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Cancer of the Esophagus

The esophagus (UK spelling: oesophagus) is a long hollow muscular tube which connects the throat to the stomach. Esophageal cancer is a disease where malignant (cancerous) cells arise in the tissues of the esophagus. The most common symptom is difficulty in swallowing. It can also be associated with weight loss and sometimes pain or discomfort behind the breast bone or in the back - these symptoms should be checked by a doctor but not are sure signs of cancer. There are two main types of esophageal cancer (depending on how the cells appear under the microscope); approximately half are classed as "squamous cell carcinomas" and half as "adenocarcinomas". People with frequent gastric reflux leading to Barrett's Esophagus have an increased risk of developing esophageal cancer.

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Molecular biology of Esophageal Cancer

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  • PubMed search for publications about Esophageal Cancer - Limit search to: [Reviews]

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    MeSH term: Esophageal Neoplasms
    International US National Library of Medicine
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Abu-Farsakh S, Wu T, Lalonde A, et al.
High expression of Claudin-2 in esophageal carcinoma and precancerous lesions is significantly associated with the bile salt receptors VDR and TGR5.
BMC Gastroenterol. 2017; 17(1):33 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Claudins are a family of integral membrane proteins and are components of tight junctions (TJs). Many TJ proteins are known to tighten the cell structure and maintain a barrier. Claudin-2 forms gated paracellular channels and allows sodium ions and other small positively charged ions to cross between adjacent cells. Recently, we found that vitamin D receptor (VDR) enhanced Claudin-2 expression in colon and that bile salt receptors VDR and Takeda G-protein coupled receptor5 (TGR5) were highly expressed in esophageal adenocarcinoma (EAC) and precancerous lesions. Here, we examined the expression of Claudin-2 in EAC and precancerous lesions and its association with VDR and TGR5 expression.
METHODS: Claudin-2 expression was examined by immunohistochemistry on tissue microarrays, containing EAC, high grade dysplasia (HGD), low grade dysplasia (LGD), Barrett's esophagus (BE), columnar cell metaplasia (CM), squamous cell carcinoma (SCC), and squamous epithelium (SE) cases. Intensity (0 to 3) and percentage were scored for each case. High expression was defined as 2-3 intensity in ≥ 10% of cells.
RESULTS: Claudin-2 was highly expressed in 77% EAC (86/111), 38% HGD (5/13), 61% LGD (17/28), 46% BE (18/39), 45% CM (29/65), 88% SCC (23/26), and 14% SE (11/76). It was significantly more highly-expressed in EAC, SCC and glandular lesions than in SE and more in EAC than in BE and CM. A significant association was found between Claudin-2 expression and VDR and TGR5 expression. No significant association was found between expression of Claudin-2 and age, gender, grade, stage, or patients' survival time in EAC and SCC.
CONCLUSIONS: We conclude that Claudin-2 expression is significantly associated with bile acid receptors VDR and TGR5 expression. Our studies identify a novel role of a tight junction protein in the development and progression of esophageal mucosal metaplasia, dysplasia and carcinoma.

Khan S, Mikhail S, Xiu J, Salem ME
Molecular biology of gastroesophageal cancers: opportunities and challenges.
Clin Adv Hematol Oncol. 2017; 15(1):75-82 [PubMed] Related Publications
Gastroesophageal (GE) malignancies make up a significant and growing segment of newly diagnosed cancers. Approximately 80% of patients who have GE cancers die within 5 years of diagnosis, which means that effective treatments for these malignancies need to be found. Currently, targeted therapies have a minimal role in this disease group. Intensive study of the molecular biology of GE cancers is a relatively new and ongoing venture, but it has already led to a significant increase in our understanding of these malignancies. This understanding, although still limited, has the potential to enhance our ability to develop targeted therapies in conjunction with the ability to identify actionable gene mutations and perform genomic profiling to predict drug resistance. Several cell surface growth factor receptors have been found to play a prominent role in GE cancer cell signaling. This discovery has led to the approval of 2 agents within the last few years: trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody used in the first-line treatment of HER2-positive GE cancers, and ramucirumab, an anti-vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody that is currently used in later lines of therapy. This review discusses the current state of molecular testing in GE cancers, along with the known molecular biology and current and investigational treatments. The development of trastuzumab and ramucirumab represents a significant advance in our ability to make use of GE tumor molecular profiles. As our understanding of the impact of molecular aberrations on drug effectiveness and disease outcomes increases, we anticipate improved therapy for patients with GE cancers.

Vrana D, Matzenauer M, Aujesky R, et al.
Potential Predictive Role of MicroRNAs in the Neoadjuvant Treatment of Esophageal Cancer.
Anticancer Res. 2017; 37(2):403-412 [PubMed] Related Publications
Esophageal cancer is a disease with disappointing prognosis. Currently, there are no predictive factors that can identify patients who on the one hand would likely benefit from tri-modality management and, on the other hand, would not be significantly affected by the morbidity accompanying the treatment. MicroRNAs are short non-coding RNAs responsible for post-transcriptional modification of gene expression by binding to 3'-UTR of messenger RNA and represent emerging potential predictive biomarkers of treatment (chemotherapy and radiotherapy) efficacy and toxicity. We reviewed the current literature, addressing the potential predictive role of microRNAs for efficacy of chemotherapy (specifically cisplatin, 5-fluorouracil, doxorubicin and paclitaxel) and radiotherapy, including predicted targets in the cell. Altogether 82 articles were identified and included in this review. This may be the first review on this topic specifically focusing on neoadjuvant treatment of esophageal cancer.

