The Role and Prognostic Significance of Aortopulmonary, Anterior Mediastinal, and Tracheobronchial Lymph Nodes in Esophageal Cancer: Update of the Eighth-Edition TNM Staging System (2018).

BACKGROUND: The eighth edition of TNM staging for esophageal cancer will be implemented at 2018. The stations 5, 6, and 10 lymph nodes (LNs) have been omitted from the regional lymph node map for the new TNM staging. However, the role and prognostic significance of these LN stations were not clear. The purpose of this study was to investigate whether the revised nodal staging is appropriate and to verify the role, prognostic significance, and therapeutic value of these LNs in esophageal cancer. METHODS: The records of patients who underwent esophagectomy for cancer in our department between 2007 and 2013 were retrospectively analyzed. The rate of metastases was calculated for stations 5, 6, and 10 LNs. LN metastasis and patient survival were analyzed. RESULTS: A total of 1637 patients were included. The calculated rate of metastasis to stations 5, 6, and 10 was 3.2%, 2.3%, and 4.9%, respectively. No difference was found in the N stage determined by the seventh and eighth edition N staging systems. The status of station 5, 6, or 10 was not associated with long-term survival according to Cox proportional hazards model analysis. CONCLUSIONS: Metastasis to stations 5, 6, or 10 LNs was infrequent. Omitting of stations 5, 6, and 10 LNs in the eighth edition TNM staging did not influence the accuracy and survival-predicting efficacy. The therapeutic value of lymphadenectomy of stations 5, 6, and 10 was limited. The status of stations 5, 6, and 10 LNs was not associated with long-term survival.

Esophagectomy after endoscopic submucosal dissection for esophageal carcinoma.

BACKGROUND: Endoscopic submucosal dissection (ESD) has been used to treat early stage esophageal cancer, but reports about additional esophagectomy after ESD and postoperative outcomes are lacking. Complete removal of cancer tissue together with lymph nodes was the advantage of esophagectomy; however, invasiveness, organ loss, postoperative complications, and worse postoperative quality of life were serious disadvantages. The purpose of this study was to find the clear indication of additional esophagectomy after ESD, and help the other patients avoid excessive surgery. METHODS: We reviewed the clinicopathologic data and outcomes consecutive patients who had esophageal cancer confirmed by endoscopic biopsy and who were treated with ESD and subsequent esophagectomy between October 2011 and December 2016 in our department. The esophagectomy necessity following ESD was defined and the groups with necessity (+) vs. (-) were compared retrospectively. The esophagectomy necessity outcomes were retrospectively analyzed to judge whether the surgery option was correct. RESULTS: Total 214 patients with esophageal and esophagogastric cancer have undergone ESD treatment in our center, of which 32 patients (23 men and 9 women; mean age, 60±8 years) ultimately required esophagectomy after ESD. All patients had complete resection (R0) from esophagectomy. Postoperative TNM staging included TisN0M0 (6 patients), T1aN0M0 (6 patients), T1bN0M0 (18 patients), T1bN1M0 (1 patient), and T2N3M0 (1 patient). Necessity of esophagectomy after ESD was associated with residual margin status. There was a significant difference in ESD specimen margin status between the esophagectomy necessity (+) vs. (-) groups (positive/negative margin: 8/3 vs. 2/9 patients; P=0.03). Esophagectomy should be delayed at least 30 days after ESD to enable resolution of esophageal edema (P=0.017) (206±68 vs. 163±56 mL, P=0.057). Median follow-up was 16.8 months (range, 11.2-54.5 months); 3 patients were lost to follow-up (9%) and 1 patient died of metastasis after esophagectomy. All other patients were alive with excellent postoperative disease-free survival. CONCLUSIONS: Indications for esophagectomy after ESD include ESD failure, cancer recurrence, esophageal rupture, esophageal stricture refractory to endoscopic dilation, and residual tumor at the ESD specimen margin. Stage T1b alone is not an indication for esophagectomy. According to our study, we recommend that esophagectomy should be delayed ≥30 dafter ESD unless urgent esophagectomy is indicated.

