zuhua; Li, Zhongwu; Zhang, Mengqi; Zou, Jianling; Dong, Bin; Gao, Jing; Shen, Lin

2018-04-10

c-Myc amplification-induced cell cycle dysregulation is a common cause for esophageal squamous cell carcinoma (ESCC), but no approved targeted drug is available so far. The bromodomain inhibitor JQ1, which targets c-Myc, exerts anti-tumor activity in multiple cancers. However, the role of JQ1 in ESCC remains unknown. In this study, we reported that JQ1 had potent anti-proliferative effects on ESCC cells in both time- and dose-dependent manners by inducing cell cycle arrest at G1 phase, cell apoptosis, and the mesenchymal-epithelial transition. Follow-up studies revealed that both c-Myc/cyclin/Rb and PI3K/AKT signaling pathways were inactivated by JQ1, as indicated by the downregulation of c-Myc, cyclin A/E, and phosphorylated Rb, AKT and S6. Tumor suppression induced by JQ1 in c-Myc amplified or highly expressed xenografts was higher than that in xenografts with low expression, suggesting its potential role in prediction. In conclusion, targeting c-Myc by JQ1 could cause significant tumor suppression in ESCC both in vitro and in vivo. Also, c-Myc amplification or high expression might serve as a potential biomarker and provide a promising therapeutic option for ESCC. Copyright © 2018 Elsevier B.V. All rights reserved.

Global metabolomics reveals potential urinary biomarkers of esophageal squamous cell carcinoma for diagnosis and staging

NASA Astrophysics Data System (ADS)

Xu, Jing; Chen, Yanhua; Zhang, Ruiping; He, Jiuming; Song, Yongmei; Wang, Jingbo; Wang, Huiqing; Wang, Luhua; Zhan, Qimin; Abliz, Zeper

2016-10-01

We performed a metabolomics study using liquid chromatography-mass spectrometry (LC-MS) combined with multivariate data analysis (MVDA) to discriminate global urine profiles in urine samples from esophageal squamous cell carcinoma (ESCC) patients and healthy controls (NC). Our work evaluated the feasibility of employing urine metabolomics for the diagnosis and staging of ESCC. The satisfactory classification between the healthy controls and ESCC patients was obtained using the MVDA model, and obvious classification of early-stage and advanced-stage patients was also observed. The results suggest that the combination of LC-MS analysis and MVDA may have potential applications for ESCC diagnosis and staging. We then conducted LC-MS/MS experiments to identify the potential biomarkers with large contributions to the discrimination. A total of 83 potential diagnostic biomarkers for ESCC were screened out, and 19 potential biomarkers were identified; the variations between the differences in staging using these potential biomarkers were further analyzed. These biomarkers may not be unique to ESCCs, but instead result from any malignant disease. To further elucidate the pathophysiology of ESCC, we studied related metabolic pathways and found that ESCC is associated with perturbations of fatty acid β-oxidation and the metabolism of amino acids, purines, and pyrimidines.

[IL-23 promotes invasion of esophageal squamous cell carcinoma cells by activating DLL4/Notch1 signaling pathway].

PubMed

Li, Wei; Zhou, Yuepeng; Su, Yuting; Ouyang, Yibo; Xie, Xiaodong; Wu, Yingying; Mao, Chaoming; Chen, Deyu

2015-06-01

To investigate the role of interlukin-23 (IL-23) in the invasion of human esophageal squamous cell carcinoma (ESCC) cells and the related mechanism. IL-23 expression in tumor and adjacent tissues from 10 ESCC patients were detected by immunohistochemistry. Real-time fluorescent PCR was used to examine the expressions of Notch1 and Foxn4 mRNAs in different concentration IL-23-treated TE-1 cells. After Notch pathway was blocked with γ-secretase inhibitor DAPT, expressions of Notch intracellular domain (NICD), Delta-like 4 (DLL4), hairy enhancer of split 1 (Hes1), matrix metalloproteinase 9 (MMP-9) in IL-23-treated TE-1 cells were measured by Western blotting. And the migration of IL-23-treated TE-1 cells was studied by TranswellTM migration assay. Compared with adjacent tissues, IL-23 was highly expressed in ESCC tissues. IL-23 treatment up-regulated significantly the expressions of NICD, DLL4, Hes1 and MMP-9 in TE-1 cells. The blockade of Notch1 pathway inhibited the expressions induced by IL-23. Migration assay revealed that IL-23 treatment significantly enhanced the migration of TE-1 cells. IL-23 could promote migration of human ESCC cells by activating DLL4/Notch1 signaling pathway.

Diisopropylamine dichloroacetate enhances radiosensitization in esophageal squamous cell carcinoma by increasing mitochondria-derived reactive oxygen species levels

PubMed Central

Yu, Decai; Mao, Qixing; Xia, Wenjie; Shi, Run; Wang, Jie; Xu, Lin

2016-01-01

Radiotherapy is generally applied in the treatment of esophageal squamous cell carcinoma (ESCC). However, the radioresistance of ESCC still remains an obstacle for the curative effect of this treatment. We hypothesized that diisopropylamine dichloroacetate (DADA), an inhibitor of pyruvate dehydrogenase kinase (PDK), might enhance radiosensitizationin resistant ESCC. The clonogenic survival assay revealed that DADA sensitized ESCC cells to radiotherapy in vitro; furthermore, the combination of DADA and radiotherapy increased the expression of γ-H2AX, which is a hallmark of DNA double-strand breaks. Arrest at G2/M phase as well as the induction of apoptosis of ESCC cells were also observed in the cells treated with the combination of DADA and radiotherapy. Notably, xenograft tumor growth was significantly suppressed in vivo by combined radiotherapy and DADA administration. It has been proven that glycolysis is highly correlated with radioresistance, which could be reversed by the shift from glycolysis to mitochondrial oxidation. In our present study, we found that DADA could modulate oxidative phosphorylation as well as increase the intracellular levels of reactive oxygen species (ROS). Collectively, we concluded that DADA-induced intracellular ROS accumulation was identified as the key factor of radiotherapy sensitization of ESCC. PMID:27626688

Somatically Acquired LINE-1 Insertions in Normal Esophagus Undergo Clonal Expansion in Esophageal Squamous Cell Carcinoma.

PubMed

Doucet-O'Hare, Tara T; Sharma, Reema; Rodić, Nemanja; Anders, Robert A; Burns, Kathleen H; Kazazian, Haig H

2016-09-01

Squamous cell carcinoma of the esophagus (SCC) is the most common form of esophageal cancer in the world and is typically diagnosed at an advanced stage when successful treatment is challenging. Understanding the mutational profile of this cancer may identify new treatment strategies. Because somatic retrotransposition has been shown in tumors of the gastrointestinal system, we focused on LINE-1 (L1) mobilization as a source of genetic instability in this cancer. We hypothesized that retrotransposition is ongoing in SCC patients. The expression of L1 encoded proteins is necessary for retrotransposition to occur; therefore, we evaluated the expression of L1 open reading frame 1 protein (ORF1p). Using immunohistochemistry, we detected ORF1p expression in all four SCC cases evaluated. Using L1-seq, we identified and validated 74 somatic insertions in eight tumors of the nine evaluated. Of these, 12 insertions appeared to be somatic, not genetically inherited, and sub-clonal (i.e., present in less than one copy per genome equivalent) in the adjacent normal esophagus (NE), while clonal in the tumor. Our results indicate that L1 retrotransposition is active in SCC of the esophagus and that insertion events are present in histologically NE that expands clonally in the subsequent tumor. © 2016 WILEY PERIODICALS, INC.

Predictive value of EGFR overexpression and gene amplification on icotinib efficacy in patients with advanced esophageal squamous cell carcinoma

PubMed Central

Fan, Qingxia; Lu, Ping; Ma, Changwu; Liu, Wei; Liu, Ying; Li, Weiwei; Hu, Shaoxuan; Ling, Yun; Guo, Lei; Ying, Jianming; Huang, Jing

2016-01-01

This study aimed to search for a molecular marker for targeted epithelial growth factor receptor (EGFR) inhibitor Icotinib by analyzing protein expression and amplification of EGFR proto-oncogene in esophageal squamous cell carcinoma (ESCC) patients. Immunohistochemistry and fluorescence in situ hybridization (FISH) was used to assess EGFR expression and gene amplification status in 193 patients with ESCC. We also examined the association between EGFR overexpression and the efficacy of a novel EGFR TKI, icotinib, in 62 ESCC patients. Of the 193 patients, 95 (49.2%) patients showed EGFR overexpression (3+), and 47(24.4%) patients harbored EGFR FISH positivity. EGFR overexpression was significantly correlated with clinical stage and lymph node metastasis (p<0.05). In addition, EGFR overexpression was significantly correlated with EGFR FISH positivity (p<0.001). Among the 62 patients who received icotinib, the response rate was 17.6% for patients with high EGFR-expressing tumors, which was markedly higher than the rate (0%) for patients with low to moderate EGFR-expressing tumors (p=0.341). Furthermore, all cases responded to icotinib showed EGFR overexpression. In conclusion, our study suggests that EGFR overexpression might potentially be used in predicting the efficacy in patients treated with Icotinib. These data have implications for both clinical trial design and therapeutic strategies. PMID:27013591

Predictive value of EGFR overexpression and gene amplification on icotinib efficacy in patients with advanced esophageal squamous cell carcinoma.

PubMed

Wang, Xi; Niu, Haitao; Fan, Qingxia; Lu, Ping; Ma, Changwu; Liu, Wei; Liu, Ying; Li, Weiwei; Hu, Shaoxuan; Ling, Yun; Guo, Lei; Ying, Jianming; Huang, Jing

2016-04-26

This study aimed to search for a molecular marker for targeted epithelial growth factor receptor (EGFR) inhibitor Icotinib by analyzing protein expression and amplification of EGFR proto-oncogene in esophageal squamous cell carcinoma (ESCC) patients.Immunohistochemistry and fluorescence in situ hybridization (FISH) was used to assess EGFR expression and gene amplification status in 193 patients with ESCC. We also examined the association between EGFR overexpression and the efficacy of a novel EGFR TKI, icotinib, in 62 ESCC patients.Of the 193 patients, 95 (49.2%) patients showed EGFR overexpression (3+), and 47(24.4%) patients harbored EGFR FISH positivity. EGFR overexpression was significantly correlated with clinical stage and lymph node metastasis (p<0.05). In addition, EGFR overexpression was significantly correlated with EGFR FISH positivity (p<0.001). Among the 62 patients who received icotinib, the response rate was 17.6% for patients with high EGFR-expressing tumors, which was markedly higher than the rate (0%) for patients with low to moderate EGFR-expressing tumors (p=0.341). Furthermore, all cases responded to icotinib showed EGFR overexpression.In conclusion, our study suggests that EGFR overexpression might potentially be used in predicting the efficacy in patients treated with Icotinib. These data have implications for both clinical trial design and therapeutic strategies.

OP16, a novel ent-kaurene diterpenoid, potentiates the antitumor effect of rapamycin by inhibiting rapamycin-induced feedback activation of Akt signaling in esophageal squamous cell carcinoma.

PubMed

Peng, Ke-Zheng; Ke, Yu; Zhao, Qi; Tian, Fei; Liu, Hong-Min; Hou, Guiqin; Lu, Zhaoming

2017-09-15

Hyperactivation of mTOR signaling pathway has been viewed as a significant molecular pathogenesis of cancer. However, inhibition of mTOR by rapamycin and its analogs could induce numerous negative feedback loops to attenuate their therapeutic efficacy. As a traditional Chinese herbal medicine, Rabdosia rubescens has been used to treat esophageal squamous cell carcinoma (ESCC) for hundreds of years, and its major effective component is oridonin. Here we reported that OP16, a novel analog of oridonin, showed potent inhibition of cell proliferation and Akt phosphorylation in ESCC cells. The combination of OP16 and rapamycin possesses synergistic anti-proliferative and pro-apoptotic effects both in ESCC cells and ESCC xenografts, and no obvious adverse effect was observed in vivo. Mechanistic analysis revealed that OP16 could inhibit rapamycin-induced Akt activation through the p70S6K-mediated negative feedback loops, and the combination of OP16 and rapamycin was more effective in activating caspase-dependent apoptotic signaling cascade. This study supports the combined use of OP16 with rapamycin as a feasible and effective therapeutic approach for future treatment of ESCC. Copyright © 2017 Elsevier Inc. All rights reserved.

Independent and combined effects of environmental factors and CYP2C19 polymorphisms on the risk of esophageal squamous cell carcinoma in Fujian Province of China.

PubMed

Peng, Xian-E; Chen, Hua-Fang; Hu, Zhi-Jian; Shi, Xi-Shun

2015-03-17

The purpose of this study was to explore the effects of CYP2C19 gene polymorphisms and various environmental factors and their interactions on the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese Han population. A 1:2 frequency-matched case control study of 285 patients and 570 controls was conducted from June 2010 to May 2011 in AnXi of Fujian province, China. Environmental factors were investigated using a self-administered questionnaire and genotypes were determined using polymerase chain reaction restriction fragment length polymorphism based methods. Unconditional logistic regression models were used for statistical evaluation. Current or former smoking, consumption of pickled vegetables or hot beverages/food, having a first degree relative with ESCC and history of reflux esophagitis were significantly associated with increased ESCC risk, whereas tea drinking and consumption of fresh vegetables and fruits were significantly associated with decreased risk. The CYP2C19*2 GA/AA genotype was significantly more prevalent in ESCC patients and individuals with at least one copy of the CYP2C19*2 A allele had a 3.19-fold increased risk (adjusted 95% confidence interval (CI): 2.21-4.61, P < 0.001) of ESCC compared with those without this allele. We found no significant associations between CYP2C19*3 genotypes and ESCC. The Cyp2C19*2 polymorphism appeared to have a multiplicative joint effect with tea drinking and hot beverage/food consumption (gene-tea drinking: P(interaction) = 0.042; hot beverage/food consumption: P(interaction) = 6.98 × 10(-6)) and an additive joint effect with pickled vegetable consumption (interaction contrast ratio = 1.96, 95% CI: 0.12-3.80). Our findings suggest that the CYP2C19*2 polymorphism plays an important role in the development of ESCC in the Chinese population, modified by tea drinking and consumption of pickled vegetables or hot beverages/food. Further studies are warranted to confirm our results.

MicroRNA-367 is a potential diagnostic biomarker for patients with esophageal squamous cell carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Jiangtao; Song, Kaifang; Feng, Xiaoshan, E-mail: xiaoshan.feng@aol.com

Purpose: In this study, we investigated whether microRNA-367 (miR-367) may serve as a circulating biomarker and tumor oncogene in esophageal squamous carcinoma (ESCC). Methods: Circulating serum miR-367 was compared by quantitative RT-PCR (qRT-PCR) between 35 ESCC patients and 35 normal control patients, as well paired ESCC tumor tissues and adjacent non-tumor esophageal epithelial tissues in 46 patients. The correlation between serum miR-367 and clinicopathological properties of ESCC patients was assessed. The overall survival (OS) was assessed by Kaplan–Meier method and compared by log-rank test between patients with high serum miR-367 and low serum miR-367. The possibility of miR-367 being independentmore » prognostic factor for ESCC was also assessed. Furthermore, lentivirus-mediated miR-367 downregulation was conducted in ESCC cell lines Kyse30 and TE-1 cells to assess the possible oncogenic effect of miR-367 on ESCC proliferation and cell cycle transition in vitro. Results: MiR-367 was aberrantly upregulated in sera and tumors of ESCC patients, whereas downregulated in ESCC patients after the treatments of esophagectomy and chemotherapy. Serum miR-367 was found to be closely correlated with the clinicopathological properties of differentiation grades, clinical stage and tumor metastasis in ESCC patients. Serum miR-367 was also confirmed to be associated with OS, as well as serving independent prognostic factor in ESCC patients. Moreover, lentivirus-induced miR-367 downregulation inhibited cancer growth and cell cycle transition in Kyse30 and TE-1 cells. Conclusion: MiR-367 is a potential biomarker for ESCC and may act as an oncogene in regulating ESCC development. - Highlights: • MiR-367 was aberrantly upregulated in sera and tumors of ESCC patients. • MiR-367 was downregulated in ESCC patients after esophagectomy or chemotherapy. • Serum miR-367 was correlated with the clinicopathological properties of ESCC patients. • Serum miR-367 was associated with OS in ESCC patients. • lentivirus-induced miR-367 downregulation inhibited ESCC growth and cell cycle transition.« less

Comparison of clinicopathologic features and survival between eastern and western population with esophageal squamous cell carcinoma.