Ishihara R, Matsuura N, Hanaoka N, et al.
Endoscopic imaging modalities for diagnosing invasion depth of superficial esophageal squamous cell carcinoma: a systematic review and meta-analysis.
BMC Gastroenterol. 2017; 17(1):24 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Diagnosis of cancer invasion depth is crucial for selecting the optimal treatment strategy in patients with gastrointestinal cancers. We conducted a meta-analysis to determine the utilities of different endoscopic modalities for diagnosing invasion depth of esophageal squamous cell carcinoma (SCC).
METHODS: We conducted a comprehensive search of MEDLINE, Cochrane Central, and Ichushi databases to identify studies evaluating the use of endoscopic modalities for diagnosing invasion depth of superficial esophageal SCC. We excluded case reports, review articles, and studies in which the total number of patients or lesions was <10.
RESULTS: Fourteen studies fulfilled our criteria. Summary receiver operating characteristic curves showed that magnified endoscopy (ME) and endoscopic ultrasonography (EUS) performed better than non-ME. ME was associated with high sensitivity and a very low (0.08) negative likelihood ratio (NLR), while EUS had high specificity and a very high (17.6) positive likelihood ratio (PLR) for the diagnosis of epithelial or lamina propria cancers. NLR <0.1 provided strong evidence to rule out disease, and PLR >10 provided strong evidence of a positive diagnosis.
CONCLUSIONS: EUS and ME perform better than non-ME for diagnosing invasion depth in SCC. ME has a low NLR and is a reliable modality for confirming deep invasion of cancer, while EUS has a high PLR and can reliably confirm that the cancer is limited to the surface. Effective use of these two modalities should be considered in patients with SCC.
TRIAL REGISTRATION: PROSPERO (International Prospective Register of Systematic Reviews); number 42015024462 .

Feng JF, Chen S, Yang X
Systemic immune-inflammation index (SII) is a useful prognostic indicator for patients with squamous cell carcinoma of the esophagus.
Medicine (Baltimore). 2017; 96(4):e5886 [PubMed] Free Access to Full Article Related Publications
The aim of the study was to determine the prognostic role of systemic immune-inflammation index (SII) in patients with esophageal squamous cell carcinoma (ESCC).A total of 298 ESCC patients were enrolled in the current retrospective study. The SII was calculated by the formula: neutrophil × platelet/lymphocyte. The optimal cut-off value was calculated by the Cutoff Finder. Univariate and multivariate analyses were evaluated for cancer-specific survival (CSS). Additional, we also established a nomogram model to predict the prognosis for patients with ESCC.The optimal cut-off value was 410 × 10/L for SII. Patients with SII ≤ 410 (×10/L) had a significantly better 5-year CSS than patients with SII > 410 (×10/L) (51.9% vs 24.0%, P < 0.001). Multivariate analyses revealed that SII was a significant independent predictive indicator (P = 0.027). A nomogram could be more accuracy for CSS for patients with ESCC (c-index: 0.68).The SII is a useful independent prognostic indicator for patients with resectable ESCC.

Fendereski M, Zia MF, Shafiee M, et al.
MicroRNA-196a as a Potential Diagnostic Biomarker for Esophageal Squamous Cell Carcinoma.
Cancer Invest. 2017; 35(2):78-84 [PubMed] Related Publications
We observed significant up-regulation of miR-196a in esophageal squamous cell carcinoma (ESCC) as compared with their adjacent normal tissue (p = .002). Receiver operating characteristics curve analysis confirmed the suitability of miR-196a as a potential tumor marker for diagnosis of ESCC. Furthermore, analysis of miR-196a levels in saliva samples determined an average of 27-fold up-regulations in ESCC patients compared with healthy group. Our results suggest that salivary miR-196a may be a suitable noninvasive biomarker for diagnosis of ESCC. In addition, molecular pathway enrichment analysis of microRNA (miR)-196a determined focal adhesion, spliceosome and p53 signaling pathways as the most relevant pathways with miR-196a targetome.

Glatz T, Kulemann B, Marjanovic G, et al.
Postoperative fluid overload is a risk factor for adverse surgical outcome in patients undergoing esophagectomy for esophageal cancer: a retrospective study in 335 patients.
BMC Surg. 2017; 17(1):6 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Restrictive intraoperative fluid management is increasingly recommended for patients undergoing esophagectomy. Controversy still exists about the impact of postoperative fluid management on perioperative outcome.
METHODS: We retrospectively examined 335 patients who had undergone esophagectomy for esophageal cancer at the University Hospital Freiburg between 1996 and 2014 to investigate the relation between intra- and postoperative fluid management and postoperative morbidity after esophagectomy.
RESULTS: Perioperative morbidity was 75%, the in-hospital mortality 8%. A fluid balance above average on the operation day was strongly associated with a higher rate of postoperative mortality (21% vs 3%, p < 0.001) and morbidity (83% vs 66%, p = 0.001). Univariate analysis for risk factors for adverse surgical outcome (Clavien ≥ III) identified ASA-score (p = 0.002), smoking (p = 0.036), reconstruction by colonic interposition (p = 0.036), cervical anastomosis (p = 0.017), blood transfusion (p = 0.038) and total fluid balance on the operation day and on POD 4 (p = 0.001) as risk factors. Multivariate analysis confirmed only ASA-score (p = 0.001) and total fluid balance (p = 0.001) as independent predictors of adverse surgical outcome.
CONCLUSION: Intra- and postoperative fluid overload is strongly associated with increased postoperative morbidity. Our results suggest restrictive intra- and especially postoperative fluid management to optimize the outcome after esophagectomy.