Notch Signaling Pathway Is Inhibited in the Development of Barrett's Esophagus: An In Vivo and In Vitro Study.

Objective: To explore the role of Notch signaling in the development of Barrett's esophagus. Methods: Patients with esophagectomy and gastric interposition were recruited as a human model of gastroesophageal reflux disease. The expressions of Notch signaling genes in normal esophagus from surgical specimen and columnar metaplasia in the esophageal remnant after esophagectomy were evaluated by real time quantitative Polymerase Chain Reaction (RT-qPCR) and immunohistochemistry (IHC). For in vitro experiments, Het-1A cells were treated with hydrochloric acid, deoxycholic acid, mixture of hydrochloric acid and deoxycholic acid, or Notch1-siRNA, and expressions of Notch1, Hes1, MUC2, and K13 were evaluated via RT-qPCR and western blot. Results: Samples were obtained from 36 patients with columnar metaplasia in the esophageal remnant. Both IHC and RT-qPCR indicated that Notch1 and Hes1 expressions were significantly higher in normal esophagus than that in metaplasia. Hydrochloric acid and deoxycholic acid suppressed Notch1, Hes1, and K13 expressions, in concert with increasing MUC2 expressions. Notch inhibition by Notch1-siRNA contributed to the downregulation of Notch1, Hes1, and K13 expressions, whereas MUC2 expression was enhanced. Conclusions: Both hydrochloric acid and deoxycholic acid could suppress Notch signaling pathway in esophageal epithelial cells, and inhibited Notch signaling has important functions in the development of Barrett's esophagus.

Overexpression of Stathmin 1 correlates with poor prognosis and promotes cell migration and proliferation in oesophageal squamous cell carcinoma.

Stathmin 1 (STMN1) is a microtubule-regulated protein that plays an important role in tumour cell proliferation and migration. Overexpression of STMN1 is associated with clinicopathological characteristics in many human cancers. The aim of the present study was to investigate STMN1 expression, its correlation with clinicopathological characteristics, and its exact biological function in oesophageal squamous cell carcinoma (ESCC). STMN1 levels were measured in the ESCC tissue specimens of 276 patients by immunohistochemistry (IHC) to assess the prognostic efficacy of STMN1. IHC showed that patients with overexpression of STMN1 had a poorer prognosis compared with those with low expression, both in regards to 5-year overall survival (OS; 21.2 vs. 53.7%, P<0.001) and disease-free survival (DFS; 20.6 vs. 50.9%, P<0.001). STMN1 overexpression was associated with lower cell differentiation in tumour grade (correlation coefficient: 0.127, P=0.037). In multivariate analysis, STMN1 expression was found to be an independent prognostic factor for both OS (P<0.001; 95% CI, 1.555-2.970) and DFS (P=0.001; 95% CI, 1.978-2.444). Compared with the control, STMN1 downregulation significantly decreased cell migration, invasion and proliferation, whereas these were increased by STMN1 upregulation. STMN1 expression was significantly associated with prognosis and tumour differentiation in ESCC, indicating that STMN1 expression is an independent prognostic factor for ESCC and could be a potential biomarker. Regulating the expression of STMN1 could influence tumour cell motility, invasion and proliferation.

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

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.

Neoadjuvant chemoradiotherapy or chemotherapy? A comprehensive systematic review and meta-analysis of the options for neoadjuvant therapy for treating oesophageal cancer.