PubMed

Zhang, Jie; Jiang, Yizhou; Wu, Chunxiao; Cai, Shuang; Wang, Rui; Zhen, Ying; Chen, Sufeng; Zhao, Kuaile; Huang, Yangle; Luketich, James; Chen, Haiquan

2015-10-01

Esophageal squamous cell carcinoma (ESCC) is the major histologic subtype of esophageal cancer, characterized by a high mortality rate and geographic differences in incidences. It is unknown whether there is difference between "eastern" ESCC and "western" ESCC. This study is attempted to demonstrate the hypothesis by comparing ESCC between Chinese residents and Caucasians living in the US. The data sources of this study are from United States SEER limited-use database and Shanghai Cancer Registries by Shanghai Municipal Center for Disease Control (SMCDC). Consecutive, non-selected patients with pathologically diagnosed ESCC, between January 1, 2002 and December 31, 2006, were included in this analysis. 1-year, 3-year and 5-year survival estimates were computed and compared between two populations. A Cox proportional hazards model was used to determine factors affecting survival differences. A total of 1,718 Chinese, 1,624 Caucasians ESCC patients with individual American Joint Commission on Cancer (AJCC) staging information were included in this study. The Caucasian group had a significantly higher proportion of female patients than Chinese (38.24% vs. 18.68% P<0.01). ESCC was diagnosed in Chinese patients at an earlier age and stage than Caucasians. Generally, Chinese patients had similar overall survival rate with Caucasian by both univariate and multivariate analysis. Overall survival was significantly worse only in male Caucasians compared to Chinese patients (median survival time, 12.4 vs. 14.5 months, P<0.01, respectively). ESCC from eastern and western countries might have some different features. These differences need to be taken into account for the management of ESCC patients in different ethnic groups.

Worldwide Esophageal Cancer Collaboration: clinical staging data.

PubMed

Rice, T W; Apperson-Hansen, C; DiPaola, L M; Semple, M E; Lerut, T E M R; Orringer, M B; Chen, L-Q; Hofstetter, W L; Smithers, B M; Rusch, V W; Wijnhoven, B P L; Chen, K N; Davies, A R; D'Journo, X B; Kesler, K A; Luketich, J D; Ferguson, M K; Räsänen, J V; van Hillegersberg, R; Fang, W; Durand, L; Allum, W H; Cecconello, I; Cerfolio, R J; Pera, M; Griffin, S M; Burger, R; Liu, J-F; Allen, M S; Law, S; Watson, T J; Darling, G E; Scott, W J; Duranceau, A; Denlinger, C E; Schipper, P H; Ishwaran, H; Blackstone, E H

2016-10-01

To address uncertainty of whether clinical stage groupings (cTNM) for esophageal cancer share prognostic implications with pathologic groupings after esophagectomy alone (pTNM), we report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for clinically staged patients from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted data using variables with standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 22,123 clinically staged patients, 8,156 had squamous cell carcinoma, 13,814 adenocarcinoma, 116 adenosquamous carcinoma, and 37 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (18.5-25 mg/kg 2 , 47%), little weight loss (2.4 ± 7.8 kg), 0-1 ECOG performance status (67%), and history of smoking (67%). Cancers were cT1 (12%), cT2 (22%), cT3 (56%), cN0 (44%), cM0 (95%), and cG2-G3 (89%); most involved the distal esophagus (73%). Non-risk-adjusted survival for squamous cell carcinoma was not distinctive for early cT or cN; for adenocarcinoma, it was distinctive for early versus advanced cT and for cN0 versus cN+. Patients with early cancers had worse survival and those with advanced cancers better survival than expected from equivalent pathologic categories based on prior WECC pathologic data. Thus, clinical and pathologic categories do not share prognostic implications. This makes clinically based treatment decisions difficult and pre-treatment prognostication inaccurate. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient characteristics, cancer categories, and treatment characteristics and should direct 9th edition data collection. © 2016 International Society for Diseases of the Esophagus.

Worldwide Esophageal Cancer Collaboration: clinical staging data

PubMed Central

Rice, T. W.; Apperson-Hansen, C.; DiPaola, L. M.; Semple, M. E.; Lerut, T. E. M. R.; Orringer, M. B.; Chen, L.-Q.; Hofstetter, W. L.; Smithers, B. M.; Rusch, V. W.; Wijnhoven, B. P. L.; Chen, K. N.; Davies, A. R.; D’Journo, X. B.; Kesler, K. A.; Luketich, J. D.; Ferguson, M. K.; Räsänen, J. V.; van Hillegersberg, R.; Fang, W.; Durand, L.; Allum, W. H.; Cecconello, I.; Cerfolio, R. J.; Pera, M.; Griffin, S. M.; Burger, R.; Liu, J.-F; Allen, M. S.; Law, S.; Watson, T. J.; Darling, G. E.; Scott, W. J.; Duranceau, A.; Denlinger, C. E.; Schipper, P. H.; Ishwaran, H.; Blackstone, E. H.

2017-01-01

SUMMARY To address uncertainty of whether clinical stage groupings (cTNM) for esophageal cancer share prognostic implications with pathologic groupings after esophagectomy alone (pTNM), we report data—simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival—for clinically staged patients from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted data using variables with standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 22,123 clinically staged patients, 8,156 had squamous cell carcinoma, 13,814 adenocarcinoma, 116 adenosquamous carcinoma, and 37 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (18.5–25 mg/kg2, 47%), little weight loss (2.4 ± 7.8 kg), 0–1 ECOG performance status (67%), and history of smoking (67%). Cancers were cT1 (12%), cT2 (22%), cT3 (56%), cNO (44%), cMO (95%), and cG2–G3 (89%); most involved the distal esophagus (73%). Non-risk-adjusted survival for squamous cell carcinoma was not distinctive for early cT or cN; for adenocarcinoma, it was distinctive for early versus advanced cT and for cNO versus cN+. Patients with early cancers had worse survival and those with advanced cancers better survival than expected from equivalent pathologic categories based on prior WECC pathologic data. Thus, clinical and pathologic categories do not share prognostic implications. This makes clinically based treatment decisions difficult and pre-treatment prognostication inaccurate. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient characteristics, cancer categories, and treatment characteristics and should direct 9th edition data collection. PMID:27731549

A new method (the "Pincers maneuver") for lymphadenectomy along the right recurrent laryngeal nerve during thoracoscopic esophagectomy in the prone position for esophageal cancer.

PubMed

Oshikiri, Taro; Nakamura, Tetsu; Miura, Yukiko; Yamamoto, Masashi; Kanaji, Shingo; Yamashita, Kimihiro; Matsuda, Takeru; Sumi, Yasuo; Suzuki, Satoshi; Kakeji, Yoshihiro

2017-03-01

In esophageal squamous cell carcinoma, the number of dissected lymph nodes (LNs), including those along the recurrent laryngeal nerves (RLNs), influences prognosis and nodal staging accuracy. However, dissection of LNs along the RLN increases the risk of complications, especially RLN palsy. Therefore, complete dissection of these LNs with prevention of RLN palsy is recommended. We present herein a new method for lymphadenectomy along the right RLN, named the Pincers maneuver, during thoracoscopic esophagectomy in the prone position (TEP). The fundamental concept in this new method is to first exfoliate the two-dimensional membrane (lateral pedicle), which includes the right RLN, LNs along the right RLN, and the primary esophageal artery, from the right side of the trachea toward the neck. Using a Pincers strategy, closing in from the inner and outer sides of the two-dimensional membrane (lateral pedicle), lymphadenectomy along the right RLN toward the right inferior thyroid artery should be easy. This technique was evaluated in 30 consecutive cases of TEP for squamous cell cancer. There were 15 patients who underwent the new method (Pincers maneuver; Pm) and 15 patients who underwent the conventional method (Cm). There were no significant differences between the two groups in the duration of the thoracic procedure and dissection along the right RLN. No intraoperative and postoperative morbidity related to the right RLN was observed in either group. The Pm group had a higher number of dissected LNs along the right RLN than the Cm group (6.3 vs 3.1, p = 0.044). The Pincers maneuver for lymphadenectomy along the right RLN during TEP is technically safe and feasible. It increases the number of dissected LNs along the right RLN.

The combination of platelet count and neutrophil lymphocyte ratio is a predictive factor in patients with esophageal squamous cell carcinoma.

PubMed

Feng, Ji-Feng; Huang, Ying; Chen, Qi-Xun

2014-10-01

The prognostic value of inflammation indexes in esophageal cancer was not established. In this study, therefore, both prognostic values of Glasgow prognostic score (GPS) and combination of platelet count and neutrophil lymphocyte ratio (COP-NLR) in patients with esophageal squamous cell carcinoma (ESCC) were investigated and compared. This retrospective study included 375 patients who underwent esophagectomy for ESCC. The cancer-specific survival (CSS) was calculated by the Kaplan-Meier method, and the difference was assessed by the log-rank test. The GPS was calculated as follows: patients with elevated C-reactive protein (> 10 mg/l) and hypoalbuminemia (< 35 g/l) were assigned to GPS2. Patients with one or no abnormal value were assigned to GPS1 or GPS0, respectively. The COP-NLR was calculated as follows: patients with elevated platelet count (> 300 × 10(9)/l) and neutrophil lymphocyte ratio (> 3) were assigned to COP-NLR2. Patients with one or no abnormal value were assigned to COP-NLR1 or COP-NLR0, respectively. The 5-year CSS in patients with GPS0, 1, and 2 was 50.0%, 27.0%, and 12.5%, respectively (P < .001). The 5-year CSS in patients with COP-NLR0, 1, and 2 was 51.8%, 27.0%, and 11.6%, respectively (P < .001). Multivariate analysis showed that both GPS (P = .003) and COP-NLR (P = .003) were significant predictors in such patients. In addition, our study demonstrated a similar hazard ratio (HR) between COP-NLR and GPS (HR = 1.394 vs HR = 1.367). COP-NLR is an independent predictive factor in patients with ESCC. We conclude that COP-NLR predicts survival in ESCC similar to GPS.

Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies

PubMed Central

Abnet, Christian C.; Wang, Zhaoming; Song, Xin; Hu, Nan; Zhou, Fu-You; Freedman, Neal D.; Li, Xue-Min; Yu, Kai; Shu, Xiao-Ou; Yuan, Jian-Min; Zheng, Wei; Dawsey, Sanford M.; Liao, Linda M.; Lee, Maxwell P.; Ding, Ti; Qiao, You-Lin; Gao, Yu-Tang; Koh, Woon-Puay; Xiang, Yong-Bing; Tang, Ze-Zhong; Fan, Jin-Hu; Chung, Charles C.; Wang, Chaoyu; Wheeler, William; Yeager, Meredith; Yuenger, Jeff; Hutchinson, Amy; Jacobs, Kevin B.; Giffen, Carol A.; Burdett, Laurie; Fraumeni, Joseph F.; Tucker, Margaret A.; Chow, Wong-Ho; Zhao, Xue-Ke; Li, Jiang-Man; Li, Ai-Li; Sun, Liang-Dan; Wei, Wu; Li, Ji-Lin; Zhang, Peng; Li, Hong-Lei; Cui, Wen-Yan; Wang, Wei-Peng; Liu, Zhi-Cai; Yang, Xia; Fu, Wen-Jing; Cui, Ji-Li; Lin, Hong-Li; Zhu, Wen-Liang; Liu, Min; Chen, Xi; Chen, Jie; Guo, Li; Han, Jing-Jing; Zhou, Sheng-Li; Huang, Jia; Wu, Yue; Yuan, Chao; Huang, Jing; Ji, Ai-Fang; Kul, Jian-Wei; Fan, Zhong-Min; Wang, Jian-Po; Zhang, Dong-Yun; Zhang, Lian-Qun; Zhang, Wei; Chen, Yuan-Fang; Ren, Jing-Li; Li, Xiu-Min; Dong, Jin-Cheng; Xing, Guo-Lan; Guo, Zhi-Gang; Yang, Jian-Xue; Mao, Yi-Ming; Yuan, Yuan; Guo, Er-Tao; Zhang, Wei; Hou, Zhi-Chao; Liu, Jing; Li, Yan; Tang, Sa; Chang, Jia; Peng, Xiu-Qin; Han, Min; Yin, Wan-Li; Liu, Ya-Li; Hu, Yan-Long; Liu, Yu; Yang, Liu-Qin; Zhu, Fu-Guo; Yang, Xiu-Feng; Feng, Xiao-Shan; Wang, Zhou; Li, Yin; Gao, She-Gan; Liu, Hai-Lin; Yuan, Ling; Jin, Yan; Zhang, Yan-Rui; Sheyhidin, Ilyar; Li, Feng; Chen, Bao-Ping; Ren, Shu-Wei; Liu, Bin; Li, Dan; Zhang, Gao-Fu; Yue, Wen-Bin; Feng, Chang-Wei; Qige, Qirenwang; Zhao, Jian-Ting; Yang, Wen-Jun; Lei, Guang-Yan; Chen, Long-Qi; Li, En-Min; Xu, Li-Yan; Wu, Zhi-Yong; Bao, Zhi-Qin; Chen, Ji-Li; Li, Xian-Chang; Zhuang, Xiang; Zhou, Ying-Fa; Zuo, Xian-Bo; Dong, Zi-Ming; Wang, Lu-Wen; Fan, Xue-Pin; Wang, Jin; Zhou, Qi; Ma, Guo-Shun; Zhang, Qin-Xian; Liu, Hai; Jian, Xin-Ying; Lian, Sin-Yong; Wang, Jin-Sheng; Chang, Fu-Bao; Lu, Chang-Dong; Miao, Jian-Jun; Chen, Zhi-Guo; Wang, Ran; Guo, Ming; Fan, Zeng-Lin; Tao, Ping; Liu, Tai-Jing; Wei, Jin-Chang; Kong, Qing-Peng; Fan, Lei; Wang, Xian-Zeng; Gao, Fu-Sheng; Wang, Tian-Yun; Xie, Dong; Wang, Li; Chen, Shu-Qing; Yang, Wan-Cai; Hong, Jun-Yan; Wang, Liang; Qiu, Song-Liang; Goldstein, Alisa M.; Yuan, Zhi-Qing; Chanock, Stephen J.; Zhang, Xue-Jun; Taylor, Philip R.; Wang, Li-Dong

2012-01-01

Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10−8, and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19–1.40) and P= 7.63 × 10−10. An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants. PMID:22323360

NFkB hyperactivation causes invasion of esophageal squamous cell carcinoma with EGFR overexpression and p120-catenin down-regulation.