Bartley AN, Washington MK, Ventura CB, et al.
HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology.
Am J Clin Pathol. 2016; 146(6):647-669 [PubMed] Related Publications
CONTEXT: ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA.
OBJECTIVES: To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making.
DESIGN: The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA.
RESULTS: The panel is proposing 11 recommendations with strong agreement from the open-comment participants.
RECOMMENDATIONS: The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance.
CONCLUSIONS: This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.

Guo Y, Li J, Zhang P, et al.
Comparative evaluation of target volumes defined by deformable and rigid registration of diagnostic PET/CT to planning CT in primary esophageal cancer.
Medicine (Baltimore). 2017; 96(1):e5528 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To evaluate the geometrical differences of target volumes propagated by deformable image registration (DIR) and rigid image registration (RIR) to assist target volume delineation between diagnostic Positron emission tomography/computed tomography (PET/CT) and planning CT for primary esophageal cancer (EC).
METHODS: Twenty-five patients with EC sequentially underwent a diagnostic F-fluorodeoxyglucose (F-FDG) PET/CT scan and planning CT simulation. Only 19 patients with maximum standardized uptake value (SUVmax) ≥ 2.0 of the primary volume were available. Gross tumor volumes (GTVs) were delineated using CT and PET display settings. The PET/CT images were then registered with planning CT using MIM software. Subsequently, the PET and CT contours were propagated by RIR and DIR to planning CT. The properties of these volumes were compared.
RESULTS: When GTVCT delineated on CT of PET/CT after both RIR and DIR was compared with GTV contoured on planning CT, significant improvements using DIR were observed in the volume, displacements of the center of mass (COM) in the 3-dimensional (3D) direction, and Dice similarity coefficient (DSC) (P = 0.003; 0.006; 0.014). Although similar improvements were not observed for the same comparison using DIR for propagated PET contours from diagnostic PET/CT to planning CT (P > 0.05), for DSC and displacements of COM in the 3D direction of PET contours, the DIR resulted in the improved volume of a large percentage of patients (73.7%; 68.45%; 63.2%) compared with RIR. For diagnostic CT-based contours or PET contours at SUV2.5 propagated by DIR with planning CT, the DSC and displacements of COM in 3D directions in the distal segment were significantly improved compared to the upper and middle segments (P > 0.05).
CONCLUSION: We observed a trend that deformable registration might improve the overlap for gross target volumes from diagnostic PET/CT to planning CT. The distal EC might benefit more from DIR.

Strøyer S, Mantoni T, Svendsen LB
Evaluation of the surgical apgar score in patients undergoing Ivor-Lewis esophagectomy.
J Surg Oncol. 2017; 115(2):186-191 [PubMed] Related Publications
BACKGROUND: The Surgical Apgar Score is a simple outcome score based on intraoperative parameters. The scoring system is recently validated in patients undergoing esophagectomy but without comparable results. This study evaluated the ability of the original and modified Surgical Apgar Scores to predict major complications in a patient population undergoing Ivor-Lewis esophagectomy.
METHODS: We retrospectively examined 234 patients who successfully underwent Ivor-Lewis esophagectomy at Rigshospitalet, Copenhagen from November 23, 2011 till November 23, 2014. Major complications were defined as Clavien-Dindo grade IIIa or higher within 30 days after surgery. Univariate and multivariate analyses were performed to assess factors associated with major complications. Receiver operating characteristics were performed for determination of the predictive value of the Surgical Apgar Score scoring systems.
RESULTS: There were 64 (27.4%) patients with at least one major complication and 4 (1.7%) deaths. The original and modified versions of the Surgical Apgar Score were not associated with major complications and the scoring systems showed no significant predictive value when receiver operating characteristics were performed.
CONCLUSIONS: The original or modified versions of the Surgical Apgar Score could possibly be useful in some subgroups of esophagectomy patients, but should not be considered to have a general predictive value. J. Surg. Oncol. 2017;115:186-191. © 2017 Wiley Periodicals, Inc.

Parry K, Sadeghi AH, van der Horst S, et al.
Intermittent pneumatic compression in combination with low-molecular weight heparin in the prevention of venous thromboembolic events in esophageal cancer surgery.
J Surg Oncol. 2017; 115(2):181-185 [PubMed] Related Publications
INTRODUCTION: Aim of this study was to evaluate the use of Intermittent Pneumatic Compression (IPC) in the prevention of symptomatic venous thromboembolic events (VTE) in patients undergoing esophagectomy for cancer.
METHODS: From a prospective database, all patients operated between 2010 and 2014 received IPC in addition to LMWH and were compared to a historical cohort of patients treated LMWH only (2004-2009).
RESULTS: Of the 313 included patients, 195 (62%) received IPC. Patients with IPC received neoadjuvant chemoradiation more often (45% vs. 3%, P < 0.001), whereas, neoadjuvant chemotherapy was equally distributed (31% vs. 34%, P = 0.631). There were no differences with regard to surgical approach, operative time, blood loss, and ICU stay. Patients treated without IPC had a longer hospital stay (18 vs. 15 days, P = 0.014). Overall, 12 clinical VTE's occurred in 11 patients, which consisted of two deep venous thromboses and 10 pulmonary embolisms. In the group of patients, who received IPC 1.5% developed a symptomatic VTE compared to 6.8% in patients without IPC (OR = 0.215; 95% CI = 0.06-0.83). Multivariate analysis identified IPC as the only independent prognostic factor correlated with a reduction in postoperative VTE's (OR = 0.225; 95% CI = 0.06-0.88).
CONCLUSION: The addition of IPC in patients undergoing esophagectomy for cancer was associated with a reduction in symptomatic VTE's. J. Surg. Oncol. 2017;115:181-185. © 2017 Wiley Periodicals, Inc.