Neoadjuvant therapy followed by surgery is a standard treatment for locally advanced oesophageal cancer. However, the roles of neoadjuvant chemoradiotherapy and chemotherapy in treating oesophageal cancer remain controversial. In this comprehensive meta-analysis, we examine the efficacy of adding radiotherapy to neoadjuvant chemotherapy for treating oesophageal cancer as reported in qualified randomized controlled trials (RCTs). We conducted a systematic literature search using PubMed, Embase, Cochrane Library databases, Google Scholar and the American Society of Clinical Oncology database to identify relevant studies up to 31 March 2016. Data including the pathological complete response rate, R0 resection rate and 3-year survival rate were extracted and analysed. Five qualified RCTs were included with a total of 709 patients. Meta-analysis showed that neoadjuvant chemoradiotherapy significantly increases the rates of pathological complete response and R0 resection in patients with oesophageal adenocarcinoma or squamous cell carcinoma (SCC). However, we found a significantly increased 3-year survival rate only in oesophageal SCC patients treated with neoadjuvant chemoradiotherapy compared with neoadjuvant chemotherapy (56.8 and 42.8%, respectively); relative risk (RR): 1.31 [95% confidence interval (CI) 1.10-1.58, P = 0.003]. In oesophageal adenocarcinoma patients, no significant survival benefit of neoadjuvant chemoradiotherapy was found compared with neoadjuvant chemotherapy alone (46.3 and 41.0%, respectively; RR: 1.13, 95% CI 0.88-1.45, P = 0.34). Our meta-analysis adds to the evidence showing that neoadjuvant chemoradiotherapy should be the standard preoperative treatment strategy for locally advanced oesophageal SCC. For oesophageal adenocarcinoma, neoadjuvant chemotherapy alone may be the best preoperative treatment strategy to avoid the risk of adverse effects of radiotherapy.

Primary adenosquamous carcinoma of the esophagus: an analysis of 39 cases.

BACKGROUND: Adenosquamous carcinoma (ASC) of the esophagus is an uncommon type of malignant esophageal neoplasm containing both squamous cell carcinoma (SCC) and adenocacinoma (AC) components. The aim of this study was to explore the clinical characteristics and prognosis of esophageal ASC. METHODS: A retrospective review of esophageal ASC patients who underwent transthoracic esophagectomy with lymphadenectomy in our hospital from July 2007 to April 2014. RESULTS: A total of 39 (1.0%) esophageal ASC patients among 3855 patients with esophageal cancers were collected to analyze. There were 34 men and 5 women with a median age of 61.0 years (range from 39-85). Median follow-up time was 30.0 months and median survival time was 44.4 months. The 1-, 3- and 5-year overall survival rates were 82.1%, 51.6% and 37.5%, respectively. Compared to esophageal SCC and AC, there were no significant difference in survive time (P=0.616). Thirty five (92.1%) of the 38 patients who underwent preoperative endoscopic biopsy were misdiagnosed, mostly as SCC. Fifteen patients (38.5%) were found to have lymph node metastasis. Thirty two patients (82.1%) had a poorly differentiated or undifferentiated tumor. According to the 2009 American Joint Committee on Cancer (AJCC) staging system for esophageal squamous cell carcinoma, 3 patients were at Stage I, 21 patients at Stage II and 15 patients at Stage III. In univariate analysis, pT stage, lymph node metastasis and pTNM Stage significantly influenced survive time. In multivariate analysis, however, only lymph node metastasis (P=0.003; 95% CI: 1.626-10.972) was found to be the independent prognostic factor. CONCLUSIONS: Primary ASC of the esophagus is a rare disease with difficultly to be histologically confirmed by endoscopic biopsy. The prognosis of esophageal ASC was no worse than esophageal SCC and AC. Lymph node metastasis is the most influent prognostic factor. The TNM staging system of esophageal SCC is applicable for esophageal ASC.

Positive esophageal proximal resection margin: an important prognostic factor for esophageal cancer that warrants adjuvant therapy.