PubMed

Lehman, Heather L; Kidacki, Michal; Warrick, Joshua I; Stairs, Douglas B

2018-02-16

Four out of five patients diagnosed with esophageal squamous cell carcinoma (ESCC) will die within five years. This is primarily a result of the aggressive invasive potential of the disease. Our research is focused on the interplay between tumor suppressors and oncogenes in the invasive process. Specifically, EGFR and p120-catenin (p120ctn) are commonly dysregulated genes that are indicative of poor prognosis in ESCC. In a previous study we demonstrated that in our 3D organotypic culture model, only when EGFR overexpression is combined with p120ctn inactivation do the cells transform and invade - as opposed to either event alone. The purpose of this present study was to identify the components of the molecular pathways downstream of p120ctn and EGFR that lead to invasion. Using both human esophageal keratinocytes and human ESCC cells, we have identified NFkB as a central regulator of the invasive process downstream of p120ctn down-regulation and EGFR overexpression. Interestingly, we found that NFkB is hyperactivated in cells with EGFR overexpression and p120ctn inactivation than with either EGFR or p120ctn alone. Inhibition of this NFkB hyperactivation results in complete loss of invasion, suggesting that NFkB signaling is necessary for invasion in this aggressive cell type. Furthermore, we have identified RhoA and Rho-kinase as upstream regulators of NFkB in this process. We believe the cooperation of p120ctn down-regulation and EGFR overexpression is not only important in the aggressive mechanisms of ESCC but could be broadly applicable to many other cancer types in which p120ctn and EGFR are involved.

Downregulation of tropomyosin-1 in squamous cell carcinoma of esophagus, the role of Ras signaling and methylation.

PubMed

Zare, Maryam; Jazii, Ferdous Rastgar; Soheili, Zahra-Soheila; Moghanibashi, Mohamad-Mehdi

2012-10-01

Tropomyosins (TMs) are a family of cytoskeletal proteins that bind to and stabilize actin microfilaments. Non-muscle cells express multiple isoforms of TMs including three high molecular weight (HMW) isoforms: TM1, TM2, and TM3. While reports have indicated downregulation of TMs in transformed cells and several human cancers, nevertheless, little is known about the underlying mechanism of TMs suppression. In present study the expression of HMW TMs was investigated in squamous cell carcinoma of esophagus (SCCE), relative to primary cell cultures of normal esophagus by western blotting and real-time RT-PCR. Our results showed that TM1, TM2, and TM3 were significantly downregulated in cell line of SCCE. Moreover, mRNA level of TPM1 and TPM2 were markedly decreased by 93% and 96%, in tumor cell line relative to esophagus normal epithelial cells. Therefore, downregulation of TMs could play an important role in tumorigenesis of esophageal cancer. To asses the mechanism of TM downregulation in esophageal cancer, the role of Ras dependent signaling and promoter hypermethylation were investigated. We found that inhibition of two Ras effectory downstream pathways; MEK/ERK and PI3K/Akt leads to significant increased expression of TM1 protein and both TPM1 and TPM2 mRNAs. In addition, methyltransferase inhibition significantly upregulated TM1, suggesting the prominent contribution of promoter hypermethylation in TM1 downregulation in esophageal cancer. These data indicate that downregulation of HMW TMs occurs basically in SCCE and the activation of MEK/ERK and PI3K/Akt pathways as well as the epigenetic mechanism of promoter hypermethylation play important role in TM1 suppression in SCCE. Copyright © 2011 Wiley Periodicals, Inc.

Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies.

PubMed

Abnet, Christian C; Wang, Zhaoming; Song, Xin; Hu, Nan; Zhou, Fu-You; Freedman, Neal D; Li, Xue-Min; Yu, Kai; Shu, Xiao-Ou; Yuan, Jian-Min; Zheng, Wei; Dawsey, Sanford M; Liao, Linda M; Lee, Maxwell P; Ding, Ti; Qiao, You-Lin; Gao, Yu-Tang; Koh, Woon-Puay; Xiang, Yong-Bing; Tang, Ze-Zhong; Fan, Jin-Hu; Chung, Charles C; Wang, Chaoyu; Wheeler, William; Yeager, Meredith; Yuenger, Jeff; Hutchinson, Amy; Jacobs, Kevin B; Giffen, Carol A; Burdett, Laurie; Fraumeni, Joseph F; Tucker, Margaret A; Chow, Wong-Ho; Zhao, Xue-Ke; Li, Jiang-Man; Li, Ai-Li; Sun, Liang-Dan; Wei, Wu; Li, Ji-Lin; Zhang, Peng; Li, Hong-Lei; Cui, Wen-Yan; Wang, Wei-Peng; Liu, Zhi-Cai; Yang, Xia; Fu, Wen-Jing; Cui, Ji-Li; Lin, Hong-Li; Zhu, Wen-Liang; Liu, Min; Chen, Xi; Chen, Jie; Guo, Li; Han, Jing-Jing; Zhou, Sheng-Li; Huang, Jia; Wu, Yue; Yuan, Chao; Huang, Jing; Ji, Ai-Fang; Kul, Jian-Wei; Fan, Zhong-Min; Wang, Jian-Po; Zhang, Dong-Yun; Zhang, Lian-Qun; Zhang, Wei; Chen, Yuan-Fang; Ren, Jing-Li; Li, Xiu-Min; Dong, Jin-Cheng; Xing, Guo-Lan; Guo, Zhi-Gang; Yang, Jian-Xue; Mao, Yi-Ming; Yuan, Yuan; Guo, Er-Tao; Zhang, Wei; Hou, Zhi-Chao; Liu, Jing; Li, Yan; Tang, Sa; Chang, Jia; Peng, Xiu-Qin; Han, Min; Yin, Wan-Li; Liu, Ya-Li; Hu, Yan-Long; Liu, Yu; Yang, Liu-Qin; Zhu, Fu-Guo; Yang, Xiu-Feng; Feng, Xiao-Shan; Wang, Zhou; Li, Yin; Gao, She-Gan; Liu, Hai-Lin; Yuan, Ling; Jin, Yan; Zhang, Yan-Rui; Sheyhidin, Ilyar; Li, Feng; Chen, Bao-Ping; Ren, Shu-Wei; Liu, Bin; Li, Dan; Zhang, Gao-Fu; Yue, Wen-Bin; Feng, Chang-Wei; Qige, Qirenwang; Zhao, Jian-Ting; Yang, Wen-Jun; Lei, Guang-Yan; Chen, Long-Qi; Li, En-Min; Xu, Li-Yan; Wu, Zhi-Yong; Bao, Zhi-Qin; Chen, Ji-Li; Li, Xian-Chang; Zhuang, Xiang; Zhou, Ying-Fa; Zuo, Xian-Bo; Dong, Zi-Ming; Wang, Lu-Wen; Fan, Xue-Pin; Wang, Jin; Zhou, Qi; Ma, Guo-Shun; Zhang, Qin-Xian; Liu, Hai; Jian, Xin-Ying; Lian, Sin-Yong; Wang, Jin-Sheng; Chang, Fu-Bao; Lu, Chang-Dong; Miao, Jian-Jun; Chen, Zhi-Guo; Wang, Ran; Guo, Ming; Fan, Zeng-Lin; Tao, Ping; Liu, Tai-Jing; Wei, Jin-Chang; Kong, Qing-Peng; Fan, Lei; Wang, Xian-Zeng; Gao, Fu-Sheng; Wang, Tian-Yun; Xie, Dong; Wang, Li; Chen, Shu-Qing; Yang, Wan-Cai; Hong, Jun-Yan; Wang, Liang; Qiu, Song-Liang; Goldstein, Alisa M; Yuan, Zhi-Qing; Chanock, Stephen J; Zhang, Xue-Jun; Taylor, Philip R; Wang, Li-Dong

2012-05-01

Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10(-8), and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19-1.40) and P= 7.63 × 10(-10). An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.

A nomogram to predict prognostic values of various inflammatory biomarkers in patients with esophageal squamous cell carcinoma

PubMed Central

Liu, Jin-Shi; Huang, Ying; Yang, Xun; Feng, Ji-Feng

2015-01-01

Background: Inflammation plays an important role in cancer progression and prognosis. However, the prognostic values of inflammatory biomarkers in esophageal cancer (EC) were not established. In the present study, therefore, we initially used a nomogram to predict prognostic values of various inflammatory biomarkers in patients with esophageal squamous cell carcinoma (ESCC). Methods: A total of 326 ESCC patients were included in this retrospective study. Glasgow prognostic score (GPS), neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR) and lymphocyte monocyte ratio (LMR) were analyzed in the current study. Kaplan-Meier method was used to calculate the cancer-specific survival (CSS). Cox regression analysis was also performed to evaluate the prognostic factors. A nomogram was established to predict the prognosis for CSS. Results: Patients were divided into 3 groups according to GPS (GPS 0, 1 and 2) and 2 groups according to NLR (≤3.45 and >3.45), PLR (≤166.5 and >166.5) and LMR (≤2.30 and >2.30). The 5-year CSS in patients with GPS 0, 1 and 2 were 49.2%, 26.8% and 11.9%, respectively (P<0.001). In addition, patients with NLR (>3.45), PLR (>166.5) and LMR (≤2.30) were significantly associated with decreased CSS, respectively (P<0.001). Multivariate analysis revealed that GPS (P<0.001), PLR (P=0.002) and LMR (P=0.002) were independent prognostic factors in patients with ESCC. In addition, a nomogram was established according to all significantly independent factors for CSS. The Harrell’s c-index for CSS prediction was 0.72. Conclusion: GPS, PLR and LMR were potential prognostic biomarkers in patients with ESCC. The nomogram based on CSS could be used as an accurately prognostic prediction for patients with ESCC. PMID:26328248

Feasibility of Elective Nodal Irradiation (ENI) and Involved Field Irradiation (IFI) in Radiotherapy for the Elderly Patients (Aged ≥ 70 Years) with Esophageal Squamous Cell Cancer: A Retrospective Analysis from a Single Institute.

PubMed

Jing, Wang; Zhu, Hui; Guo, Hongbo; Zhang, Yan; Shi, Fang; Han, Anqin; Li, Minghuan; Kong, Li; Yu, Jinming

2015-01-01

We conducted a retrospective analysis to assess the feasibility of involved field irradiation (IFI) in elderly patients with esophageal squamous cell cancer (ESCC). We performed a retrospective review of the records of elderly patients (≥ 70 years) with unresectable ESCC and no distant metastases who received treatment with radiotherapy between January 2009 and March 2013. According to the irradiation volume, patients were allocated into either the elective nodal irradiation (ENI) group or the IFI group. Overall survival (OS), progression-free survival (PFS) and treatment-related toxicities were compared between the two groups. A total of 137 patients were enrolled. Fifty-four patients (39.4%) were allocated to the ENI group and 83 patients (60.6%) to the IFI group, the median doses in the two groups were 60 Gy and 59.4 Gy, respectively. For the entire group, the median survival time (MST) and PFS were 16 months and 12 months, respectively. The median PFS and 3-year PFS rate in the ENI group were 13 months and 20.6%, compared to 11 months and 21.0% in the IFI groups (p = 0.61). The MST and 3-year OS rate in the ENI and IFI groups were 17 months and 26.4% and 15.5 months and 21.7%, respectively (p = 0.25). The rate of grade ≥ 3 acute irradiation esophagitis in the ENI group was significantly higher than that in the IFI group (18.5% vs. 6.0%; p = 0.027). Other grade ≥ 3 treatment-related toxicities did not significantly differ between the two groups. IFI resulted in decreased irradiation toxicities without sacrificing OS in elderly patients with ESCC.

Postoperative Radiation Therapy With or Without Concurrent Chemotherapy for Node-Positive Thoracic Esophageal Squamous Cell Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Junqiang; Pan, Jianji; Liu, Jian, E-mail: liujianfj@yahoo.com.cn

Purpose: To retrospectively compare the efficacy of radiation therapy (RT) and chemotherapy plus RT (CRT) for the postoperative treatment of node-positive thoracic esophageal squamous cell carcinoma (TESCC) and to determine the incidence and severity of toxic reactions. Methods and Materials: We retrospectively reviewed data from 304 patients who had undergone esophagectomy with 3-field lymph node dissection for TESCC and were determined by postoperative pathology to have lymph node metastasis without distant hematogenous metastasis. Of these patients, 164 underwent postoperative chemotherapy (cisplatin 80 mg/m{sup 2}, average days 1-3, plus paclitaxel 135 mg/m{sup 2}, day 1; 21-day cycle) plus RT (50 Gy),more » and 140 underwent postoperative RT alone. Results: The 5-year overall survival rates for the CRT and RT groups were 47.4% and 38.6%, respectively (P=.030). The distant metastasis rate, the mixed (regional lymph node and distant) metastasis rate, and the overall recurrence rate were significantly lower in the CRT group than in the RT group (P<.05). However, mild and severe early toxic reactions, including neutropenia, radiation esophagitis, and gastrointestinal reaction, were significantly more common in the CRT group than in the RT group (P<.05). No significant differences in incidence of late toxic reactions were found between the 2 groups. Conclusions: Our results show that in node-positive TESCC patients, postoperative CRT is significantly more effective than RT alone at increasing the overall survival and decreasing the rates of distant metastasis, mixed metastasis, and overall recurrence. Severe early toxic reactions were more common with CRT than with RT alone, but patients could tolerate CRT.« less

Radiofrequency Ablation Versus Endoscopic Submucosal Dissection in Treating Large Early Esophageal Squamous Cell Neoplasia

PubMed Central

Wang, Wen-Lun; Chang, I-Wei; Chen, Chien-Chuan; Chang, Chi-Yang; Mo, Lein-Ray; Lin, Jaw-Town; Wang, Hsiu-Po; Lee, Ching-Tai

2015-01-01

Abstract Radiofrequency ablation (RFA) and endoscopic submucosal dissection (ESD) can potentially be applied for early esophageal squamous cell neoplasia (ESCN); however, no study has directly compared these 2 modalities. We retrospectively enrolled the patients with flat-type “large” (length ≥3 cm extending ≥1/2 of the circumference of esophagus) early ESCNs treated endoscopically. The main outcome measurements were complete response at 12 months, and adverse events. Of a total of 65 patients, 18 were treated with RFA and 47 with ESD. The procedure time of RFA was significantly shorter than that of ESD (126.6 vs 34.8 min; P < 0.001). The complete resection rate of ESD and complete response rate after primary RFA were 89.3% and 77.8%, respectively. Based on the histological evaluation of the post-ESD specimens showed 14 of 47 (29.8%) had histological upstaging compared with the pre-ESD biopsies, and 4 of them had lymphovascular invasion requiring chemoradiation or surgery. After additional therapy for residual lesions, 46 (97.9%) patients in the ESD group and 17 (94.4%) patients in the RFA group achieved a complete response at 12 months. Four patients (8.5%) developed major procedure-related adverse events in the ESD group, but none in the RFA group. In patients with lesions occupying more than 3/4 of the circumference, a significantly higher risk of esophageal stenosis was noted in the ESD group compared with RFA group (83% vs 27%, P = 0.01), which required more sessions of dilatation to resolve the symptoms (median, 13 vs 3, P = 0.04). There were no procedure-related mortality or neoplastic progression in either group; however, 1 patient who received ESD and 1 who received RFA developed local recurrence during a median follow-up period of 32.4 (range, 13–68) and 18.0 (range, 13–41) months, respectively. RFA and ESD are equally effective in the short-term treatment of early flat large ESCNs; however, more adverse events occur with ESD, especially in lesions extending more than 3/4 of the circumference. RFA does not allow for pathology to evaluate the curability after ablation, and thus currently the use for invasive ESCNs should be conservative until longer follow-up studies are available. PMID:26656367

Human esophageal myofibroblasts secrete proinflammatory cytokines in response to acid and Toll-like receptor 4 ligands

PubMed Central

Gargus, Matthew; Niu, Chao; Vallone, John G.; Binkley, Jana; Rubin, Deborah C.