Fujita H
Anesthesia of Torek's operation: the first successful resection of a cancer in the thoracic esophagus-an abridged translation of an essay in Japanese.
Gen Thorac Cardiovasc Surg. 2017; 65(2):80-84 [PubMed] Related Publications
The first successful resection of a cancer in the thoracic esophagus was performed by Franz Torek around one hundred years ago. Awareness of developments in surgery and the early history can stimulate and foster innovation among surgeons, as well as promote a deeper appreciation of the pioneers of the methods still used today. Here we report the conditions leading to Torek's operation performed in 1913. In the operation, anesthesia was achieved by tracheal insufflation. Ernst Sauerbruch, a surgeon in Germany, first developed a negative-pressure chamber for anesthesia in 1903 and subsequently used this in many open-chest operations. Then in 1909 Samuel Meltzer, a physiologist in New York, proposed ventilation through an intratracheal tube while under anesthesia. Soon afterwards, Sauerbruch gave his chamber to Willey Meyer, a surgeon in the New York German Hospital, who reported Sauerbruch's success in operations in the American journal. The negative-pressure chamber was sent to the Meltzer's laboratory where Meltzer demonstrated that tracheal insufflation was superior to the negative-pressure chamber for open thoracic operations. These findings were conveyed to Meyer and to Franz Torek, a surgeon in the New York German Hospital and a colleague of Meyer, who succeeded in the historical first resection of a cancer in the thoracic esophagus according to Meltzer.

Huang Y, Wang H, Luo G, et al.
A systematic review and network meta-analysis of neoadjuvant therapy combined with surgery for patients with resectable esophageal squamous cell carcinoma.
Int J Surg. 2017; 38:41-47 [PubMed] Related Publications
BACKGROUND: The role of neoadjuvant therapy combined with surgery for treating esophageal squamous cell carcinoma (ESCC) remains controversial. We performed a network meta-analysis to synthesize direct and indirect evidence to identify the optimal therapeutic method for ESCC.
METHODS: We identified 15 randomized controlled trials that compared any of the following 4 therapeutic measures: surgery alone (S), preoperative chemotherapy followed by surgery (CTS), preoperative radiotherapy followed by surgery (RTS), and preoperative chemoradiotherapy followed by surgery (CRTS). The main outcomes were 5-year survival, rate of radical resection, operative mortality and postoperative complications.
RESULTS: Network meta-analysis showed that CRTS was associated with improved survival as compared with S (OR = 1.50 [95% CI 1.21 to 1.97]) and decreased occurrence of complications as compared with RTS (OR = 0.50 [95% CI 0.22 to 0.99]). Direct evidence revealed CRTS associated with improved survival (OR = 1.61 [95% CI 1.01 to 2.57]) and radical resection (OR = 4.01 [95% CI 1.66 to 9.69]) as compared with S. In terms of radical resection, CTS was more effective than S (OR = 1.73 [95% CI 1.09 to 2.76]). Findings for CTS and RTS did not differ for 5-year survival, operative mortality and postoperative complications.
CONCLUSIONS: Overall, CRTS might be the best choice for resectable ESCC because it could increase the radical resection rate and lower the occurrence of complications, thereby prolonging survival time.

Chen P, Shan Z, Zhao J, et al.
NFAT1 promotes cell motility through MMP-3 in esophageal squamous cell carcinoma.
Biomed Pharmacother. 2017; 86:541-546 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors and the prognosis of patients remains poor. Increasing evidence suggests that nuclear factor of activated T cell (NFAT1) plays an important role in the development and progression of cancers. Herein, we show that NFAT1 was overexpressed in human ESCC, which was significantly associated with advanced tumor stage and lymph node metastasis. Functional studies found that NFAT1 silencing could suppress cell migration and invasion through MMP-3. The data therefore suggest that NFAT1 plays an important adverse role in the development and progression of ESCC, implicating possible application in clinics as a biomarker and a potential new therapeutic target.

Imai T, Oue N, Sentani K, et al.
KIF11 Is Required for Spheroid Formation by Oesophageal and Colorectal Cancer Cells.
Anticancer Res. 2017; 37(1):47-55 [PubMed] Related Publications
BACKGROUND: Oesophageal squamous cell carcinoma (ESCC) and colorectal cancer (CRC) are common types of human cancer. Spheroid colony formation is used to characterize cancer stem cell (CSCs). In the present study, we analyzed the significance of kinesin family 11 (KIF11 in human ESCC and CRC.
MATERIALS AND METHODS: Expression of KIF11 in 105 ESCC and 100 CRC cases was determined using immunohistochemistry. RNA interference was used to inhibit KIF11 expression in ESCC and CRC cell lines.
RESULTS: In total, 61 out of 105 (58%) ESCC and 62 out of 100 (62%) CRC cases were positive for KIF11. Expression of KIF11 was not associated with any clinicopathological characteristics. Both the number and size of spheres produced by from TE-5 ESCC cells and DLD-1 CRC cells were significantly reduced upon KIF11 siRNA transfection compared to negative control siRNA transfection.
CONCLUSION: These results indicate that KIF11 plays an important role in CSCs of ESCC and CRC.