BACKGROUND: Positive esophageal proximal resection margin (ERM+) following esophagectomy was considered as incomplete or R1 resection. The clinicopathological data and long-term prognosis of esophageal cancer (EC) patients with ERM+ after esophagectomy were still unknown. Therefore, the aim of this study was to assess the clinical significance of ERM+ and its therapeutic option. METHODS: From November 2008 to December 2014, 3,594 patients with histologically confirmed EC underwent radical resection in our department. Among them there were 37 patients (1.03%) who had ERM+. ERM+ was defined as carcinoma or atypical hyperplasia (severe or moderate) at the residual esophageal margin in our study. For comparison, another 74 patients with negative esophageal proximal resection margin (ERM-) were propensity-matched at a ratio of 1:2 as control group according to sex, age, tumor location and TNM staging. The relevant prognostic factors were investigated by univariate and multivariate regression analysis. RESULTS: In this large cohort of patients, the rate of ERM+ was 1.03%. The median survival time was 35.000 months in patients with ERM+, significantly worse than 68.000 months in those with ERM- (Chi-square =4.064, P=0.044). Survival in patients with esophageal residual atypical hyperplasia (severe or moderate) was similar to those with esophageal residual carcinoma. Survival rate in stage I-II was higher than that in stage III-IV (Chi-square =27.598, P=0.000) in ERM-; But there was no difference between the two subgroups of patients in ERM+. Furthermore, in those patients with ERM+, survival was better in those who having adjuvant therapy, compared to those without adjuvant therapy (Chi-square =5.480, P=0.019). And the average survival time which was improved to a well situation for ERM+ patients who have adjuvant therapy was 68.556 months which is comparable to average survival time (65.815 months) of ERM- for those patients who are at earlier stages. CONCLUSIONS: ERM+ after esophagectomy nowadays is of low incidence but still an important prognostic factor for patients with EC. Survival of ERM+ patients who have adjuvant therapy was improved to a well situation which is comparable to overall survival (OS) rate of ERM- for those patients who are at earlier stages.

Long noncoding RNAs are novel potential prognostic biomarkers for esophageal squamous cell carcinoma: an overview.

Esophageal squamous cell carcinoma (ESCC) still has a poor prognosis. The prognostic biomarkers of ESCC are not yet well established. Long noncoding RNAs (lncRNAs) have recently been intensively investigated in various cancers including ESCC, and are found to be closely correlated to ESCC. Dysregulated expression of lncRNAs was widely observed in ESCC tumor tissue and was closely related to the tumorigenesis and progression of ESCC. More and more studies have found that lncRNAs were significantly correlated with the prognosis and diagnosis of patients with ESCC. Therefore, all those accumulating evidence indicated that lncRNAs could serve as a prognostic biomarker of ESCC. In this, we summarized the relation between lncRNAs and ESCC as well as the potential biomarker role of lncRNAs in ESCC, especially the prognostic value of lncRNAs. Our current review highlighted the need of further studies to explore the biomarker functions as well as therapeutic values of lncRNAs in ESCC.

Neuroendocrine carcinoma of the esophagus: clinical characteristics and prognostic evaluation of 49 cases with surgical resection.

BACKGROUND: The clinicopathological features and optimum treatment of esophageal neuroendocrine carcinoma (NEC) are hardly known due to its rarity. Therefore, we conducted a retrospective study to analyze the clinical characteristics and prognosis of patients with surgically resected esophageal NEC. METHODS: We collected clinicopathological data on consecutive limited disease stage esophageal NEC patients who underwent esophagectomy with regional lymphadenectomy in West China Hospital from January 2007 to December 2013. RESULTS: A total of forty-nine patients were analyzed retrospectively. The mean age of the patients was 58.4±8.2 years with male predominance. Fifty-five percent of the esophageal NEC were located in the middle thoracic esophagus. Histologically, 28 (57.1%) patients were found to be small cell NECs. Fifty-one percent of the patients were found to have lymph node metastasis. According to the 2009 American Joint Committee on Cancer (AJCC) staging system for esophageal squamous cell carcinoma, 9 patients were at stage I, 21 patients stage II, and 19 patients stage III. Twenty-six patients (53.1%) received adjuvant therapy. After a median follow-up of 44.8 months [95% confidence interval (CI), 35.2-50.4 months], the median survival time of the patients was 22.4 months (95% CI, 14.0-30.8 months). The 1-year and 3-year survival rates for the whole cohort patients were 74.9% and 35.3%, respectively. In univariate analysis, TNM staging, lymph node metastasis and adjutant therapy significantly influenced survival time. In multivariate analysis, TNM staging was the only independent prognostic factor. CONCLUSIONS: Esophageal NEC has a poor prognosis. The 2009 AJCC TNM staging system for esophageal squamous cell carcinoma may also fit for esophageal NEC. Surgery combined with adjuvant therapy may be a good option for treating limited disease stage esophageal NEC. Further prospective studies defining the optimum therapeutic regimen for esophageal NEC are needed.