2015-01-01

The pathophysiology of esophageal injury, repair, and inflammation in gastroesophageal reflux-disease (GERD) is complex. Whereas most studies have focused on the epithelial response to GERD injury, we are interested in the stromal response. We hypothesized that subepithelial esophageal myofibroblasts in GERD secrete proinflammatory cytokines in response to injurious agents encountered via epithelial barrier breaches or through dilated epithelial intercellular spaces. We determined the percentage of myofibroblasts [α-smooth muscle actin (α-SMA)+vimentin+CD31−] in the subepithelial GERD and normal esophageal stroma by immunomorphologic analysis. We performed α-SMA coimmunostaining with IL-6 and p65. We established and characterized primary cultures of α-SMA+vimentin+CD31−CD45− human esophageal myofibroblasts (HuEso MFs). We modeled GERD by treatment with pH 4.5-acidified media and Toll-like receptor 4 (TLR4) ligands, LPS and high-mobility group box 1 protein (HMGB1), and determined myofibroblast cytokine secretion in response to GERD injury. We demonstrate that spindle-shaped cell myofibroblasts are located near the basement membrane of stratified squamous epithelium in normal esophagus. We identify an increase in subepithelial myofibroblasts and activation of proinflammatory pathways in patients with GERD. Primary cultures of stromal cells obtained from normal esophagus retain myofibroblast morphology and express the acid receptor transient receptor potential channel vanilloid subfamily 1 (TRPV1) and TLR4. HuEso MFs stimulated with acid and TLR4 agonists LPS and HMGB1 increase IL-6 and IL-8 secretion via TRPV1 and NF-κB activation. Our work implicates a role for human subepithelial stromal cells in the pathogenesis of GERD-related esophageal injury. Findings of this study can be extended to the investigation of epithelial-stromal interactions in inflammatory esophageal mucosal disorders. PMID:25882613

Immunohistochemical assessment of NY-ESO-1 expression in esophageal adenocarcinoma resection specimens.

PubMed

Hayes, Stephen J; Hng, Keng Ngee; Clark, Peter; Thistlethwaite, Fiona; Hawkins, Robert E; Ang, Yeng

2014-04-14

To assess NY-ESO-1 expression in a cohort of esophageal adenocarcinomas. A retrospective search of our tissue archive for esophageal resection specimens containing esophageal adenocarcinoma was performed, for cases which had previously been reported for diagnostic purposes, using the systematised nomenclature of human and veterinary medicine coding system. Original haematoxylin and eosin stained sections were reviewed, using light microscopy, to confirm classification and tumour differentiation. A total of 27 adenocarcinoma resection specimens were then assessed using immunohistochemistry for NY-ESO-1 expression: 4 well differentiated, 14 moderately differentiated, 4 moderate-poorly differentiated, and 5 poorly differentiated. Four out of a total of 27 cases of esophageal adenocarcinoma examined (15%) displayed diffuse cytoplasmic and nuclear expression for NY-ESO-1. They displayed a heterogeneous and mosaic-type pattern of diffuse staining. Diffuse cytoplasmic staining was not identified in any of these structures: stroma, normal squamous epithelium, normal submucosal gland and duct, Barrett's esophagus (goblet cell), Barrett's esophagus (non-goblet cell) and high grade glandular dysplasia. All adenocarcinomas showed an unexpected dot-type pattern of staining at nuclear, paranuclear and cytoplasmic locations. Similar dot-type staining, with varying frequency and size of dots, was observed on examination of Barrett's metaplasia, esophageal submucosal gland acini and the large bowel negative control, predominantly at the crypt base. Furthermore, a prominent pattern of apical (luminal) cytoplasmic dot-type staining was observed in some cases of Barrett's metaplasia and also adenocarcinoma. A further morphological finding of interest was noted on examination of haematoxylin and eosin stained sections, as aggregates of lymphocytes were consistently noted to surround submucosal glands. We have demonstrated for the first time NY-ESO-1 expression by esophageal adenocarcinomas, Barrett's metaplasia and normal tissues other than germ cells.

Immunohistochemical assessment of NY-ESO-1 expression in esophageal adenocarcinoma resection specimens

PubMed Central

Hayes, Stephen J; Hng, Keng Ngee; Clark, Peter; Thistlethwaite, Fiona; Hawkins, Robert E; Ang, Yeng

2014-01-01

AIM: To assess NY-ESO-1 expression in a cohort of esophageal adenocarcinomas. METHODS: A retrospective search of our tissue archive for esophageal resection specimens containing esophageal adenocarcinoma was performed, for cases which had previously been reported for diagnostic purposes, using the systematised nomenclature of human and veterinary medicine coding system. Original haematoxylin and eosin stained sections were reviewed, using light microscopy, to confirm classification and tumour differentiation. A total of 27 adenocarcinoma resection specimens were then assessed using immunohistochemistry for NY-ESO-1 expression: 4 well differentiated, 14 moderately differentiated, 4 moderate-poorly differentiated, and 5 poorly differentiated. RESULTS: Four out of a total of 27 cases of esophageal adenocarcinoma examined (15%) displayed diffuse cytoplasmic and nuclear expression for NY-ESO-1. They displayed a heterogeneous and mosaic-type pattern of diffuse staining. Diffuse cytoplasmic staining was not identified in any of these structures: stroma, normal squamous epithelium, normal submucosal gland and duct, Barrett’s esophagus (goblet cell), Barrett’s esophagus (non-goblet cell) and high grade glandular dysplasia. All adenocarcinomas showed an unexpected dot-type pattern of staining at nuclear, paranuclear and cytoplasmic locations. Similar dot-type staining, with varying frequency and size of dots, was observed on examination of Barrett’s metaplasia, esophageal submucosal gland acini and the large bowel negative control, predominantly at the crypt base. Furthermore, a prominent pattern of apical (luminal) cytoplasmic dot-type staining was observed in some cases of Barrett’s metaplasia and also adenocarcinoma. A further morphological finding of interest was noted on examination of haematoxylin and eosin stained sections, as aggregates of lymphocytes were consistently noted to surround submucosal glands. CONCLUSION: We have demonstrated for the first time NY-ESO-1 expression by esophageal adenocarcinomas, Barrett’s metaplasia and normal tissues other than germ cells. PMID:24744590

p16 gene silencing along with p53 single-nucleotide polymorphism and risk of esophageal cancer in Northeast India.

PubMed

Das, Mandakini; Sharma, Santanu Kumar; Sekhon, Gaganpreet Singh; Mahanta, Jagadish; Phukan, Rup Kumar; Jalan, Bimal Kumar

2017-05-01

The high incidence of esophageal cancer in Northeast India and the unique ethnic background and dietary habits provide a great opportunity to study the molecular genetics behind esophageal squamous cell carcinoma in this part of the region. We hypothesized that in addition to currently known environmental risk factors for esophageal cancer, genetic and epigenetic factors are also involved in esophageal carcinogenesis in Northeast India. Therefore, in this study, we explored the possible association between the two important G1 cell cycle regulatory genes p16 and p53 and environmental risk factors and risk of esophageal carcinogenesis. A total of 100 newly diagnosed esophageal cancer cases along with equal number of age-, sex-, and ethnicity-matched controls were included in this study. Methylation-specific polymerase chain reaction was used to determine the p16 promoter methylation status. Single-nucleotide polymorphism at codon 72 of p53 gene was assessed by the polymerase chain reaction-restriction fragment length polymorphism method. Aberrant methylation of p16 gene was seen in 81% of esophageal cancer cases. Hypermethylation of p16 gene was not found in healthy controls. p53 Pro/Pro genotype was found to be a risk genotype in Northeast India compared with Arg/Pro and Arg/Arg. p53 variant/polymorphism was significantly associated with esophageal cancer risk in the study population under all three genetic models, namely, dominant model (Arg/Pro + Pro/Pro vs Arg/Arg odds ratio = 2.25, confidence interval = 1.19-4.26; p = 0.012), recessive model (Arg/Arg + Arg/Pro vs Pro/Pro odds ratio = 2.35, confidence interval = 1.24-4.44; p = 0.008), and homozygous model (Pro/Pro vs Arg/Arg odds ratio = 3.33, confidence interval = 1.54-7.20; p = 0.002). However, p53 variant/polymorphism was not statistically associated with esophageal cancer risk under the heterozygous model (Pro/Pro vs Arg/Pro). In the case-only analysis based on p16 methylation, the p53 variant/polymorphism (Pro/Pro or Arg/Pro) showed significant association for esophageal cancer risk (odds ratio = 3.33, confidence interval = 1.54-7.20; p = 0.002). Gene-gene and gene-environment interaction using the case-only approach revealed a strong association between p16 methylation, p53 single-nucleotide polymorphism, and environmental factors and esophageal cancer risk. Cases with p16 methylation and p53 variant/polymorphism (Pro/Pro or Arg/Pro) along with both betel quid and tobacco chewing habit (odds ratio = 8.29, confidence interval = 1.14-60.23; p = 0.037) conferred eightfold increased risk toward esophageal cancer development. This study reveals a synergistic interaction between epigenetic, genetic, and environmental factors and risk of esophageal cancer in this high-incidence region of Northeast India. The inactivation of either p16 or p53 in a majority of esophageal cancer cases in this study suggests the possible crosstalk between the important cell cycle genes.

Prognostic significance of tumor-infiltrating immune cells and PD-L1 expression in esophageal squamous cell carcinoma.

PubMed

Jiang, Yubo; Lo, Anthony W I; Wong, Angela; Chen, Wenfeng; Wang, Yan; Lin, Li; Xu, Jianming

2017-05-02

Programmed death-1 receptor (PD-1) and its ligand (PD-L1) play an integral role in regulating the immune response against cancer. This study investigated the prognostic significance of PD-L1 expression on tumor cells and tumor-infiltrating immune cells (TILs) in the tumor microenvironment in Chinese patients with esophageal squamous cell carcinoma (ESCC). Archival formalin-fixed, paraffin-embedded ESCC samples from treatment-naïve patients with ESCC after surgery or by diagnostic endoscopic biopsy were collected between 2004 and 2014. Expression of PD-L1 in ESCC tumor specimens was assessed by immunohistochemistry (IHC), and the degree of TIL infiltration was evaluated by examining hematoxylin and eosin-stained (H&E) specimens. PD-L1+ as defined as ≥1% of tumor cell membranes showing ≥1+ intensity. In 428 patients, specimens from 341 (79.7%) were PD-L1+. In the definitive treatment group (patients who received curative esophagectomy or definitive [chemo-]radiation therapy), PD-L1 positivity was associated with a significantly shorter DFS and OS. In the palliative chemotherapy group exhibited, neither PFS nor OS correlated significantly with PD-L1 expression. PD-L1 expression was positively associated with TIL density. In 17 paired tumor tissues collected before and after treatment, an increase in PD-L1 expression was associated with disease progression, whereas a decrease in PD-L1 expression was associated with response to chemotherapy or disease control. So, PD-L1 expression was associated with a significantly worse prognosis in patients with ESCC. These observations suggest that PD-L1 may play a critical role in ESCC cancer progression and provide a rationale for developing PD-L1 inhibitors for treatment of a subset of ESCC patients.

Prognostic value of PAX9 in patients with esophageal squamous cell carcinoma and its prediction value to radiation sensitivity.

PubMed

Tan, Bingxu; Wang, Jianbo; Song, Qingxu; Wang, Nana; Jia, Yibin; Wang, Cong; Yao, Bin; Liu, Zhulong; Zhang, Xiaomei; Cheng, Yufeng

2017-07-01

Abnormal paired box 9 (PAX9) expression is associated with tumorigenesis, cancer development, invasion and metastasis. The present study investigated the prognostic significance of PAX9 in esophageal squamous cell carcinoma (ESCC) and its role in predicting radiation sensitivity. A total of 52.8% (121/229) ESCC tissues were positive for PAX9. The 1‑, 3‑ and 5‑year disease‑free survival (DFS) rates were 72.2, 35.2 and 5.6%, respectively, and the overall survival (OS) rates were and 86.1, 44.4, and 23.1%, respectively, in PAX9‑positive tumors. In PAX9‑negative tumors, the one‑, three‑ and five‑year DFS rates were 76.9, 47.9 and 24.0%, and the OS rates were 90.9, 57.9 and 38.8%, respectively. Univariate analysis revealed that PAX9, differentiation, T stage, lymph node metastasis, and tumor‑node‑metastasis stage were associated with OS. Multivariate analysis of DFS and OS revealed that the hazard ratios for PAX9 were 0.624 (95% CI: 0.472‑0.869, P=0.004) and 0.673 (95% CI: 0.491‑0.922, P=0.014), respectively. Patients that received adjuvant therapy exhibited significant differences in the 5‑year DFS (P<0.001) and OS (P<0.001). PAX9‑positive ESCC patients who received post‑surgery radiotherapy had a significantly greater 5‑year DFS (P=0.011) and OS (P=0.009) than patients who received surgery only. Thus, PAX9 may be an independent prognostic factor for the surgical treatment of ESCC and a possible predictor of radiation sensitivity.

Interleukin 1B rs16944 G>A polymorphism was associated with a decreased risk of esophageal cancer in a Chinese population.

PubMed

Zheng, Liang; Yin, Jun; Wang, Liming; Wang, Xu; Shi, Yijun; Shao, Aizhong; Tang, Weifeng; Ding, Guowen; Liu, Chao; Chen, Suocheng; Gu, Haiyong

2013-10-01

Esophageal cancer is the sixth leading cause of cancer-associated deaths worldwide and represents a particularly aggressive type of cancer. Genetic polymorphisms may partly explain individual differences in esophageal cancer susceptibility. We conducted a hospital-based case-control study to evaluate the genetic effects of functional single nucleotide polymorphisms (SNPs) in the interleukin 1 (IL1A and IL1B), IL1f7, IL3 and IL7Ra genes on the development of esophageal cancer. A total of 380 esophageal squamous cell carcinoma (ESCC) cases and 380 controls were recruited for this study. The genotypes were determined using a custom-by-design 48-Plex SNPscan™ Kit. When the IL1B rs16944 GG homozygote genotype was used as the reference group, the GA genotype was associated with a significantly decreased risk of ESCC (GA vs. GG: adjusted OR=0.69, 95% CI=0.49-0.99, p=0.041). However, there were no significant associations between the other five SNPs and ESCC risk. Stratified analyses indicated no significantly different risks of ESCC associated with the IL1B rs16944 G>A polymorphism according to sex, age, smoking status or alcohol consumption. IL3 rs2073506 G>A polymorphism was associated with an increased risk for ESCC higher tumor, nodal, and metastatic (TNM) stages. These findings indicated that the functional IL1B rs16944 G>A polymorphism might contribute to ESCC susceptibility. IL3 rs2073506 G>A polymorphism was associated with an increased risk for ESCC higher TNM stages. However, the results were based on a limited sample size and larger well-designed studies are warranted to confirm these initial findings. Copyright © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

A Safety and Tolerability Study of INCAGN02385 in Select Advanced Malignancies

ClinicalTrials.gov

2018-05-15

Cervical Cancer; Microsatellite Instability (MSI)-High Endometrial Cancer; Gastric Cancer (Including Stomach and Gastroesophageal Junction [GEJ]); Esophageal Cancer; Hepatocellular Carcinoma; Melanoma (Uveal Melanoma Excluded); Merkel Cell Carcinoma; Mesothelioma; MSI-high Colorectal Cancer; Non-small Cell Lung Cancer (NSCLC); Ovarian Cancer; Squamous Cell Carcinoma of the Head and Neck (SCCHN); Small Cell Lung Cancer (SCLC); Renal Cell Carcinoma (RCC); Triple-negative Breast Cancer; Urothelial Carcinoma; Diffuse Large B-cell Lymphoma

Antiproliferative effect of a novel mTOR inhibitor temsirolimus contributes to the prolonged survival of orthotopic esophageal cancer-bearing mice.

