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Background: Currently, preoperative staging of esophageal adenocarcinoma (EAC) has modest reliability and accuracy for pT and pN stages prediction, which heavily affects overall survival. The interplay among immune checkpoints, oncogenes, and intratumoral and peritumoral immune infiltrating cells could be used to predict loco‐regional metastatic disease in early EAC. Methods: We prospectively evaluated immune markers expression and oncogenes status as well as intratumoral and peritumoral immune infiltrating cells populations in esophageal mucosa samples obtained from neoadjuvant therapy‐naïve patients who had esophagectomy for EAC. Results: Vascular invasion and high infiltration of lamina propria mononuclear cells resulted associated with nodal metastasis. Low infiltration of activated CD8+CD28+ T cells was observed in both intratumoral and peritumoral mucosa of patients with nodal metastasis. Low levels of CD69, MYD88, and TLR4 transcripts were detected in the intratumoral specimen of patients with lymph node involvement. Receiver operating characteristic curve analysis showed good accuracy for detecting nodal metastasis for all the markers tested. Significant lower infiltration of CD8 T cells and M1 macrophages and a lower expression of CD8A, CD8B, and TBX21 were found also in Esophageal Adenocarcinoma TCGA panCancer Atlas in the normal tissue of patients with nodal metastasis. Conclusions: Our data suggest that immune surveillance failure is the main driver of nodal metastasis onset. Moreover, nodal metastasis containment also involves the immune microenvironment of the peritumoral healthy tissue. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text Objective: To identify the most prevalent symptoms and those with greatest impact upon health-related quality of life (HRQOL) among esophageal cancer survivors. Background: Long-term symptom burden after esophagectomy, and associations with HRQOL, are poorly understood. Patients and Methods: Between 2010 and 2016, patients from 20 European Centers who underwent esophageal cancer surgery, and were disease-free at least 1 year postoperatively were asked to complete LASER, EORTC-QLQ-C30, and QLQ-OG25 questionnaires. Specific symptom questionnaire items that were associated with poor HRQOL as identified by EORTC QLQ-C30 and QLQ-OG25 were identified by multivariable regression analysis and combined to form a tool. Results: A total of 876 of 1081 invited patients responded to the questionnaire, giving a response rate of 81%. Of these, 66.9% stated in the last 6 months they had symptoms associated with their esophagectomy. Ongoing weight loss was reported by 10.4% of patients, and only 13.8% returned to work with the same activities. Three LASER symptoms were correlated with poor HRQOL on multivariable analysis; pain on scars on chest (odds ratio (OR) 1.27; 95% CI 0.97–1.65), low mood (OR 1.42; 95% CI 1.15–1.77) and reduced energy or activity tolerance (OR 1.37; 95% CI 1.18–1.59). The areas under the curves for the development and validation datasets were 0.81 ± 0.02 and 0.82 ± 0.09 respectively. Conclusion: Two-thirds of patients experience significant symptoms more than 1 year after surgery. The 3 key symptoms associated with poor HRQOL identified in this study should be further validated, and could be used in clinical practice to identify patients who require increased support. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemoradiotherapy (CTRT) can effectively downstage esophageal squamous cell carcinoma (SCC) in patients with locally advanced disease and prolonged survival have been observed in patients with a pathological complete response (ypCR). Aims and methods: This exploratory study aimed to identify immunological predictors of pCR after neoadjuvant CTRT within SCC microenvironment. The tumor regression after neoadjuvant therapy was measured according to the Mandard score system. Eighty‐eight consecutive patients with SCC of the thoracic esophagus who received neoadjuvant CTRT were included in this retrospective study. Inclusion criteria were neoadjuvant CTRT and the availability of representative histological samples taken at diagnosis. We investigated immunohistochemical expression of CD4, Tbet, FoxP3, CD8, CD80, PD‐L1, and PD‐1, in the pretreatment biopsies and correlated the immunohistochemical profiles to patients' outcomes. Results: After neoadjuvant CTRT, 23 patients had pCR, while 65 ones had partial response, stable disease or progression. PD‐L1 expression and CD8+ and CD4+ lymphocyte rate were significantly higher in patients who had ypCR compared to those who had not (10 (0‐55) vs 0 (0‐0), P = 0.004, 73 (36‐147) vs 21 (7‐47), P = 0.0006 and 39 (23‐74) vs 5 (0‐13), P < 0.0001 respectively). The accuracy of expression of PD‐L1+, CD8+, and CD4+ lymphocyte rate in identifying responders was AUC = 0.76 (P = 0.001), AUC = 0.81 (P = 0.0001) and AUC = 0.75 (P = 0.0001), respectively. Within the ypCR group, all patients with high infiltration of CD4+ T cell recurred/relapsed while only the 38.9% of those with low CD4+ T cell infiltration did the same (P = 0.058). Conclusions: PD‐L1 expression and CD8+ and CD4+ lymphocyte rate were predictive of ypCR after neoadjuvant CTRT for SCC of the thoracic esophagus with adequate accuracy. Furthermore, recurrence/relapse was associated with high level of CD4+ T cell infiltration. However, the small sample size prevented to draw definitive conclusions; further studies are necessary to evaluate the prognostic role of these markers. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate trends in patients' characteristics and comorbidities in esophageal cancer (EC) patients. Background: Identifying changing pattern is essential to understand and predict further changes and to plan surgical procedures and resource allocation. Methods: Trends in patients' characteristics and comorbidities were evaluated in 4440 EC patients at the Center for Esophageal Diseases in Padova, Italy, during 1980 to 2011. Joinpoint regression analysis was performed to evaluate trends and to estimate annual percentage changes (APCs). Results: During the study period, there has been a statistically significant increment of the rate of esophageal adenocarcinoma (APC 3.70). The rates of elderly and of asymptomatic patients increased over time (APCs 0.98 and 6.24), whereas the rates of malnutrition, alcoholic drinking, and gastric ulcer decreased (APCs -1.50, -1.72, and -5.20). Reflux rate increased until 1997 and decreased thereafter (APCs 6.96 and -4.48), whereas the rate of Barrett esophagus increased until 1992 (APC 35.84) and then leveled. The rates of patients with previous neoplasms increased over time (APCs 3.22 and 4.86). There have been significant changes in systemic comorbidities, with an increase of hypertension and cardiac disease (APCs 7.56 and 1.86) and a decrease of advanced liver disease and pulmonary disease (APCs -2.67 and -1.74). Conclusion: The current EC patient has more often an esophageal adenocarcinoma and is more frequently elderly, asymptomatic, a survivor of previous neoplasms, and a patient with hypertension and cardiac disease than 30 years ago. On the contrary, malnutrition, alcoholic drinking, gastric ulcer, pulmonary disease, and advanced liver disease decreased. [ABSTRACT FROM AUTHOR]