Sohda M, Kuwano H
Current Status and Future Prospects for Esophageal Cancer Treatment.
Ann Thorac Cardiovasc Surg. 2017; 23(1):1-11 [PubMed] Related Publications
The local control effect of esophagectomy with three-field lymph node dissection (3FLD) is reaching its limit pending technical advancement. Minimally invasive esophagectomy (MIE) by thoracotomy is slowly gaining acceptance due to advantages in short-term outcomes. Although the evidence is slowly increasing, MIE is still controversial. Also, the results of treatment by surgery alone are limiting, and multimodality therapy, which includes surgical and non-surgical treatment options including chemotherapy, radiotherapy, and endoscopic treatment, has become the mainstream therapy. Esophagectomy after neoadjuvant chemotherapy (NAC) is the standard treatment for clinical stages II/III (except for T4) esophageal cancer, whereas chemoradiotherapy (CRT) is regarded as the standard treatment for patients who wish to preserve their esophagus, those who refuse surgery, and those with inoperable disease. CRT is also usually selected for clinical stage IV esophageal cancer. On the other hand, with the spread of CRT, salvage esophagectomy has traditionally been recognized as a feasible option; however, many clinicians oppose the use of surgery due to the associated unfavorable morbidity and mortality profile. In the future, the improvement of each treatment result and the establishment of individual strategies are important although esophageal cancer has many treatment options.

Wu N, Zhu Y, Kadel D, et al.
The prognostic influence of body mass index, resting energy expenditure and fasting blood glucose on postoperative patients with esophageal cancer.
BMC Gastroenterol. 2016; 16(1):142 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Body mass index (BMI), resting energy expenditure (REE) and fasting blood glucose (FBG) are major preoperative assessments of patients' nutrition and metabolic state. The relations and effects of these indices on esophageal cancer patients' postoperative short-term and long-term outcomes remain controversial and unclear. We aimed to study the impact of BMI, REE and FBG in esophageal cancer patients undergoing esophagectomy.
METHODS: Three hundred and six esophageal cancer patients who underwent esophagectomy were observed retrospectively. Clinical characteristics, postoperative complications and survival analysis were compared among different BMI, REE and FBG groups.
RESULTS: There were significant linear relationships between REE, BMI and FBG indices, patients with low BMI tended to have low REE (p < 0.001) and low FBG (p = 0.003). No significant difference was found in case of mortality and postoperative complications among different groups. Low BMI (X (2) = 6.141, p = 0.046), REE (X (2) = 6.630, p = 0.010) and FBG (X (2) = 5.379, p = 0.020) were related to poor survival. FBG ≤90 mg/dL was independently associated with poor survival (HR = 0.695; 95 % CI 0.489-0.987, p = 0.042). BMI and REE came to be stronger prognostic factors on lymph node-negative patients and proved to be independent prognostic indicators (HR = 0.540; 95 % CI 0.304-0.959, p = 0.035 and HR = 0.457; 95 % CI 0.216-0.967, p = 0.041, respectively).
CONCLUSIONS: BMI, REE and FBG are important prognostic factors in patients with esophageal cancer undergoing esophagectomy and preoperative evaluation of these indices help to determine the prognosis in these patients.

Wang J, Liu W, Parikh K, Post AB
Alpha-fetoprotein-producing esophageal adenocarcinoma: a mimicker of hepatocellular carcinoma.
Clin J Gastroenterol. 2017; 10(1):7-12 [PubMed] Related Publications
Alpha-fetoprotein (AFP)-producing esophageal adenocarcinoma (EAC) is a rare occurrence. Elevation of serum AFP is commonly associated with hepatocellular carcinoma and yolk sac tumors, but rarely with esophageal carcinoma. Here, we report a rare case of AFP-producing EAC. A 51-year-old man presented with two weeks of acid reflux and a 35-lb weight loss. Laboratory data were notable for transaminitis and AFP was 2524 ng/mL. Computed tomography of the abdomen revealed abnormal thickening of the esophagus and multiple metastatic masses throughout the liver. Biopsy of one of the masses revealed adenocarcinoma of gastrointestinal origin. Subsequent upper endoscopy revealed an esophageal mass with biopsy notable for ulcerated dysplastic glandular mucosa with likely underlying malignancy. The patient underwent palliative esophageal stent placement but died two months later. Elevated AFP levels are an unusual occurrence in EAC. Prognosis is poor given its advanced presenting stage and high metastatic potential. Most cases are unsuccessfully treated with surgery and chemotherapy. Serial measurement of serum AFP may be useful for monitoring clinical status and treatment response. Clinicians should consider AFP-producing EAC in their differential diagnosis in the work-up of a liver mass in the setting of elevated AFP or liver function impairment, especially in the absence of chronic liver disease.