PubMed

Nishikawa, Toshio; Takaoka, Munenori; Ohara, Toshiaki; Tomono, Yasuko; Hao, Huifang; Bao, Xiaohong; Fukazawa, Takuya; Wang, Zhigang; Sakurama, Kazufumi; Fujiwara, Yasuhiro; Motoki, Takayuki; Shirakawa, Yasuhiro; Yamatsuji, Tomoki; Tanaka, Noriaki; Fujiwara, Toshiyoshi; Naomoto, Yoshio

2013-03-01

Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive cancers with poor prognosis regardless of a several reports that indicate a better therapeutic efficacy using some new chemotherapeutic agents. Recent drug development has contributed to an improved specificity to suppress mTOR activity by which many types of malignancies can be explosively progressed. Temsirolimus (CCI-779, TricelTM) is one of recently synthesized analogs of rapamycin and has provided better outcomes for patients with renal cell carcinoma. In this study, we experimentally evaluated an efficacy of targeting mTOR by temsirolimus for ESCC treatment, with an assessment of its survival advantage using an advanced ESCC animal model. First, we confirmed that the expression of phosphorylated mTOR was increased in 46 of 58 clinical ESCC tumor tissues (79.3%) and appeared to get strengthened with tumor progression. All of ESCC cell lines used in this study revealed an increase of mTOR phosphorylation, accompanied with the upregulation of hypoxia inducible factor-I α (HIF-1α), one of the critical effectors regulated by mTOR. Temsirolimus treatment apparently suppressed the activation of mTOR and its downstream effectors, resulting in the reduced ability of ESCC cell proliferation. Finally, the weekly administration of temsirolimus significantly diminished the size of subcutaneous tumors (vehicle, 3261.6 ± 722.0; temsirolimus, 599.2 ± 122.9; p = 0.007) in nude mice and effectively prolonged orthotopic esophageal cancer-bearing mice (median survival periods: control, 31 d; temsirolimus, 43 d; p = 0.0024). These data suggests that targeting mTOR by temsirolimus may become a therapeutic alternative for esophageal cancer, with a contribution to a better outcome.

Postoperative Infectious Complications are Associated with Adverse Oncologic Outcomes in Esophageal Cancer Patients Undergoing Preoperative Chemotherapy.

PubMed

Yamashita, Kotaro; Makino, Tomoki; Miyata, Hiroshi; Miyazaki, Yasuhiro; Takahashi, Tsuyoshi; Kurokawa, Yukinori; Yamasaki, Makoto; Nakajima, Kiyokazu; Takiguchi, Shuji; Mori, Masaki; Doki, Yuichiro

2016-06-01

For some types of cancer, postoperative complications can negatively influence survival, but the association between these complications and oncological outcomes is unclear for patients with esophageal cancer who receive preoperative treatments. Data were retrospectively analyzed for patients who underwent curative resection following preoperative chemotherapy for esophageal squamous cell carcinoma from 2001 to 2011. Clinicopathological parameters and cancer-specific survival (CSS) were compared between patients with and without severe postoperative complications, grade III or higher, using the Clavien-Dindo classification. Of 255 patients identified, 104 (40.8 %) postoperatively developed severe complications. The most common complication was atelectasis in 61 (23.9 %), followed by pulmonary infection in 22 (8.6 %). Three-field lymphadenectomy, longer operation time, and more blood loss were significantly associated with a higher incidence of severe complications. Multivariate analysis of CSS revealed severe complications [hazard ratio (HR) = 1.642, 95 % confidence interval (95 % CI) 1.095-2.460, p = 0.016] as a significant prognostic factor along with pT stage [HR = 2.081, 95 % CI 1.351-3.266, p < 0.001] and pN stage [HR = 3.724, 95 % CI 2.111-7.126, p < 0.001], whereas postoperative serum C-reactive protein value was not statistically significant. Among all complications, severe pulmonary infection was the only independent prognostic factor [HR = 2.504, 95 % CI 1.308-4.427, p = 0.007]. The incidence of postoperative infectious complications, in particular pulmonary infection, is associated with unfavorable prognosis in patients with esophageal cancer undergoing preoperative chemotherapy.

Deficiency of IL-18 Aggravates Esophageal Carcinoma Through Inhibiting IFN-γ Production by CD8+T Cells and NK Cells.

PubMed

Li, Jiantao; Qiu, Gang; Fang, Baoshuan; Dai, Xiaohui; Cai, Jianhui

2018-03-01

To investigate the potential role of interleukin-18 (IL-18) in immunomodulation during tumorigenesis of esophageal carcinoma and elucidate the underlying molecular mechanism, we employed IL-18 knockout mice for this purpose. Carcinogen 4-nitroquinoline 1-oxide (4NQO) was administrated in drinking water to induce occurrence of esophageal squamous cell carcinoma (ESCC). T cell activation as indicated by the surface CD molecules was analyzed with flow cytometry. The serous content of interferon-γ (IFN-γ) along with other cytokines was determined by inflammatory human cytokine cytometric bead array. The cytotoxicity assay was performed by co-culture of tumor cells with immune cells and relative cell viability was determined by lactate dehydrogenase (LDH) assay. Apoptotic cells were stained with Annexin-V/propidium iodide (PI) and analyzed by flow cytometry. Cell proliferation was measured with Cell Counting Kit-8 (CCK-8) assay. Our data demonstrated that deficiency of IL-18 promoted the progression and development of 4NQO-induced ESCC. Loss of IL-18 suppressed the activation of T cells in the esophagus. Deficiency of IL-18 inhibited the IFN-γ production by CD8 + T cells and natural killer (NK) cells. Absence of IL-18 inhibited the cytotoxicity of CD8 + T cells and NK cell in vitro. Moreover, deficiency of IL-18 promoted the apoptosis of CD8 + T cells and inhibited the proliferation of CD8 + T cells in vitro. Our data elucidated the immunomodulatory role of IL-18 during tumorigenesis of ESCC, whose deficiency compromised antitumor immunity and contributed to immune escape of esophageal carcinoma. Our results also indicated the therapeutic potential of exogenous IL-18 against ESCC, which warrants further investigations.

Poultry and fish intake and risk of esophageal cancer: A meta-analysis of observational studies.

PubMed

Jiang, Gengxi; Li, Bailing; Liao, Xiaohong; Zhong, Chongjun

2016-03-01

Mixed results regarding the association between white meat (including poultry and fish) intake and the risk of esophageal cancer (EC) have been reported. We performed a meta-analysis to provide a quantitative assessment of this association. Relevant studies were identified in MEDLINE until December 31, 2012. Summary relative risks (SRRs) with 95% confidence intervals (CIs) were pooled with a random-effects model. A total of 20 articles, including 3990 cases with EC, were included in this meta-analysis. Compared to individuals with the lowest level of fish intake, individuals with the highest fish intake were found to have reduced risk of EC (SRRs = 0.69; 95% CIs: 0.57-0.85), while poultry intake was not associated with EC (SRRs = 0.83; 95% CIs: 0.62-1.12). Total fish consumption is associated with reduced esophageal squamous cell carcinoma (ESCC) risk, while poultry consumption was not associated with ESCC risk. Additionally, neither poultry nor fish consumption was associated with esophageal adenocarcinoma risk. Our results suggest that fish consumption may have a potential role in EC prevention, while poultry intake has no effect. However, because the majority of data was from case-control studies, further well-designed prospective studies are warranted. © 2013 Wiley Publishing Asia Pty Ltd.

[Efficacy and side-effects of docetaxel combined with cisplatin on the treatment of local advanced esophageal cancer with concomitant radiation therapy].

PubMed

Zhang, Ting-rong; Zhao, Tao; Xu, Xin; Gu, Xiao-wei; Pan, Yu-kai

2010-10-01

To investigate the therapeutical effect and side-effect of docetaxel combined with cisplatin (DDP) on the treatment of local advanced esophageal cancer with concomitant radiation therapy. Ninety patients with LOCAL advanced esophageal squamous cell carcinoma were divided into two groups: (DDP + 5-Fu) group and (docetaxel + DDP) group. Chemotherapy was carried out every 4 weeks for a total of 4 courses. The radiation dose was 50.4 Gy/28FX. The median survival time of patients in the (DDP + 5-Fu) group was 16 months and that in (docetaxel + DDP) group was 21 months (P = 0.0278). The 3-year survival rate in the (docetaxel + DDP) group was obviously higher than that in the (DDP + 5-Fu) group (23.9% vs. 12.1%). The ORR in (docetaxel + DDP) group (84.5%) was significantly higher than that in the (DDP + 5-Fu) group (71.1%) (P = 0.025). No significant differences were observed in the incidence of side-effects in the two groups. The conventional dose chemotherapy of docetaxel + DDP with concomitant radiation therapy showed a better partial remission rate and long-term survival rate for the treatment of local advanced esophageal cancer than the traditional chemotherapy (DDP + 5-Fu) with concomitant radiation therapy and the side-effects are not increased.

Retrospective Analysis of Outcome Differences in Preoperative Concurrent Chemoradiation With or Without Elective Nodal Irradiation for Esophageal Squamous Cell Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hsu, Feng-Ming; Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan

2011-11-15

Purpose: To evaluate the efficacy and patterns of failure of elective nodal irradiation (ENI) in patients with esophageal squamous cell carcinoma (SCC) undergoing preoperative concurrent chemoradiation (CCRT) followed by radical surgery. Methods and Materials: We retrospectively studied 118 patients with AJCC Stage II to III esophageal SCC undergoing preoperative CCRT (median, 36 Gy), followed by radical esophagectomy. Of them, 73 patients (62%) had ENI and 45 patients (38%) had no ENI. Patients with ENI received radiotherapy to either supraclavicular (n = 54) or celiac (n = 19) lymphatics. Fifty-six patients (57%) received chemotherapy with paclitaxel plus cisplatin. The 3-year progression-freemore » survival, overall survival, and patterns of failure were analyzed. Distant nodal recurrence was classified into M1a and M1b regions. A separate analysis using matched cases was conducted. Results: The median follow-up was 38 months. There were no differences in pathological complete response rate (p = 0.12), perioperative mortality rate (p = 0.48), or delayed Grade 3 or greater cardiopulmonary toxicities (p = 0.44), between the groups. More patients in the non-ENI group had M1a failure than in the ENI group, with 3-year rates of 11% and 3%, respectively (p = 0.05). However, the 3-year isolated distant nodal (M1a + M1b) failure rates were not different (ENI, 10%; non-ENI, 14%; p = 0.29). In multivariate analysis, pathological nodal status was the only independent prognostic factor associated with overall survival (hazard ratio = 1.78, p = 0.045). The 3-year overall survival and progression-free survival were 45% and 45%, respectively, in the ENI group, and 52% and 43%, respectively, in the non-ENI group (p = 0.31 and 0.89, respectively). Matched cases analysis did not show a statistical difference in outcomes between the groups. Conclusions: ENI reduced the M1a failure rate but was not associated with improved outcomes in patients undergoing preoperative CCRT for esophageal SCC. Pathological nodal metastasis predicted poor outcome.« less

HIF-1α induces VE-cadherin expression and modulates vasculogenic mimicry in esophageal carcinoma cells

PubMed Central

Tang, Na-Na; Zhu, Hong; Zhang, Hong-Jie; Zhang, Wei-Feng; Jin, Hai-Lin; Wang, Lu; Wang, Pin; He, Gui-Jun; Hao, Bo; Shi, Rui-Hua

2014-01-01

AIM: To investigate whether hypoxia inducible factor (HIF)-1α modulates vasculogenic mimicry (VM) by upregulating VE-cadherin expression in esophageal squamous cell carcinoma (ESCC). METHODS: Esophageal squamous cancer cell lines Eca109 and TE13 were transfected with plasmids harboring small interfering RNAs targeting HIF-1α or VE-cadherin. The proliferation and invasion of esophageal carcinoma cells were detected by MTT and Transwell migration assays. The formation of tubular networks of cells was analyzed by 3D culture in vitro. BALB/c nude mice were used to observe xenograft tumor formation. The relationship between the expression of HIF-1α and VE-cadherin, ephrinA2 (EphA2) and laminin5γ2 (LN5γ2) was measured by Western blot and real-time polymerase chain reaction. RESULTS: Knockdown of HIF-1α inhibited cell proliferation (32.3% ± 6.1% for Eca109 cells and 38.6% ± 6.8% for TE13 cells, P < 0.05). Both Eca109 and TE13 cells formed typical tubular networks. The number of tubular networks markedly decreased when HIF-1α or VE-cadherin was knocked down. Expression of VE-cadherin, EphA2 and LN5γ2 was dramatically inhibited, but the expression of matrix metalloproteinase 2 had no obvious change in HIF-1α-silenced cells. Knockdown of VE-cadherin significantly decreased expression of both EphA2 and LN5γ2 (P < 0.05), while HIF-1α expression was unchanged. The time for xenograft tumor formation was 6 ± 1.2 d for Eca109 cells and Eca109 cells transfected with HIF-1α Neo control short hairpin RNA (shRNA) vector, and 8.4 ± 2.1 d for Eca109 cells transfected with an shRNA against HIF-1α. Knockdown of HIF-1α inhibited vasculogenic mimicry (VM) and tumorigenicity in vivo. CONCLUSION: HIF-1α may modulate VM in ESCC by regulating VE-cadherin expression, which affects VM formation through EphA2 and LN5γ2. PMID:25548487

Macronutrients, vitamins and minerals intake and risk of esophageal squamous cell carcinoma: a case-control study in Iran

PubMed Central

2011-01-01

Background Although Iran is a high-risk region for esophageal squamous cell carcinoma (ESCC), dietary factors that may contribute to this high incidence have not been thoroughly studied. The aim of this study was to evaluate the effect of macronutrients, vitamins and minerals on the risk of ESCC. Methods In this hospital-based case-control study, 47 cases with incident ESCC and 96 controls were interviewed and usual dietary intakes were collected using a validated food frequency questionnaire. Data were modeled through unconditional multiple logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), controlling for age, sex, gastrointestinal reflux, body mass index, smoking history (status, intensity and duration), physical activity, and education. Results ESCC cases consumed significantly more hot foods and beverages and fried and barbecued meals, compared to the controls (p < 0.05). After adjusting for potential confounders, the risk of ESCC increased significantly in the highest tertiles of saturated fat [OR:2.88,95%CI:1.15-3.08], cholesterol [OR:1.53, 95%CI: 1.41-4.13], discretionary calorie [OR:1.51, 95%CI: 1.06-3.84], sodium [OR:1.49,95%CI:1.12-2.89] and total fat intakes [OR:1.48, 95%CI:1.09-3.04]. In contrast, being in the highest tertile of carbohydrate, dietary fiber and (n-3) fatty acid intake reduced the ESCC risk by 78%, 71% and 68%, respectively. The most cancer-protective effect was observed for the combination of high folate and vitamin E intakes (OR: 0.02, 95%CI: 0.00-0.87; p < 0.001). Controls consumed 623.5 times higher selenium, 5.48 times as much β-carotene and 1.98 times as much α-tocopherol as the amount ESCC cases consumed. Conclusion This study suggests that high intake of nutrients primarily found in plant-based foods is associated with a reduced esophageal cancer risk. Some nutrients such as folate, vitamin E and selenium might play major roles in the etiology of ESCC and their status may eventually be used as an epidemiological marker for esophageal cancer in Iran, and perhaps other high-risk regions. PMID:22185224

Retrospective analysis of outcome differences in preoperative concurrent chemoradiation with or without elective nodal irradiation for esophageal squamous cell carcinoma.