Background: Nodal skip metastasis is a prognostic factor in some sites of malignancies, but its role in esophageal cancer is still unclear. The present study aimed to investigate occurrence and effect of nodal skip metastases in thoracic esophageal squamous cell carcinoma.Methods: All 578 patients undergoing esophagectomy for thoracic esophageal squamous cell carcinoma at the Center for Esophageal Diseases located in Padova between January 1992 and December 2010 were retrospectively evaluated. Selection criteria were R0 resection, pathological M0 stage and pathological lymph node involvement. Patients receiving neoadjuvant therapy were excluded.Results: The selection identified 88 patients with lymph node involvement confirmed by pathological evaluation. Sixteen patients (18.2%) had nodal skip metastasis. Adjusting for the number of lymph node metastases, patient with nodal skip metastasis had similar 5-year overall survival (14% vs. 13%, p = 0.93) and 5-year disease free survival (14% vs. 9%, p = 0.48) compared to patients with both peritumoral and distant lymph node metastases. The risk difference of nodal skip metastasis was: -24.1% (95% C.I. -43.1% to -5.2%) in patients with more than one lymph node metastasis compared to those with one lymph node metastasis; -2.3% (95% C.I. -29.8% to 25.2%) in middle thoracic esophagus and -23.0% (95% C.I. -47.8% to 1.8%) in lower thoracic esophagus compared to upper thoracic esophagus; 18.1% (95% C.I. 3.2% to 33.0%) in clinical N0 stage vs. clinical N+ stage.Conclusions: Nodal skip metastasis is a common pattern of metastatic lymph involvement in thoracic esophageal squamous cell carcinoma. However, neither overall survival nor disease free survival are associated with nodal skip metastasis occurrence. [ABSTRACT FROM AUTHOR]