Jing W, Guo H, Kong L, et al.
Clinical outcomes of elderly patients (≥70 years) with resectable esophageal squamous cell carcinoma who underwent esophagectomy or chemoradiotherapy: A retrospective analysis from a single cancer institute.
Medicine (Baltimore). 2016; 95(50):e5630 [PubMed] Free Access to Full Article Related Publications
A retrospective analysis was conducted to investigate outcomes of elderly patients with resectable esophageal squamous cell carcinoma (ESCC) who underwent surgery or chemoradiotherapy (CRT).We performed a retrospective review of the records of elderly patients (≥70 years) with resectable ESCC who underwent esophagectomy or CRT between January 2009 and March 2013. According to the main treatment strategy, patients were allocated into either surgery group or CRT group. Overall survival (OS), cancer-specific survival and progression-free survival were calculated by the Kaplan-Meier method. Univariate and multivariate survival analyses were performed by the Kaplan-Meier method and Cox proportional hazards model, respectively.A total of 188 patients were enrolled. Eighty-eight patients underwent esophagectomy, and 100 patients underwent CRT. The median age of the patients was 73 years (range, 70-81 years) in the surgery group and 76 years (range, 70-88 years) in the CRT group. The median survival time (MST) for the whole cohort was 25.6 months, and 1-, 3-, and 5-year survival rates were 69.2%, 36.1%, and 21.9%, respectively. The MST in the surgery group and the CRT group was 36 months and 15 months, respectively. The 1-, 3-, and 5-year survival rates in the surgery group were 82.4%, 49.0%, and 33.3%, compared to 58.0%, 24.1%, and 7.8% in the CRT group (P < 0.0001). Multivariate analysis revealed that lymph node status (hazard ratio [HR] = 0.598, P = 0.011) and treatment strategies (HR = 0.538, P = 0.001) were independent and significant prognostic factors for OS in elderly patients.Surgery was the main treatment strategy for elderly patients with ESCC. Advanced age and comorbidities should not be the cause for elderly patients to avoid aggressive regimens. Delivered therapeutic approaches should be individualized on the basis of carefully evaluating the balance of benefits, risks, and life expectancy.

Zhang H, Zhao JH, Suo ZM
Knockdown of HOXA5 inhibits the tumorigenesis in esophageal squamous cell cancer.
Biomed Pharmacother. 2017; 86:149-154 [PubMed] Related Publications
Homeobox A5 (HOXA5) is a member of the homeobox (HOX) family and was upregulated in many types of tumors. However, its expression and role in esophageal squamous cell carcinoma (ESCC) remain unclear. In this study, the aim of this study was to investigate the expression and function of HOXA5 in ESCC. Our results showed that HOXA5 was highly expressed in ESCC cell lines. The in vitro experiments demonstrated that knockdown of HOXA5 significantly inhibited the proliferation, migration and invasion of ESCC cells. Furthermore, the in vivo experiments showed that knockdown of HOXA5 significantly inhibited the tumor growth of ESCC in mice xenograft model. Finally, sh-HOXA5 inhibited the expression of β-catenin, cyclin D1 and c-Myc in ESCC cells. Taken together, these data revealed that knockdown of HOXA5 suppressed the proliferation and metastasis partly by interfering with Wnt/β-catenin signaling pathway in ESCC cells. Therefore, these findings suggest that HOXA5 may be a potential therapeutic target for the treatment of ESCC.

Chaber-Ciopinska A, Kiprian D, Kawecki A, Kaminski MF
Surveillance of patients at high-risk of squamous cell esophageal cancer.
Best Pract Res Clin Gastroenterol. 2016; 30(6):893-900 [PubMed] Related Publications
Currently curative treatment for esophageal squamous cell cancer (ESCC) is possible only in patients with early-stage, usually asymptomatic disease. In Western countries, where the incidence of ESCC is relatively low, a screening of asymptomatic, average-risk population is untenable. In order to detect early-stage ESCC or its precursor lesions it is important to identify high-risk patients and consider endoscopic surveillance in these groups. These high-risk groups include patients after curative treatment for head and neck cancer, previous endoscopic resection of ESCC, caustic injury, and patients with tylosis or achalasia. This paper discuss the evidence and proposed method of endoscopy surveillance of these high-risk patients.

Libânio D, Pimentel-Nunes P, Dinis-Ribeiro M
Complications of endoscopic resection techniques for upper GI tract lesions.
Best Pract Res Clin Gastroenterol. 2016; 30(5):735-748 [PubMed] Related Publications
Adverse events can occur during and after the endoscopic resection of upper gastrointestinal lesions. Their incidence can be minimized through the adoption of preventive measures and their final outcomes can be optimized through prompt identification and adequate treatment. In this evidence-based review we describe the risk factors for adverse events, preventive measures to avoid them and their management when they occur. Algorithms of action are also provided. Oesophageal strictures can be prevented with corticosteroids (either locally injected or systemically administered) and treated with endoscopic dilatation. Bleeding can be minimized through the adoption of prophylactic coagulation and novel preventive measures are emerging and being evaluated. Bleeding management includes coagulation therapy, clips and haemostatic powders. Perforations can nowadays be successfully treated endoscopically in the majority of the cases and conservative treatment is associated with favourable outcomes although optimal management is unclear.

Darabi M, Asadi Lari M, Motevalian SA, et al.
Trends in gastrointestinal cancer incidence in Iran, 2001-2010: a joinpoint analysis.
Epidemiol Health. 2016; 38:e2016056 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: The main purpose of this study was to evaluate changes in the time trends of stomach, colorectal, and esophageal cancer during the past decade in Iran.
METHODS: Cancer incidence data for the years 2001 to 2010 were obtained from the cancer registration of the Ministry of Health. All incidence rates were directly age-standardized to the world standard population. In order to identified significant changes in time trends, we performed a joinpoint analysis. The annual percent change (APC) for each segment of the trends was then calculated.
RESULTS: The incidence of stomach cancer increased from 4.18 and 2.41 per 100,000 population in men and women, respectively, in 2001 to 17.06 (APC, 16.7%) and 8.85 (APC, 16.2%) per 100,000 population in 2010 for men and women, respectively. The corresponding values for colorectal cancer were 2.12 and 2.00 per 100,000 population for men and women, respectively, in 2001 and 11.28 (APC, 20.0%) and 10.33 (APC, 20.0%) per 100,000 in 2010. For esophageal cancer, the corresponding increase was from 3.25 and 2.10 per 100,000 population in 2001 to 5.57 (APC, 12.0%) and 5.62 (APC, 11.2%) per 100,000 population among men and women, respectively. The incidence increased most rapidly for stomach cancer in men and women aged 80 years and older (APC, 23.7% for men; APC, 18.6% for women), for colorectal cancer in men aged 60 to 69 years (APC, 24.2%) and in women aged 50 to 59 years (APC, 25.1%), and for esophageal cancer in men and women aged 80 years and older (APC, 17.5% for men; APC,15.3% for women) over the period of the study.
CONCLUSIONS: The incidence of gastrointestinal cancer significantly increased during the past decade. Therefore, monitoring the trends of cancer incidence can assist efforts for cancer prevention and control.