PubMed

Hsu, Feng-Ming; Lee, Jang-Ming; Huang, Pei-Ming; Lin, Chia-Chi; Hsu, Chih-Hung; Tsai, Yu-Chieh; Lee, Yung-Chie; Chia-Hsien Cheng, Jason

2011-11-15

To evaluate the efficacy and patterns of failure of elective nodal irradiation (ENI) in patients with esophageal squamous cell carcinoma (SCC) undergoing preoperative concurrent chemoradiation (CCRT) followed by radical surgery. We retrospectively studied 118 patients with AJCC Stage II to III esophageal SCC undergoing preoperative CCRT (median, 36 Gy), followed by radical esophagectomy. Of them, 73 patients (62%) had ENI and 45 patients (38%) had no ENI. Patients with ENI received radiotherapy to either supraclavicular (n = 54) or celiac (n = 19) lymphatics. Fifty-six patients (57%) received chemotherapy with paclitaxel plus cisplatin. The 3-year progression-free survival, overall survival, and patterns of failure were analyzed. Distant nodal recurrence was classified into M1a and M1b regions. A separate analysis using matched cases was conducted. The median follow-up was 38 months. There were no differences in pathological complete response rate (p = 0.12), perioperative mortality rate (p = 0.48), or delayed Grade 3 or greater cardiopulmonary toxicities (p = 0.44), between the groups. More patients in the non-ENI group had M1a failure than in the ENI group, with 3-year rates of 11% and 3%, respectively (p = 0.05). However, the 3-year isolated distant nodal (M1a + M1b) failure rates were not different (ENI, 10%; non-ENI, 14%; p = 0.29). In multivariate analysis, pathological nodal status was the only independent prognostic factor associated with overall survival (hazard ratio = 1.78, p = 0.045). The 3-year overall survival and progression-free survival were 45% and 45%, respectively, in the ENI group, and 52% and 43%, respectively, in the non-ENI group (p = 0.31 and 0.89, respectively). Matched cases analysis did not show a statistical difference in outcomes between the groups. ENI reduced the M1a failure rate but was not associated with improved outcomes in patients undergoing preoperative CCRT for esophageal SCC. Pathological nodal metastasis predicted poor outcome. Copyright © 2011 Elsevier Inc. All rights reserved.

Bacterial Composition of the Human Upper Gastrointestinal Tract Microbiome Is Dynamic and Associated with Genomic Instability in a Barrett’s Esophagus Cohort

PubMed Central

Gall, Alevtina; Fero, Jutta; McCoy, Connor; Claywell, Brian C.; Sanchez, Carissa A.; Blount, Patricia L.; Li, Xiaohong; Vaughan, Thomas L.; Matsen, Frederick A.; Reid, Brian J.; Salama, Nina R.

2015-01-01

Background The incidence of esophageal adenocarcinoma (EAC) has increased nearly five-fold over the last four decades in the United States. Barrett’s esophagus, the replacement of the normal squamous epithelial lining with a mucus-secreting columnar epithelium, is the only known precursor to EAC. Like other parts of the gastrointestinal (GI) tract, the esophagus hosts a variety of bacteria and comparisons among published studies suggest bacterial communities in the stomach and esophagus differ. Chronic infection with Helicobacter pylori in the stomach has been inversely associated with development of EAC, but the mechanisms underlying this association remain unclear. Methodology The bacterial composition in the upper GI tract was characterized in a subset of participants (n=12) of the Seattle Barrett’s Esophagus Research cohort using broad-range 16S PCR and pyrosequencing of biopsy and brush samples collected from squamous esophagus, Barrett’s esophagus, stomach corpus and stomach antrum. Three of the individuals were sampled at two separate time points. Prevalence of H. pylori infection and subsequent development of aneuploidy (n=339) and EAC (n=433) was examined in a larger subset of this cohort. Results/Significance Within individuals, bacterial communities of the stomach and esophagus showed overlapping community membership. Despite closer proximity, the stomach antrum and corpus communities were less similar than the antrum and esophageal samples. Re-sampling of study participants revealed similar upper GI community membership in two of three cases. In this Barrett’s esophagus cohort, Streptococcus and Prevotella species dominate the upper GI and the ratio of these two species is associated with waist-to-hip ratio and hiatal hernia length, two known EAC risk factors in Barrett’s esophagus. H. pylori-positive individuals had a significantly decreased incidence of aneuploidy and a non-significant trend toward lower incidence of EAC. PMID:26076489

The long-term spatial-temporal trends and burden of esophageal cancer in one high-risk area: A population-registered study in Feicheng, China

PubMed Central

Sun, Xiubin; Zhao, Deli; Liu, Yi; Liu, Yunxia; Yuan, Zhongshang; Wang, Jialin; Xue, Fuzhong

2017-01-01

Background Feicheng County is a high-risk area for esophageal cancer in Shandong province, China. It is important to determine the long-term spatio-temporal trends in epidemiological characteristics and the burden of esophageal cancer, especially since the implementation of the national esophageal cancer screening program for early detection and treatment in 2005. Methods The data collected in Feicheng County from 2001 to 2012 was extracted from the whole-population cancer registry system. The incidence, mortality, disability-adjusted life years (DALY) and changing trends in esophageal cancer according to age and sex were calculated and described. Results The incidence rate of esophageal cancer in Feicheng was consistently high, and increased significantly for male, but not for female from 2001 to 2012, according to the joinpoint regression analysis. The highest and lowest yearly crude incidence rates were 160.78 and 95.97 per 100000 for males, and 81.36 and 52.17 per 100000 for females. The highest and lowest crude yearly mortality rates were 122.26 and 94.40 per 100000 for males, and 60.75 and 49.35 per 100000for females. Esophageal squamous cell carcinoma was the main pathology type and the tumor location changed significantly from 2001 to 2012. Overall, the DALY remained roughly stable and was estimated as 11.50 for males and 4.90 for females per 1000 people. The burden was mainly caused by premature death. There is an obvious spatial pattern in the distribution of incidence density and burden. Conclusion Esophageal cancer remains a public health issue in Feicheng County with a high incidence, mortality and disease burden. The incidence and burden have obvious spatial heterogeneity, and further studies should be conducted to identify geographical risk factors for precise local prevention and control measures. PMID:28267769

Laparogastroscopy and Esophageal Stenosis.

PubMed

Sabău, Alexandru-Dan; Hassan, Noor; Smarandache, Cătălin Gabriel; Miheţiu, Alin; Ţîţu, Ștefan; Sabău, Dan

2018-01-01

An original technique using laparoscopic instruments in a gastric endocavitary work chamber with potential for esophagus, stomach and D1 vizualisation. The main purpose of laparagastroscopy is to improve the quality of life of the patient disabling by the esophageal tumor. This method has several advantages: providing physiological feeding, harvesting materials for histopathological examination, solving eso-tracheal fistulas concurrently with the proposed operation and hemostatic role through compression, low energy and plastic consumption, rapid socio-economic reintegration, mental psychological care of the patient. Patients and Methods: The paper deals with 162 cases with different tumors of the esophagus, patients with different grades of esophageal stenosis, different stages of esophageal neoplasm. Both the patients with eso-tracheal fistulas and those with gastro- or jejunostoma were included. Results: From 162 cases, 33 cases (20%) with cervical esophageal neoplasm, 66 (41%) cases with thoracic esophageal neoplasm and 63 (39%) cases with abdominal esophageal neoplasm. The histopathological type is 37% adenocarcinomas and 63% squamous carcinomas. From total number of cases, 87 (54%) had no metastasis, and 75 (46%) had secondary determinations. The most frequent localization of metastasis was pulmonary, followed by liver (Fig. 1) and bone. The analysis of this intervention has shown that complications have been much lower both in terms of their numerical value and their severity, a longer survival time with a much higher satisfaction index is ensured. Esophageal endoprosthesis (EPE) through laparagastroscopic approach should be a a reserve procedure instead of a disabling gastrostomy or jejunostomy. EPE is an extremely effective procedure specially by keeping the physiology of food bowl. The approach is minimally invasive with minimal attack on the body with significant plastic and aesthetic reductions. This procedure allows the prosthesis to be viewed both during and after stenting to check its correct position. This method increases the survival time by keeping a relatively normal regimen. Celsius.

Palliative Radiotherapy in the Local Management of Stage IVB Esophageal Cancer: Factors Affecting Swallowing and Survival.

PubMed

Suzuki, Gen; Yamazaki, Hideya; Aibe, Norihiro; Masui, Koji; Tatekawa, Kotoha; Sasaki, Naomi; Kimoto, Takuya; Nishimura, Takeshi; Nakashima, Akihiro; Takenaka, Tadashi; Fujiwara, Hitoshi; Ishikawa, Takeshi; Yamada, Kei

2017-06-01

To clarify the role of external-beam radiotherapy in the local management of state IVB esophageal cancer. We reviewed records of 31 patients with histopathologically-proven squamous cell carcinoma who underwent radiotherapy for their primary lesion. The change in dysphagia score from before to after treatment was assessed. Nutritional support-free survival (NSFS) was also evaluated. The median overall survival was 6 months. The overall rate of improvement in dysphagia score was 73% (23/31). The median NSFS was 5 months. Age at presentation <67 years, tumor location in the middle thoracic esophagus, and tumor length <7 cm were associated with significant improvement in swallowing scores. Responders to radiotherapy had significantly longer NSFS than non-responders (p=0.04). Palliative radiotherapy in the local management of stage IVB esophageal cancer is an effective treatment option for dysphagia. Factors highly associated with improvement of swallowing are age, tumor location, and tumor length. Response to radiotherapy is the most important factor in improving NSFS. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

A short-term increase of the postoperative naturally circulating dendritic cells subsets in flurbiprofen-treated patients with esophageal carcinoma undergoing thoracic surgery

PubMed Central

Chai, Xiao-qing; Shu, Shu-hua; Zhang, Xiao-lin; Xie, Yan-hu; Wei, Xin; Wu, Yu-jing; Wei, Wei

2016-01-01

The present study evaluated whether flurbiprofen increased the naturally circulating dendritic cells (DCs) subsets in patients with esophageal squamous cell carcinoma (ESCC) undergoing esophageal resection. Compared to healthy donors (n=20), the significantly depressed percentages of plasmacytoid DCs (pDCs), CD1c+ myeloid DCs (mDCs), and CD141+ mDCs among ESCC patients (n=60) were confirmed. Flurbiprofen was administered before skin incision and at the end of operation in group F (n=30), as well as placebo in group C (n=30). The postoperative suppressed percentages of pDCs, CD1c+ mDCs, and CD141+ mDCs increased significantly following the perioperative treatment with flurbiprofen. Flurbiprofen also significantly stimulated the postoperative IFN-f and IL-17 production, but inhibited the immunosuppressive IL-10 and TGF-β levels. Furthermore, flurbiprofen exerted a similar analgesic effect and brought a significantly less sufentanil consumption compared to group C. Taken together, flurbiprofen provided a short-term increase of postoperative naturally circulating DCs in ESCC patients. PMID:26959879

A short-term increase of the postoperative naturally circulating dendritic cells subsets in flurbiprofen-treated patients with esophageal carcinoma undergoing thoracic surgery.

PubMed

Wang, Di; Yang, Xin-lu; Chai, Xiao-qing; Shu, Shu-hua; Zhang, Xiao-lin; Xie, Yan-hu; Wei, Xin; Wu, Yu-jing; Wei, Wei

2016-04-05

The present study evaluated whether flurbiprofen increased the naturally circulating dendritic cells (DCs) subsets in patients with esophageal squamous cell carcinoma (ESCC) undergoing esophageal resection. Compared to healthy donors (n=20), the significantly depressed percentages of plasmacytoid DCs (pDCs), CD1c+ myeloid DCs (mDCs), and CD141+ mDCs among ESCC patients (n=60) were confirmed. Flurbiprofen was administered before skin incision and at the end of operation in group F (n=30), as well as placebo in group C (n=30). The postoperative suppressed percentages of pDCs, CD1c+ mDCs, and CD141+ mDCs increased significantly following the perioperative treatment with flurbiprofen. Flurbiprofen also significantly stimulated the postoperative IFN-f and IL-17 production, but inhibited the immunosuppressive IL-10 and TGF-β levels. Furthermore, flurbiprofen exerted a similar analgesic effect and brought a significantly less sufentanil consumption compared to group C. Taken together, flurbiprofen provided a short-term increase of postoperative naturally circulating DCs in ESCC patients.

Esophageal stenosis: a differential diagnosis between esophageal cancer and metastasis from other neoplasia.

PubMed

Paris, Ida; Prelaj, Arsela; Onesti, Concetta Elisa; Baldoni, Alessandra; Giovagnoli, Maria Rosaria; Bassanelli, Maria; Lauro, Salvatore; Marchetti, Paolo

2014-01-01

The occurrence of radiological mediastinal lymphadenopathy as the only evidence of tumor recurrence of cervical carcinoma is very rare. We report on such a case with stenosis of the esophagus. A 36-year-old Caucasian woman, without any relevant history of gynecological cancer, underwent a trans-vaginal ultrasound with evidence of any cervical lesion locally extended. After histologically-proven diagnosis of squamous cell carcinoma of the cervix uterine, the patient was treated by neoadjuvant chemoradiation, followed by total abdominal hysterectomy with bilateral salpingoophorectomy. A subsequent close follow-up was negative for recurrence of disease until December 2008, two years after diagnosis. At that period, the patient experienced cough and severe dysphagia and for this reason she underwent several examinations including esophagogastroduodenoscopy, whole-body computed tomographic scan and bronchoscopy with transbronchial needle aspiration. Histology led to diagnosis of recurrence of cervical cancer, HPV31-positive, in multiple mediastinal lymphnodes, with infiltration of the esophageal mucosa. Mediastinal lymphade-nopathy in patients with a history of cervical carcinoma should be suspicious of metastatic disease, even if there is no radiological evidence of distant metastases.

[Clinical value of para-recurrent laryngeal nerve lymphadenectomy for middle thoracic esophageal squamous cell carcinoma].