Background: Esophagectomy is contraindicated in case of advanced cancer (i.e., carcinomatosis, distant metastasis, and invasion of other organs). In some cases, preoperative imaging may fail to identify advanced neoplasm and esophagectomy is inappropriately planned. The aim of the study was to identify preoperative biomarkers of occult advanced disease that force surgeons to abort the planned esophagectomy. Methods: From 2008 to 2014, 244 consecutive patients were taken to the operative room to have esophagectomy for cancer in our department. All of them had blood test at admission and their preoperative biomarker data were retrieved. Their medical history was collected and the intraoperative findings and outcome were recorded. Non parametric tests, multiple regression analysis, and ROC curves analysis were performed. Results: In our study group, 14 (5.7 %) patients, scheduled for esophagectomy, were discovered to have occult advanced disease at laparotomy/laparoscopy or at thoracotomy. Six of them had peritoneal carcinomatosis, three had advanced tumor invading other organs, three had small liver metastasis, and two pleural carcinomatosis. In all these cases, esophagectomy was aborted and a feeding jejunostomy was placed. In patients with unresectable esophageal cancer, CA19.9 and CEA serum levels were significantly higher than patients who could have esophagectomy ( p < 0.001 and p = 0.003, respectively). CA19.9 and CEA resulted to be accurate biomarkers of occult advanced disease (AUC = 85 %, p < 0.001 and AUC = 73 %, p = 0.002, respectively). Conclusions: Preoperative CEA and CA19.9 serum levels should be taken in consideration when evaluating patients candidate to esophagectomy for esophageal cancer to prevent inappropriate laparotomy or thoracotomy. If any doubt arises minimally invasive exploration is warranted. [ABSTRACT FROM AUTHOR]

Chronic gastro-duodenal reflux in the esophagus is a major risk for intestinal metaplasia and Barrett’s adenocarcinoma. A role for chronic use of proton pump inhibitor (PPI) in the increased incidence of esophageal adenocarcinoma in Western countries has been previously suggested. The aim of this work was to study the effect of chronic administration of omeprazole (a proton pump inhibitor) per os in a model of reflux induced esophageal carcinogenesis. One week after esophago-gastro-jejunostomy, 115 Sprague-Dawley rats were randomized to receive 10 mg/Kg per day of omeprazole or placebo, 5 days per week. The esophago-gastric specimens were collected 28±2 weeks after randomization and analyzed in a blinded fashion. Mortality and esophageal metaplasia rates did not differ between the two groups (p = 0.99 for mortality, p = 0.36 for intestinal metaplasia and p = 0.66 for multi-layered epithelium). Gastric pancreatic acinar cell metaplasia (PACM) was more frequently observed in PPI-treated rats (p = 0.003). Severe ulcer lesions significantly prevailed in the placebo group (p = 0.03). Locally invasive esophageal epithelial neoplasia were observed in 23/39 PPI-treated versus 14/42 placebo-animals (p = 0.03). In conclusion, chronic omeprazole treatment improved the healing of esophageal ulcerative lesions. Locally invasive neoplastic lesions and PACM prevailed among PPI-treated animals. However, neither an effect on the overall mortality nor on the incidence of pre-neoplastic lesions was observed in this work. [ABSTRACT FROM AUTHOR]

Background The aims of this prospective study were to analyze the predictors of postoperative sleep disturbance after esophagectomy for cancer and to identify patients at risk for postoperative hypnotic administration. Methods Sixty two consecutive patients who underwent cancer-related esophagectomy were enrolled in this study from May 2011 to February 2012. Data about perioperative management, postoperative complications, ICU stay, and vasopressor, hypnotic, and painkiller administration were retrieved. The EORTC QLQ-C30 was used and global quality of life (QL2 item) and sleep disturbance (SL item) were the primary endpoints. Univariate and multivariate analyses were performed. Results Postoperative request of hypnotics independently predicted bad quality of life outcome. Sleep disturbance after esophagectomy was independently predicted by the duration of dopamine infusion in the ICU and the daily request of benzodiazepines. Even in this case, only sleep disturbance at diagnosis revealed to be an independent predictor of hypnotic administration need. ROC curve analysis showed that sleep disturbance at diagnosis was a good predictor of benzodiazepine request (AUC = 73%, P = 0.02). Conclusions The use of vasopressors in the ICU affects sleep in the following postoperative period and the use of hypnotics is neither completely successful nor lacking in possible consequences. Sleep disturbance at diagnosis can successfully predict patients who can develop sleep disturbance during the postoperative period. [ABSTRACT FROM AUTHOR]