Liu J, Motoyama S, Sato Y, et al.
Decreased Skeletal Muscle Mass After Neoadjuvant Therapy Correlates with Poor Prognosis in Patients with Esophageal Cancer.
Anticancer Res. 2016; 36(12):6677-6685 [PubMed] Related Publications
BACKGROUND: Loss of skeletal muscle is predictive of a poor prognosis in patients with various malignant lesions. Our aim was to determine whether changes in skeletal muscle after neo-adjuvant therapy (NAT) predict prognosis in patients with esophageal squamous cell carcinoma (ESCC) undergoing esophagectomy.
PATIENTS AND METHODS: The cross-sectional areas of the psoas muscles were measured on computed tomographic images collected at the initial visit, preoperatively and postoperatively in 84 patients. The psoas muscle index (PMI) was calculated by normalizing the cross-sectional areas to the patients' heights.
RESULTS: Low PMI at the initial visit was not associated with a poor prognosis. The majority of patients showed decreased PMI after NAT and surgery. The group in which the post-NAT PMI decreased had poorer overall survival than group without PMI decrease (p=0.025).
CONCLUSION: Decreased PMI correlates well with a poor prognosis in patients with ESCC. Changes in PMI over a period of time may have greater sensitivity when evaluating prognosis than the PMI at any single time point.

Miyazaki T, Sakai M, Sohda M, et al.
Prognostic Significance of Inflammatory and Nutritional Parameters in Patients with Esophageal Cancer.
Anticancer Res. 2016; 36(12):6557-6562 [PubMed] Related Publications
BACKGROUND: We evaluated the following preoperative prognostic factors in patients who underwent esophagectomy for esophageal cancer: C-Reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), serum albumin, prognostic nutritional index (PNI), and body mass index (BMI).
PATIENTS AND METHODS: This retrospective study included 173 men and 19 women with a mean age of 65.8 years (range=42-86 years) who were scheduled to undergo esophagectomy for esophageal cancer. The association of CRP, NLR, albumin, PNI, and BMI with various clinicopathological factors and prognosis were evaluated.
RESULTS: Univariate analysis revealed that male sex, depth of invasion, nodal metastasis, pStage, high CRP, low PNI, high NLR, and low BMI were significant risk factors for a poor prognosis. Multivariate analysis identified depth of invasion, pStage, and BMI as significant prognostic factors in the Cox proportional hazard model.
CONCLUSION: The preoperative nutritional status affected the postoperative survival time in patients with esophageal cancer. In particular, a low BMI was an independent prognostic factor for poorer survival in the multivariate analysis.

Ohashi T, Komatsu S, Ichikawa D, et al.
Overexpression of PBK/TOPK Contributes to Tumor Development and Poor Outcome of Esophageal Squamous Cell Carcinoma.
Anticancer Res. 2016; 36(12):6457-6466 [PubMed] Related Publications
BACKGROUND: PDZ-binding kinase/T-cell-originated protein kinase (PBK/TOPK) is a serine-threonine kinase and overexpressed in various types of cancer. PBK/TOPK is associated with tumor cell development and progression through suppression of p53 function. In this study, we tested whether PBK acts as a cancer-promoting factor by being overexpressed in esophageal squamous cell carcinoma (ESCC).
MATERIALS AND METHODS: We analyzed PBK/TOPK expression in 15 ESCC cell lines, and 54 primary ESCC tumors that were curatively resected between 1994 and 2007.
RESULTS: Overexpression of the PBK/TOPK protein was detected in 93% (14/15) ESCC cell lines and 19% (10/54) primary ESCC tumor samples, and significantly correlated with macroscopic appearance and tumor depth. PBK/TOPK positivity was independently associated with worse outcome in multivariate analysis (p=0.0235, hazard ratio=3.58). Knockdown of PBK/TOPK using specific siRNAs inhibited the cell proliferation, invasion/migration of PBK/TOPK-overexpressing ESCC cell lines.
CONCLUSION: These findings suggest that PBK/TOPK plays a crucial role in tumor malignant potential through its overexpression in ESCC.

Pfeiffer P, Qvortrup C, Krogh M, et al.
S-1 in combination with docetaxel and oxaliplatin in patients with advanced gastro-esophageal adenocarcinoma: two parallel phase 1/2a studies.
Acta Oncol. 2017; 56(1):46-51 [PubMed] Related Publications
BACKGROUND: Docetaxel in combination with cisplatin and 5-fluorouracil (5-FU) is one of several standard chemotherapy regimens for patients with advanced gastro-esophageal adenocarcinoma (aGEA) in Europe. To enable outpatient treatment, we evaluated the maximum tolerated dose (MTD), recommended dose (RD), dose limiting toxicity (DLT) and safety of docetaxel in combination with oxaliplatin (O) and S-1 (DOS) in Caucasian patients with aGEA.
METHODS: We present final results of two parallel phase 1/2a studies (3 + 3 design). Escalating doses of docetaxel and S-1 with fixed dose O were given for 18 weeks every second week (DOS2w) or every third week (DOS3w) followed by S-1 maintenance therapy.
RESULTS: Thirty-four patients (18 in DOS2w and 16 in DOS3w) were enrolled between October 2013 and June 2015. Median age was 65 years (range 49-78). DLT was most often febrile neutropenia. Most common severe non-hematological adverse events were diarrhea (9%) and fatigue (6%). The RD of DOS3w was: docetaxel 50 mg/m(2), O 100 mg/m(2) and S-1 25 mg/m(2) twice daily and of DOS2w was: docetaxel 40 mg/m(2), O 70 mg/m(2) and S-1 35 mg/m(2) twice daily. Overall, response rate was 56%; median progression-free survival was 9.1 months; and median overall survival was 13.2 months in 34 patients.
CONCLUSIONS: At the RD, DOS2w and DOS3w showed an acceptable safety profile in patients with aGEA. Clinical trials ID: NCT-01928524 and EudraCT 2012-005187-10.