Non-intubated video-assisted thoracoscopic surgery under loco-regional anaesthesia for thoracic surgery: a meta-analysis.

OBJECTIVES: The short-term feasibility and safety of non-intubated video-assisted thoracoscopic surgery under loco-regional anaesthesia for thoracic surgery remains unknown. Therefore, we conducted a meta-analysis to provide evidence for the short-term efficacy and safety profile of non-intubated video-assisted thoracoscopic surgery under loco-regional anaesthesia for thoracic surgery. METHODS: We performed a systematic literature search in PubMed, Embase, Cochrane Library databases and Google Scholar, as well as American Society of Clinical Oncology to identify relevant studies comparing non-intubated video-assisted thoracoscopic surgery under loco-regional anaesthesia with conventionally intubated video-assisted thoracoscopic surgery under general anaesthesia, dated up to 31 August 2015. Data concerning global in-operating room time, hospital stays, rate of postoperative complications and perioperative mortality were extracted and analysed. We conducted a meta-analysis of the overall results and two subgroup analyses based on study design (a meta-analysis of randomized controlled trials and a second meta-analysis of observational studies). RESULTS: Four randomized controlled trials and six observational studies with a total of 1283 patients were included. We found that in the overall analysis, patients treated with non-intubated video-assisted thoracoscopic surgery under loco-regional anaesthesia achieved significantly shorter global in-operating room time [weighted mean difference = -41.96; 95% confidence interval (CI) = (-57.26, -26.67); P < 0.001] and hospital stays [weighted mean difference = -1.24; 95% CI = (-1.46, -1.02); P < 0.001] as well as a lower rate of postoperative complications [relative risk = 0.55; 95% CI = (0.40, 0.74); P < 0.001] than patients treated with intubated video-assisted thoracoscopic surgery under general anaesthesia. Subgroup meta-analyses based on study design achieved the same outcomes as overall analysis. In our meta-analysis, no perioperative mortality was observed in patients treated with non-intubated video-assisted thoracoscopic surgery under loco-regional anaesthesia. CONCLUSIONS: Non-intubated video-assisted thoracoscopic surgery under loco-regional anaesthesia for thoracic surgery proved to be feasible and safe. Future multicentre and well-designed randomized controlled trials with longer follow-up are needed to confirm and update the findings of our study, as well as the long-term efficacy of non-intubated video-assisted thoracoscopic surgery under loco-regional anaesthesia.

Refining the Nodal Staging for Esophageal Squamous Cell Carcinoma Based on Lymph Node Stations.

BACKGROUND: The current N category of the American Joint Committee on Cancer (AJCC) staging system for esophageal carcinoma is controversial and inapplicable for precise counting. We tested the classifiers used in the AJCC staging system and proposed a modification to this system based on the number of metastatic lymph node (LN) stations to better represent the survival characteristics of esophageal squamous cell carcinoma (ESCC) in the Chinese population. METHODS: Data from 1,351 patients with ESCC who underwent radical-intent surgical resection were reviewed. Univariate and multivariate analyses were performed to identify prognostic factors. The revised nodal categories are based on the number of metastatic LN stations. RESULTS: There was no significant difference in overall survival between patients with N2 disease and those with N3 disease (p = 0.103). Furthermore, according to the seventh edition of the AJCC staging system, no significant difference was found between stage IIIB and IIIC (p = 0.118). Based on a scatter plot, we revised the nodal classification into 4 categories: rN0 (no LN involvement), rN1 (1 station involved), rN2 (2-3 stations involved), and rN3 (≥ 4 stations involved). According to the revised nodal staging system, survival could easily be distinguished between patients in rN2 and rN3 (p = 0.001) groups and also between patients with modified stage IIIB disease and modified stage IIIC disease (p = 0.007). CONCLUSIONS: The nodal categories for ESCC should be based on the number of metastatic LN stations and be classified into the following 4 groups: N0 (no LN involvement), N1 (1 station involved), N2 (2-3 stations involved), and N3 (≥ 4 stations involved).