Simple Summary: In the last decades, there has been a rapid increase in the incidence and prevalence of esophageal cancer in many countries around the world. Although several important risk factors have been identified, strong evidence-based preventive strategies are still lacking, and the prognosis of patients diagnosed with esophageal cancer remains poor, with an average survival rate of 5 years for only 20%. This review is an attempt to summarize the epidemiology and risk factors of EC and to highlight the unresolved aspects of current prevention strategies in order to plan more fruitful future initiatives aimed at ameliorating the disappointing prognosis of this kind of digestive tumor. In the last 30 years, we have witnessed a rapid increase in the incidence and prevalence of esophageal cancer in many countries around the word. However, despite advancements in diagnostic technologies, the early detection of this cancer is rare, and its prognosis remains poor, with only about 20% of these patients surviving for 5 years. The two major forms are the esophageal squamous cell carcinoma (ESCC), which is particularly frequent in the so-called Asian belt, and the esophageal adenocarcinoma (EAC), which prevails in Western populations. This review provides a summary of the epidemiological features and risk factors associated with these tumors. Moreover, a major focus is posed on reporting and highlighting the various preventing strategies proposed by the most important international scientific societies, particularly in high-risk populations, with the final aim of detecting these lesions as early as possible and therefore favoring their definite cure. Indeed, we have conducted analysis with attention to the current primary, secondary and tertiary prevention guidelines in both ESCC and EAC, attempting to emphasize unresolved research and clinical problems related to these topics in order to improve our diagnostic strategies and management. [ABSTRACT FROM AUTHOR]

Background Treatment of distal esophageal and gastroesophageal junction (GEJ) cancers is challenging. The therapy for these cancers mainly consist of (neo)adjuvant chemo(radio)therapy and surgery. There are different surgical approaches possible for these patients: transthoracic esophagectomy with a cervical anastomosis (McKeown) or an intrathoracic anastomosis (Ivor Lewis). However, there is no evidence which is the preferred approach in terms of oncology, morbidity and quality of life. The aim of this study was to investigate the difference in the long-term quality of life in patients undergoing McKeown (McK) versus Ivor Lewis (IL) esophagectomy in a tertiary referral center. Methods Consecutive patients after either McK or IL for distal oesophagus, GEJ or proximal gastric carcinoma were asked to fill in EORTC QLQ-C30 and EORTC QLQ-OG25 questionnaires to evaluate quality of life during the period of January 2014 – December 2017. EORTC QLQ-INFO25 quality of life questionnaire was used to evaluate information needs of patients in both groups. All answers with a long follow up (> 1 year) after surgery were analysed. Results In the McK group 62 and in the IL group 110 patients were included. Median follow up was 3 years for McK and 2 years for IL. Median age was 62,4 years. Cognitive functioning was significantly better in the IL group (P  = 0.038). Complaints of dyspnoe (P  = 0.004) and dysphagia (P  = 0.028) were significantly higher in the McK group. Patients after IL had significantly less trouble with eating with others (P  = 0.003), trouble with taste (P  = 0.032), chocking when swallowing (P  = 0.022) and trouble with talking (P  = 0.038). There was no significant difference in global health status or physical, role, social or emotional functioning. Furthermore there was no difference in symptoms of nausea, fatigue, pain, discomfort or information scores between McK and IL groups. Conclusion After a follow up of > 1 year no differences in global health status or physical, role, social or emotional functioning scales between McK and IL esophagectomy were found. However, significant differences in some symptom scales and cognitive functioning were observed in favor of IL. These findings should be taken into consideration when deciding between a McK and IL esophagectomy in patients where both procedures are feasible. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "What is the optimal management of dysphagia in metastatic esophageal cancer?," by W. C. Hanna and colleagues in the 2012 issue.

A letter to the editor is presented in response to the article "Intraoperative blood transfusion contributes to decreased long-term survival of patients with esophageal cancer," by Y. Komatsu and colleagues in the 2012 issue.