Yu J, Wang R, Wu J, et al.
Knockdown of Minichromosome Maintenance Proteins Inhibits Foci Forming of Mediator of DNA-Damage Checkpoint 1 in Response to DNA Damage in Human Esophageal Squamous Cell Carcinoma TE-1 Cells.
Biochemistry (Mosc). 2016; 81(10):1221-1228 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) has a high morbidity in China and its treatment depends greatly on adjuvant chemotherapy. However, DNA damage repair in cancer cells severely affects the outcome of treatment. This study investigated the potential mechanism regarding mediator of DNA-damage checkpoint 1 (MDC1) and minichromosome maintenance proteins (MCMs) during DNA damage in ESCC. Recombinant vectors of MDC1 and MCMs with tags were constructed and transfected into human ESCC cell line TE-1. Immunoprecipitation and mass spectrometry were performed to screen the MCMs interacting with MDC1, and direct interaction was confirmed by glutathione S-transferase (GST) pull-down assay in vitro. MCM2 and MCM6 were knocked down by shRNAs, after which chromatin fraction and foci forming of MDC1 upon bleomycin-induced DNA damage were examined. The results showed that MCM2/3/5/6 were immunoprecipitated by antibodies against the tag of MDC1 in TE-1 nuclei, and the GST pull-down assay indicated the direct interaction. Knockdown of MCM2 or MCM6 reduced the chromatin fraction of MDC1 according to Western blot results. Moreover, knockdown of MCM2 or MCM6 could significantly inhibit foci forming of MDC1 in TE-1 nuclei in response to bleomycin-induced DNA damage (p < 0.001). This study indicates the direct interaction between MDC1 and MCMs in TE-1 nuclei. Downregulation of MCMs can inhibit chromatin fraction and foci forming of MDC1 in TE-1 cells upon DNA damage, which suggests MCMs and MDC1 as potential targets to improve the outcome of chemotherapy in ESCC.

Shiraishi O, Yamasaki M, Makino T, et al.
Feasibility of Preoperative Chemotherapy with Docetaxel, Cisplatin, and 5-Fluorouracil versus Adriamycin, Cisplatin, and 5-Fluorouracil for Resectable Advanced Esophageal Cancer.
Oncology. 2017; 92(2):101-108 [PubMed] Related Publications
BACKGROUND: Neoadjuvant chemotherapy for resectable advanced esophageal squamous cell carcinoma (ESCC) requires reassessment. We have conducted a trial aiming at the comparison between DCF and ACF concerning perioperative adverse events.
METHODS: Patients were randomly assigned to receive either DCF [docetaxel 70 mg/m2, cisplatin 70 mg/m2 on day 1, and 5-fluorouracil (5-FU) 700 mg/m2 for 5 days] every 3 weeks or ACF (adriamycin 35 mg/m2, cisplatin 70 mg/m2 on day 1, and 5-FU 700 mg/m2 for 7 days) every 4 weeks. Each group consisted of 81 patients. Two cycles of preoperative chemotherapy were planned, after which patients underwent subtotal esophagectomy via a right thoracotomy with lymphadenectomy. Chemotherapy- and surgery-related adverse effects were assessed.
RESULTS: Grade 3-4 neutropenia and febrile neutropenia occurred in 90 and 39% of patients, respectively, in the DCF group compared with 69 and 17% of patients, respectively, in the ACF group (p < 0.01). Perioperative complications did not differ significantly between the groups. The overall response rates of DCF and ACF were 61 and 40%, respectively, while the histopathological complete responses were 15 and 3%, respectively (p < 0.01).
CONCLUSION: The DCF and ACF regimens were found to be equally feasible in patients with resectable advanced ESCC; however, DCF delivered an antitumor effect and therefore potentially improved the long-term outcomes.

Martin-Richard M, Díaz Beveridge R, Arrazubi V, et al.
SEOM Clinical Guideline for the diagnosis and treatment of esophageal cancer (2016).
Clin Transl Oncol. 2016; 18(12):1179-1186 [PubMed] Free Access to Full Article Related Publications
Esophageal cancer (EC) is an aggressive tumor that represents the 6th most common cause of cancer death worldwide. The estimated incidence in Spain is 2090 cases/year. Two main pathological subtypes exist, squamous cell carcinoma and adenocarcinoma. The main differences between them are localization and underlying factors which are the principal cause of the recent incidence changes observed in west countries. Staging techniques and treatment options which combine surgery, chemotherapy and radiotherapy, reflected the high complexity of the EC management. An undeniably multidisciplinary approach is, therefore, required. In this guide, we review the status of current diagnosis and treatment, define evidence and propose recommendations.

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