PubMed

Wang, Zhen; Liu, Shuoyan

2015-09-01

To analyze the pattern of lymphatic metastasis in middle thoracic esophageal squamous cell carcinoma (ESCC) with different T staging and to investigate the clinical value of para-recurrent laryngeal nerve lymphadenectomy. Clinicopathological data of 717 patients with middle thoracic ESCC undergoing Mckeown esophagectomy plus three-field lymph node dissection in Fujian Provincial Hospital from January 1999 to December 2007 were analyzed retrospectively. Lymph node metastatic rates of different T stages were calculated. Clinical value of each station lymphadenectomy, especially the para-recurrent laryngeal nerve lymphadenectomy, was evaluated by the efficacy index (EI, cross product of one station metastatic rate and 5-year survival of patient with positive lymph nodes of above station). Rates of lymph node metastasis were 29.0% (18/62), 61.1% (91/149) and 64.8% (328/506) in stage T1, T2 and T3 patients respectively. Despite T staging, metastatic rates of right para-recurrent laryngeal nerve lymph node (rRLN LN) were 21.0% (13/62), 28.9% (43/149) and 29.4% (149/506) in stage T1, T2 and T3 patients respectively, which was the most common among all lymph node stations. Metastatic rates of left para-recurrent laryngeal nerve lymph node (lRLN LN) were the second, with 8.1% (5/62), 17.4% (26/149) and 24.7% (125/506) in stage T1, T2, T3 patients respectively. Follow-up period lasted more than 5 years. The 5-year survival rates of positive rRLN LN were 53.8%, 39.5% and 32.2% in stage T1, T2 and T3 patients respectively, whose EI values were 11.3, 11.4 and 9.5 respectively. The 5-year survival rates of positive lRLN LN were 40.0%, 34.6% and 40.0% in stage T1, T2 and T3 patients respectively, whose EI values were 3.2, 6.0 and 9.9 respectively. Bilateral para-recurrent laryngeal nerve lymph nodes are the common sites of metastasis in middle thoracic esophageal squamous cell carcinoma. Right para-recurrent laryngeal nerve lymphadenectomy is of high clinical value despite the T staging. Left para-recurrent laryngeal nerve lymphadenectomy has better efficacy in stage T2 and T3 patients, but is limited in stage T1 patients.

Measurement of glutathione S-transferase and its class-pi in plasma and tissue biopsies obtained after laparoscopy and endoscopy from subjects with esophagus and gastric cancer.

PubMed

Mohammadzadeh, G S; Nasseri Moghadam, S; Rasaee, M J; Zaree, A B; Mahmoodzadeh, H; Allameh, A

2003-06-01

To develop an indirect enzyme-linked immunosorbent assay (ELISA) for measuring class-pi glutathione S-transferase (GST) in plasma, and tissue biopsies obtained from upper gastrointestinal cancer (UGI Ca) patients. GST activity and GST-pi concentration were detected in normal human squamous esophageal epithelium, normal gastric cardia and their corresponding malignant tumor biopsies. Plasma GST was significantly higher (p < 0.05) in UGI Ca patients as compared to those obtained from normal individuals. Plasma GST-pi concentration in normal subjects was 6.6 +/- 1.9 ng/mg protein, whereas it was higher in UGI Ca patients (esophageal, 10.0 +/- 1.8; gastric, 10.7 +/- 1.7 ng/mL, p

Prognostic value of MLH1 promoter methylation in male patients with esophageal squamous cell carcinoma.

PubMed

Wu, Dongping; Chen, Xiaoying; Xu, Yan; Wang, Haiyong; Yu, Guangmao; Jiang, Luping; Hong, Qingxiao; Duan, Shiwei

2017-04-01

The DNA mismatch repair (MMR) gene MutL homolog 1 ( MLH1 ) is critical for the maintenance of genomic integrity. Methylation of the MLH1 gene promoter was identified as a prognostic marker for numerous types of cancer including glioblastoma, colorectal, ovarian and gastric cancer. The present study aimed to determine whether MLH1 promoter methylation was associated with survival in male patients with esophageal squamous cell carcinoma (ESCC). Formalin-fixed, paraffin-embedded ESCC tissues were collected from 87 male patients. MLH1 promoter methylation was assessed using the methylation-specific polymerase chain reaction approach. Kaplan-Meier survival curves and log-rank tests were used to evaluate the association between MLH1 promoter methylation and overall survival (OS) in patients with ESCC. Cox regression analysis was used to obtain crude and multivariate hazard ratios (HR), and 95% confidence intervals (CI). The present study revealed that MLH1 promoter methylation was observed in 53/87 (60.9%) of male patients with ESCC. Kaplan-Meier survival analysis demonstrated that MLH1 promoter hypermethylation was significantly associated with poorer prognosis in patients with ESCC (P=0.048). Multivariate survival analysis revealed that MLH1 promoter hypermethylation was an independent predictor of poor OS in male patients with ESCC (HR=1.716; 95% CI=1.008-2.921). Therefore, MLH1 promoter hypermethylation may be a predictor of prognosis in male patients with ESCC.

Expression of SLP-2 was associated with invasion of esophageal squamous cell carcinoma.

PubMed

Cao, Wenfeng; Zhang, Bin; Ding, Fang; Zhang, Weiran; Sun, Baocun; Liu, Zhihua

2013-01-01

Stomatin-like protein 2 (SLP-2), a member of the Stomatin superfamily, has been identified as an oncogenic-related protein and found to be up-regulated in multi-cancers. Nonetheless, the expression pattern and regulation of SLP-2 in human esophageal squamous cell carcinoma (ESCC) remain unexplored. Immunohistochemistry and immunofluorescence staining analysis were performed to show SLP-2 expression and location. RNAi method was used to inhibit specific protein expression. Transwell assay was done to investigate cells invasive capability. RT-PCR and Western blot analysis were used to detect mRNA and protein expression levels. Immunohistochemical analysis showed that up-regulation of SLP-2 was found in invasive front compared with cancer central tissue in ESCC. Inhibition of SLP-2 by SLP-2 siRNA can decrease ESCC cells invasive capability through MMP-2 dependent manner. Up-regulation of SLP-2 was effectively abrogated by the ERK1/2 inhibitors either PD98059 or U0126, but no effect was showed by the treatment of AKT inhibitors either LY294002 or MK-2206. So the regulation of SLP-2 was involved in activation of the MAPK/ERK pathway. We found that PMA/EGF could induce the up-regulated expression of SLP-2 probably through activating ERK signalling. The current study suggests that SLP-2 may represent an important molecular hallmark that is clinically relevant to the invasion of ESCC.

Socioeconomic status and esophageal squamous cell carcinoma risk in Kashmir, India.

PubMed

Dar, Nazir A; Shah, Idrees A; Bhat, Gulzar A; Makhdoomi, Muzamil A; Iqbal, Beenish; Rafiq, Rumaisa; Nisar, Iqra; Bhat, Arshid B; Nabi, Sumaiya; Masood, Akbar; Shah, Sajad A; Lone, Mohd M; Zargar, Showkat A; Islami, Farhad; Boffetta, Paolo

2013-09-01

Studies have persistently associated esophageal squamous cell carcinoma (ESCC) risk with low socioeconomic status (SES), but this association is unexplored in Kashmir, an area with a high incidence of ESCC in the northernmost part of India. We carried out a case-control study to assess the association of multiple indicators of SES and ESCC risk in the Kashmir valley. A total number of 703 histologically confirmed ESCC cases and 1664 controls matched to the cases for age, sex, and district of residence were recruited from October 2008 to January 2012. Conditional logistic regression models were used to calculate unadjusted and adjusted odds ratios and 95% confidence intervals. Composite wealth scores were constructed based on the ownership of several appliances using multiple correspondence analyses. Higher education, living in a kiln brick or concrete house, use of liquefied petroleum gas and electricity for cooking, and higher wealth scores all showed an inverse association with ESCC risk. Compared to farmers, individuals who had government jobs or worked in the business sector were at lower risk of ESCC, but this association disappeared in fully adjusted models. Occupational strenuous physical activity was strongly associated with ESCC risk. In summary, we found a strong relationship of low SES and ESCC in Kashmir. The findings need to be studied further to understand the mechanisms through which such SES parameters increase ESCC risk. © 2013 Japanese Cancer Association.

Downregulation of microRNA-370 in esophageal squamous-cell carcinoma is associated with cancer progression and promotes cancer cell proliferation via upregulating PIN1.

PubMed

Chen, Mingzhi; Xia, Yang; Tan, Yongfei; Jiang, Guojun; Jin, Hai; Chen, Yijiang

2018-06-30

PIN1 is a peptidyl-prolyl cis/trans isomerase (PPIase) that controls cell fate by regulating multiple signal transduction pathways and is found to be overexpressed in a variety of malignant tumors. Herein, we found the expression of PIN1 is up-regulated while miRNA-370 (miR-370) down-regulated in both esophageal squamous-cell carcinoma (ESCC) tissues and cells. Transfection of miR-370 can significantly decrease PIN1 expression in targeting ESCC cells. Overexpression of miR-370 can induce decreased cell proliferation and cell cycle arrest, as well as increased apoptosis in ESCC cells, while this function can be significantly prevented by co-transfection of PIN1. Further experimental results demonstrated that β-catenin, cyclin D1, and caspase activation might be involved in miR-370/PIN1 induced growth inhibition and apoptosis. Besides, low miR-370 and high PIN1 expression significantly correlated with tumor diameter, poor differentiation, tumor invasion and lymph node metastasis in patients diagnosed with ESCC. In conclusion, downregulation of miR-370 in ESCC is associated with cancer progression and promotes cancer cell proliferation via upregulating PIN1, which might be a potential therapeutic target and adverse prognostic factor in the clinic. Copyright © 2018 Elsevier B.V. All rights reserved.

Large body size and sedentary lifestyle during childhood and early adulthood and esophageal squamous cell carcinoma in a high-risk population.

PubMed

Etemadi, A; Golozar, A; Kamangar, F; Freedman, N D; Shakeri, R; Matthews, C; Islami, F; Boffetta, P; Brennan, P; Abnet, C C; Malekzadeh, R; Dawsey, S M

2012-06-01

Little is known about the association of obesity and physical activity at young ages with subsequent risk of esophageal squamous cell carcinoma (ESCC). Between 2003 and 2007, we conducted a case-control study in a high-risk population in northeastern Iran. Three hundred ESCC cases and 571 matched controls were recruited. Each individual was shown a standard pictogram, to report body size at ages 15 and 30. Demographic and health-related information, including physical activity at these ages was also collected. In the fully adjusted models, very obese body size (last two pictograms) at age 15 [odds ratio (OR) 3.2, 95% confidence interval (CI) 1.3-7.7] and age 30 (OR 3.1; 95% CI 1.1-8.5) were associated with ESCC in women, but not in men. Sedentary work at age 15 (OR 3.3, 95% CI 1.3-8.3) and 30 (OR 18.2, 95% CI 3.9-86.2) were also associated with ESCC risk in women only. The increased risk in women at age 15 remained high after later reduction in body size, while women who became very obese only at age 30 did not show a significantly increased risk. These results highlight the importance of early lifestyle modifications in the context of cancer prevention, particularly in women.

Comprehensive immunohistochemical analysis of tumor microenvironment immune status in esophageal squamous cell carcinoma

PubMed Central

Hatogai, Ken; Kitano, Shigehisa; Fujii, Satoshi; Kojima, Takashi; Daiko, Hiroyuki; Nomura, Shogo; Yoshino, Takayuki; Ohtsu, Atsushi; Takiguchi, Yuichi; Doi, Toshihiko; Ochiai, Atsushi

2016-01-01

Immunotherapy with anti-PD-1 antibody preliminarily showed promising efficacy for treating esophageal squamous cell carcinoma (ESCC). Herein, we used tissue microarrays and immunohistochemically analyzed PD-L1 and various tumor infiltrating immune cells (TIICs) in specimens from 196 ESCC patients who had undergone curative resection without preoperative therapy. PD-L1 expressions in tumor cells (TCs) and TIICs, as well as infiltration of lymphocytes (CD4+, CD8+, FOXP3+, and PD- 1+) and macrophages (CD68+ and CD204+), were evaluated. PD-L1 was expressed in TCs of 18.4% and in TIICs of 83.3% of these patients. PD-L1 expressions in TCs and TIICs were associated with significant infiltration of various TIIC types, especially CD8+ cells. PD-L1 expressions in both TCs and TIICs were significantly associated with favorable overall survival, and combining their levels enhanced prognostic accuracy. Prognostic impacts of PD-L1 expressions in TCs and TIICs, abundant PD-1+ cell infiltration, a high CD8+/FOXP3+ ratio, and the CD8+/CD204+ ratio remained significant after adjusting for clinicopathological factors. In conclusion, PD-L1 expression reflects anti-tumor immunity, and PD-1/PD-L1 expression and the ratio of infiltrating effector to immune suppressor cells have prognostic value. Therapeutic strategies inhibiting the PD-1/PD-L1 signal and immune suppressor cells are anticipated in ESCC patients. PMID:27322149

Cumulated Activity Comparison of 64Cu-/177Lu-Labeled Anti-Epidermal Growth Factor Receptor Antibody in Esophageal Squamous Cell Carcinoma Model.

PubMed

Laffon, Eric; Thumerel, Matthieu; Jougon, Jacques; Marthan, Roger

2017-06-01

This work aimed at estimating the kinetic parameters, and hence cumulated activity (A C ), of a diagnostic/therapeutic convergence radiopharmaceutical, namely 64 Cu-/ 177 Lu-labeled antibody ( 64 Cu-/ 177 Lu-cetuximab), that acts as anti-epidermal growth factor receptor. Methods: In mice bearing esophageal squamous cell carcinoma tumors, to estimate uptake (K), release rate constant (k R ), and hence A C , a kinetic model analysis was applied to recently published biodistribution data of immuno-PET imaging with 64 Cu-cetuximab and of small-animal SPECT/CT imaging with 177 Lu-cetuximab, including blood and TE-8 tumor. Results: K, k R , and A C were estimated to be 0.0566/0.0593 g⋅h -1 ⋅g -1 , 0.0150/0.0030 h -1 , and 2.3 × 10 10 /4.1 × 10 12 disintegrations (per gram of TE-8 tumor), with an injected activity of 3.70/12.95 MBq, for 64 Cu-/ 177 Lu-cetuximab, respectively. Conclusion: A model is available for comparing kinetic parameters and A C of the companion diagnostic/therapeutic 64 Cu-/ 177 Lu-cetuximab that may be considered as a step for determining whether one can really use the former to predict dosimetry of the latter. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Objective evaluation of visibility in virtual chromoendoscopy for esophageal squamous carcinoma using a color difference formula

NASA Astrophysics Data System (ADS)

Inoue, Masahito; Miyake, Yoichi; Odaka, Takeo; Sato, Toru; Watanabe, Yoshiyuki; Sakama, Atsunori; Zenbutsu, Satoki; Yokosuka, Osamu

2010-09-01

Computed virtual chromoendoscopy with flexible spectral imaging color enhancement (FICE) is a new dyeless imaging technique that enhances mucosal and vascular patterns. However, a method for selecting a suitable wavelength for a particular condition has not been established. The aim of this study is to evaluate the color difference method for quality assessment of FICE images of the intrapapillary capillary loop in magnifying endoscopy for esophageal squamous cell carcinoma. The color difference between 60 microvessels and background mucosa observed using the magnifying endoscope was 8.31+/-2.84 SD under white light and 12.26+/-3.14 (p=0.0031), 11.70+/-4.49 (p=0.0106), and 17.49+/-5.40 (p<0.0001) in FICE modes A, B, and C, respectively. The visibility scores for microvessels observed by medical students were 6.00+/-1.12 points under white light and 11.1+/-2.25 (p<0.0001), 8.65+/-2.06 (p=0.0001), and 12.55+/-2.56 (p<0.0001) in FICE modes A, B, and C, respectively. Furthermore, the measurement of color difference was correlated with the visibility score assigned by medical students (Pearson's correlation coefficient=0.583, p<0.0001) In conclusion, the color difference method corresponds to human vision and is an appropriate method for evaluation of endoscopic images.

Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations.

PubMed

Wu, Chen; Wang, Zhaoming; Song, Xin; Feng, Xiao-Shan; Abnet, Christian C; He, Jie; Hu, Nan; Zuo, Xian-Bo; Tan, Wen; Zhan, Qimin; Hu, Zhibin; He, Zhonghu; Jia, Weihua; Zhou, Yifeng; Yu, Kai; Shu, Xiao-Ou; Yuan, Jian-Min; Zheng, Wei; Zhao, Xue-Ke; Gao, She-Gan; Yuan, Zhi-Qing; Zhou, Fu-You; Fan, Zong-Min; Cui, Ji-Li; Lin, Hong-Li; Han, Xue-Na; Li, Bei; Chen, Xi; Dawsey, Sanford M; Liao, Linda; Lee, Maxwell P; Ding, Ti; Qiao, You-Lin; Liu, Zhihua; Liu, Yu; Yu, Dianke; Chang, Jiang; Wei, Lixuan; Gao, Yu-Tang; Koh, Woon-Puay; Xiang, Yong-Bing; Tang, Ze-Zhong; Fan, Jin-Hu; Han, Jing-Jing; Zhou, Sheng-Li; Zhang, Peng; Zhang, Dong-Yun; Yuan, Yuan; Huang, Ying; Liu, Chunling; Zhai, Kan; Qiao, Yan; Jin, Guangfu; Guo, Chuanhai; Fu, Jianhua; Miao, Xiaoping; Lu, Changdong; Yang, Haijun; Wang, Chaoyu; Wheeler, William A; Gail, Mitchell; Yeager, Meredith; Yuenger, Jeff; Guo, Er-Tao; Li, Ai-Li; Zhang, Wei; Li, Xue-Min; Sun, Liang-Dan; Ma, Bao-Gen; Li, Yan; Tang, Sa; Peng, Xiu-Qing; Liu, Jing; Hutchinson, Amy; Jacobs, Kevin; Giffen, Carol; Burdette, Laurie; Fraumeni, Joseph F; Shen, Hongbing; Ke, Yang; Zeng, Yixin; Wu, Tangchun; Kraft, Peter; Chung, Charles C; Tucker, Margaret A; Hou, Zhi-Chao; Liu, Ya-Li; Hu, Yan-Long; Liu, Yu; Wang, Li; Yuan, Guo; Chen, Li-Sha; Liu, Xiao; Ma, Teng; Meng, Hui; Sun, Li; Li, Xin-Min; Li, Xiu-Min; Ku, Jian-Wei; Zhou, Ying-Fa; Yang, Liu-Qin; Wang, Zhou; Li, Yin; Qige, Qirenwang; Yang, Wen-Jun; Lei, Guang-Yan; Chen, Long-Qi; Li, En-Min; Yuan, Ling; Yue, Wen-Bin; Wang, Ran; Wang, Lu-Wen; Fan, Xue-Ping; Zhu, Fang-Heng; Zhao, Wei-Xing; Mao, Yi-Min; Zhang, Mei; Xing, Guo-Lan; Li, Ji-Lin; Han, Min; Ren, Jing-Li; Liu, Bin; Ren, Shu-Wei; Kong, Qing-Peng; Li, Feng; Sheyhidin, Ilyar; Wei, Wu; Zhang, Yan-Rui; Feng, Chang-Wei; Wang, Jin; Yang, Yu-Hua; Hao, Hong-Zhang; Bao, Qi-De; Liu, Bao-Chi; Wu, Ai-Qun; Xie, Dong; Yang, Wan-Cai; Wang, Liang; Zhao, Xiao-Hang; Chen, Shu-Qing; Hong, Jun-Yan; Zhang, Xue-Jun; Freedman, Neal D; Goldstein, Alisa M; Lin, Dongxin; Taylor, Philip R; Wang, Li-Dong; Chanock, Stephen J

2014-09-01

We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) in individuals of Chinese ancestry (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.82-0.88; P = 7.72 × 10(-20)) and rs1642764 at 17p13.1 (per-allele OR = 0.88, 95% CI = 0.85-0.91; P = 3.10 × 10(-13)). rs7447927 is a synonymous SNP in TMEM173, and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR = 1.33, 95% CI = 1.22-1.46; P = 1.99 × 10(-10)). Our joint analysis identifies new ESCC susceptibility loci overall as well as a new locus unique to the population in the Taihang Mountain region at high risk of ESCC.

Activation of choline kinase drives aberrant choline metabolism in esophageal squamous cell carcinomas.

PubMed

Ma, Wang; Wang, Shuangyuan; Zhang, Tengfei; Zhang, Erik Y; Zhou, Lina; Hu, Chunxiu; Yu, Jane J; Xu, Guowang

2018-06-05

Esophageal squamous cell carcinoma (ESCC) is a major health threat worldwide. Research focused on molecular events associated with ESCC carcinogenesis for diagnosis, treatment and prevention is needed. Our goal is to discover novel biomarkers and investigate the underlying molecular mechanisms of ESCC progression by employing a global metabolomic approach. Sera from 34 ESCC patients and 32 age and sex matched healthy controls were profiled using two-dimensional liquid chromatography-mass spectrometry (2D LC-MS). We identified 120 differential metabolites in ESCC patient serums compared to healthy controls. Several amino acids, serine, arginine, lysine and histidine were significantly changed in ESCC patients. Most importantly, we found dysregulated lipid metabolism as an important characteristic in ESCC patients. Several free fat acids (FFA) and carnitines were found down-regulated in ESCC patients. Choline was significantly increased and phosphatidylcholines (PC) were significantly decreased in ESCC serum. The high expression of choline and low expression of total PC in patient serum were associated with the high expression of choline kinase (Chok) and activated Kennedy pathway in ESCC cells. Chok expression can serve as a significant biomarker for ESCC prognosis. In conclusion, metabolite profiles in the ESCC patient serum were significantly different from those in the healthy controls. Phosphatidylcholines and Chok, the key enzyme in the PC metabolism pathway, may serve as novel biomarkers for ESCC. Copyright © 2018 Elsevier B.V. All rights reserved.

Predictive factors for the sensitivity of radiotherapy and prognosis of esophageal squamous cell carcinoma.

PubMed

Wu, Shaobin; Wang, Xianwei; Chen, Jin-Xiang; Chen, Yuxiang

2014-05-01

To identify predictive biomarkers for radiosensitization and prognosis of esophageal squamous cell carcinoma (ESCC). A total of 150 advanced stage ESCC patients were treated with preoperative radiotherapy. The protein levels of Dicer 1, DNA methyltransferase 1 (Dnmt1), and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and the mRNA levels of Dicer 1, Dnmt1, and let-7b microRNA (miRNA) were measured in ESCC tumor tissues before and after radiotherapy. Global DNA methylation was measured and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was performed. Negative Dicer 1, Dnmt1, and DNA-PKcs protein expression were observed in 72%, 67.3%, and 50.7% of ESCC patients, respectively. Primary Dicer 1 and Dnmt1 expression positively correlated with radiation sensitization and longer survival of ESCC patients, while increased Dicer 1 and Dnmt1 expression after radiation correlated with increased apoptosis in residual tumor tissues. Dicer 1 and Dnmt1 expression correlated with let-7b miRNA expression and global DNA methylation levels, respectively. In contrast, positive DNA-PKcs expression negatively correlated with radiation-induced pathological reactions, and increased DNA-PKcs expression correlated with increased apoptosis after radiation. Global DNA hypomethylation and low miRNA expression are involved in the sensitization of ESCC to radiotherapy and prognosis of patients with ESCC.

Elevated levels of serum nidogen-2 in esophageal squamous cell carcinoma.

PubMed

Chai, Annie Wai Yeeng; Cheung, Arthur Kwok Leung; Dai, Wei; Ko, Josephine Mun Yee; Lee, Nikki Pui Yue; Chan, Kin Tak; Law, Simon Ying-Kit; Lung, Maria Li

2018-02-14

Nidogen-2 (NID2), a secretory basement membrane protein, has been implicated as a potential biomarker in ovarian cancer and hepatocellular carcinoma. In this study, we aimed to investigate the utility of detecting serum NID2 levels for identification of esophageal squamous cell carcinoma (ESCC) patients and prediction of poor survival outcome. Using an in-house NID2 enzyme-linked immunosorbent assay (ELISA), serum samples from 101 ESCC patients and 50 healthy controls were screened for their NID2 levels. The serum NID2 levels in ESCC patients (median 24.4 μg/L) are significantly higher (p= 4.3e-09) than that of the healthy controls (median 15.85 μg/L). The receiver operating characteristic (ROC) curve demonstrated an area under the curve of 0.756. At the threshold of 17.95 μg/L, the sensitivity and specificity achieved are 0.76 and 0.63, respectively. Kaplan-Meier survival analysis revealed that patients with high serum NID2 levels (⩾ 32.6 μg/L) have significantly higher risk of death (HR = 1.984, 95% CI: 1.175-3.349; log-rank p-value = 0.012) compared to those with low serum NID2 levels (< 20.0 μg/L). In conclusion, we show that detecting the elevation of serum NID2 levels has potential diagnostic and prognostic value for ESCC patients.

Human papillomavirus burden in different cancers in Iran: a systematic assessment.

PubMed

Jalilvand, Somayeh; Shoja, Zabihollah; Hamkar, Rasool

2014-01-01

Certain types of human papillomaviruses (HPVs) are undoubtedly involved in genesis of human malignancies. HPV plays an etiological role in cervical cancer, but also in many vaginal, vulvar, anal and penile cancers, as well as head and neck cancers. In addition, a number of non-malignant diseases such as genital warts and recurrent respiratory papillomatosis are attributable to HPV. Moreover, HPV forms have detected in several other cancers including esophageal squamous cell carcinoma, lung, prostate, ovarian, breast, skin, colorectal and urinary tract cancers, but associations with etiology in these cases is controversial. The aim of this systematic assessment was to estimate the prevalence of HPV infection and HPV types in HPV-associated cancers, HPV-related non-malignant diseases and in cancers that may be associated with HPV in Iran. The present investigation covered 61 studies on a variety of cancers in Iranian populations. HPV prevalence was 77.5 % and 32.4% in cervical cancer and head and neck cancers, respectively. HPV was detected in 23.1%, 22.2%, 10.4%, 30.9%, 14% and 25.2% of esophageal squamous cell, lung, prostate, urinary tract cancers, breast and skin cancers, respectively. HPV16 and 18 were the most frequent HPV types in all cancers. The findings of present study imply that current HPV vaccines for cervical cancer may decrease the burden of other cancers if they are really related to HPV.

Cigarette Smoking and Risk of Lung Metastasis from Esophageal Cancer

PubMed Central

Abrams, Julian A.; Lee, Paul C.; Port, Jeffrey L.; Altorki, Nasser K.; Neugut, Alfred I.

2008-01-01

Background While extensive research has explored the impact of environmental factors on the etiology of specific cancers, the influence of exposures such as smoking on risk of site-specific metastasis is unknown. We investigated the association of cigarette smoking with lung metastasis in esophageal cancer. Methods We performed a case-control study of esophageal cancer patients from two centers, comparing cases with lung metastases to controls without lung metastases. Information was gathered from medical records on smoking history, imaging results, site(s) of metastasis, and other patient and tumor characteristics. We used logistic regression to assess association. Results We identified 354 esophageal cancer cases; smoking status was known in 289 (82%). Among patients with lung metastases, 73.6% (39/53) were ever smokers, versus 47.8% (144/301) of patients without lung metastases (p=0.001) (summary OR 2.52, 95%CI 1.17-5.45; stratified by histology). Smoking was associated with a nonsignificant increased adjusted odds of lung metastasis (OR 1.89, 95%CI 0.80-4.46). Upper esophageal subsite (OR 4.71, 95%CI 1.20-18.5) but not histology (squamous OR 0.65,95%CI 0.27-1.60) was associated with lung metastasis. Compared to the combined never/unknown smoking status group, smoking was associated with a significantly increased odds of lung metastasis (OR 2.35, 95%CI 1.11-4.97). There was no association between liver metastasis and smoking (OR 0.88, 95%CI 0.42-1.83) Conclusions Smoking is associated with increased odds of lung metastasis from esophageal cancer, and this relationship appears to be site-specific. Future studies are needed to determine whether smoking affects the tumor cell or the site of metastasis, and whether this changes the survival outcome. PMID:18843013

Cigarette smoking and risk of lung metastasis from esophageal cancer.

PubMed

Abrams, Julian A; Lee, Paul C; Port, Jeffrey L; Altorki, Nasser K; Neugut, Alfred I

2008-10-01

Whereas extensive research has explored the effect of environmental factors on the etiology of specific cancers, the influence of exposures such as smoking on risk of site-specific metastasis is unknown. We investigated the association of cigarette smoking with lung metastasis in esophageal cancer. We conducted a case-control study of esophageal cancer patients from two centers, comparing cases with lung metastases to controls without lung metastases. Information was gathered from medical records on smoking history, imaging results, site(s) of metastasis, and other patient and tumor characteristics. We used logistic regression to assess association. We identified 354 esophageal cancer cases; smoking status was known in 289 (82%). Among patients with lung metastases, 73.6% (39 of 53) were ever smokers, versus 47.8% (144 of 301) of patients without lung metastases [P=0.001; summary odds ratio (OR), 2.52; 95% confidence interval (95% CI), 1.17-5.45; stratified by histology]. Smoking was associated with a nonsignificant increased adjusted odds of lung metastasis (OR, 1.89; 95% CI, 0.80-4.46). Upper esophageal subsite (OR, 4.71; 95% CI, 1.20-18.5), but not histology (squamous OR 0.65,95% CI 0.27-1.60), was associated with lung metastasis. Compared with the combined never/unknown smoking status group, smoking was associated with a significantly increased odds of lung metastasis (OR, 2.35; 95% CI, 1.11-4.97). There was no association between liver metastasis and smoking (OR, 0.88; 95% CI, 0.42-1.83). Smoking is associated with increased odds of lung metastasis from esophageal cancer, and this relationship seems to be site specific. Future studies are needed to determine whether smoking affects the tumor cell or the site of metastasis, and whether this changes the survival outcome.

Dietary N-nitroso compounds, endogenous nitrosation, and the risk of esophageal and gastric cancer subtypes in the Netherlands Cohort Study.

PubMed

Keszei, András P; Goldbohm, R Alexandra; Schouten, Leo J; Jakszyn, Paula; van den Brandt, Piet A

2013-01-01

Dietary N-nitroso compounds and endogenous nitrosation are important carcinogenic factors, but human evidence of their role is scarce for esophageal cancer and inconsistent for gastric cancer. We studied the relation between risks of esophageal and gastric cancer subtypes and dietary intake of N-nitrosodimethylamine, heme iron, nitrite, and nitrate in the Netherlands Cohort Study. A total of 120,852 men and women aged 55-69 y were recruited in 1986, and diet, based on a 150-item food-frequency questionnaire, and other risk factors were assessed. The cohort was followed for 16.3 y, and 110 esophageal squamous cell carcinoma (ESCC), 151 esophageal adenocarcinoma, 166 gastric cardia adenocarcinoma, and 497 gastric noncardia adenocarcinoma (GNCA) cases were analyzed along with 4032 subcohort members in a case-cohort analysis. Positive associations were observed between N-nitrosodimethylamine intake and ESCC risk (HR for 0.1-μg/d increase in intake: 1.15; 95% CI: 1.05, 1.25; P-trend = 0.01 based on tertiles of intake) and GNCA risk (1.06; 95% CI: 1.01, 1.10; P-trend = 0.09) in men. ESCC risk was associated with nitrite intake (HR for 0.1-mg/d increase: 1.19; 95% CI: 1.05, 1.36; P-trend = 0.06) and heme-iron intake (HR for 1-mg/d increase: 1.83; 95% CI: 0.98, 3.39; P-trend = 0.03). Among women, exposure levels were lower, and we found no convincing positive associations. These results suggest that N-nitroso compounds may influence the risk of ESCC in men, but there are no clear associations for other esophageal and gastric subtypes.