HER2/neu (ERBB2) expression and gene amplification correlates with better survival in esophageal adenocarcinoma.

BACKGROUND: HER2 (ERBB2 or HER2/neu) is a tyrosine-kinase increasing cell proliferation. Overexpression/amplification of HER2 is correlated with worse prognosis in solid malignancies. Consequently, HER2 targeting is established in breast and upper gastrointestinal tract cancer. There are conflicting data concerning the impact of HER2 overexpression on esophageal adenocarcinoma (EAC), as most studies do not differ between cancers of the esophagus/gastroesophageal junction and the stomach. The aim of this study was to analyze the expression/amplification of HER2 in EAC in correlation to clinicopathological data to verify its prognostic impact. METHODS: We analyzed 428 EAC patients that underwent transthoracic thoraco-abdominal esophagectomy between 1997 and 2014. We performed HER2 immunohistochemistry (IHC) according to the guidelines and fluorescence-in-situ-hybridization (FISH) for IHC score2+, using tissue micro arrays (TMA) with up to eight biopsies from the surface and infiltration area of a single tumor for evaluating HER2-heterogeneity and single-spot TMA. The HER2-status was correlated with clinicopathological data. RESULTS: HER2-positivity was found in up to 14.9% in our cohort (IHC score 3+ or IHC score 2+ with gene amplification) and demonstrated a significantly better overall survival (OS) in correlation to HER2-negative tumors (median OS 70.1 vs. 24.6 months, p = 0.006). HER2-overexpression was more frequently seen in lower tumor stages (pT1/pT2, p = 0.038), in the absence of lymphatic metastases (pN0/pN+, p = 0.020), and was significantly associated with better histological grading (G1/G2) (p = 0.041). CONCLUSION: We demonstrated a positive prognostic impact of HER2 overexpression in a large cohort of EAC, contrary to other solid malignancies including gastric cancer and breast cancer, but consistent to the results of a large study on EAC from 2012.

Outcome of Self-Expanding Metal Stents in the Treatment of Anastomotic Leaks After Ivor Lewis Esophagectomy.

BACKGROUND: Esophageal anastomotic leakages after Ivor Lewis esophagectomy are severe and life-threatening complications. We analyzed the outcome of using self-expanding metal stents (SEMS) in the treatment of postoperative leakage after esophagogastrostomy. METHODS: Seventy patients with esophageal anastomotic leakage after Ivor Lewis esophagectomy for esophageal cancer who had received SEMS treatment between January 2006 and December 2015 at our clinic were identified in this retrospective study. The patients were analyzed according to demographic characteristics, risk factors, leakage characteristics, stent characteristics, stent-related complications, sealing success rate and mortality. RESULTS: Over a 10-year period, 70 patients received SEMS as treatment for postoperative anastomotic leakage after esophagectomy. Technical success of esophageal stenting in anastomotic leakage was achieved in 50 out of 70 cases (71.4%). Sealing success rate was 70% (n = 49) with a median treatment of 28 days (range 7-87). In 20 patients (28.6%), stent-related complications, such as stenosis, dislocation, leakage persistence, perforation or esophagotracheal fistula occurred after the SEMS treatment. Sixty-one patients (87.1%) survived SEMS treatment of esophagogastric anastomotic leakage. Mean follow-up for all patients was 38 months (IQR 10-76), and no significant difference was found in a comparison of the long-term survival rate between patients with successful and unsuccessful SEMS treatment. CONCLUSIONS: The management of esophageal anastomotic leaks after Ivor Lewis esophagectomy with SEMS is effective, safe and technically feasible. Aggressive non-surgical management should be considered when developing a treatment plan for stenting.

Prognosis of patients with superficial T1 esophageal cancer who underwent endoscopic resection before esophagectomy-A propensity score-matched comparison.

BACKGROUND: The aim of this retrospective study was to compare the prognosis of patients with esophageal cancer after non-curative endoscopic resection (ER) followed by esophagectomy (ER + S) with that of patients after primary surgery (PS). METHODS: Between 2000 and 2015, 287 patients had esophagectomy for T1 esophageal cancer. 81 of these patients underwent at least one ER in curative intention before surgery (7 squamous cell carcinomas, 74 adenocarcinomas). Indications for esophagectomy were R1-resection, submucosal infiltration, multifocality, long-segment Barrett esophagus, recurrence, postinterventional stenosis or a combination of these factors. Using propensity-score matching with gender, age, year of diagnosis, tumor localization, mucosal/submucosal infiltration and histology, the clinicopathologic and survival data of these patients were compared to those of 81 patients after PS (median follow-up: 5.5 years). RESULTS: There were no significant differences between both groups concerning number of resected lymph nodes and percentage of nodal metastasis (9.3% total). 9% of esophagectomy specimens after ER showed pT2/pT3-tumors. The 5-year survival rate was 86% in the PS and 85% in the ER + S group (p = 0.498). The disease-free survival was 85% in patients with ER + S and 98% in PS (p < 0.005). The recurrence rate after esophagectomy was higher after ER + S compared to PS (p = 0.015). More than 3 months time delay between ER and surgery was associated with reduced survival, but only within the first postinterventional year. CONCLUSIONS: As the disease-free survival was inferior in the ER + S compared to the PS group the indication for ER, especially repeated ERs, should be restricted to cases with high expectation of success.

Glucose transporters 1, 3, 6, and 10 are expressed in gastric cancer and glucose transporter 3 is associated with UICC stage and survival.

BACKGROUND: Due to proliferation and increased metabolism, cancer cells have high glucose requirements. The glucose uptake of cells is influenced by a group of membrane proteins denoted the glucose transporter family (Glut-1 to -12). Whereas increased expression and a negative correlation with survival have been described for Glut-1 in several types of cancer, the impact of other glucose transporters on tumor biology is widely unknown. METHODS: In this retrospective study, gastric cancer specimens of 150 patients who underwent total gastrectomy between 2005 and 2010 were stained for Glut-1, -3, -6, and -10 by immunohistochemistry. Expression of Glut-1, -3, -6, and 10 was correlated to prognosis as well as clinical and pathological parameters. RESULTS: Glut-1, Glut-3, Glut-6, and Glut-10 were expressed in 22.0, 66.0, 38.0, and 43.3 % of the analyzed samples. Whereas Glut-1, -6, and -10 did not show a correlation with prognosis, positive staining for Glut-3 was associated with higher UICC stage and inferior prognosis. The mean overall survival was 38.6 months for Glut-3 positive patients, as compared to 51.2 months for Glut-3 negative patients (p < 0.05). Coexpression of two or more of the analyzed glucose transporters was correlated to inferior prognosis. Glut-3 and UICC stage were significant prognostic factors in multivariate analysis. CONCLUSIONS: All of the analyzed glucose transporters were expressed in a significant proportion of the gastric cancer samples. Glut-3 was associated with higher UICC stage and inferior prognosis. These findings are relevant to therapeutic approaches that target glucose metabolism as well as to imaging using radioactively labeled glucose.

Short-term outcome of Ivor Lewis esophagectomy following neoadjuvant chemoradiation versus perioperative chemotherapy in patients with locally advanced adenocarcinoma of the esophagus and gastroesophageal junction: a propensity score-matched analysis.

BACKGROUND: Patients with locally advanced esophageal or gastroesophageal adenocarcinoma benefit from multimodal therapy concepts including neoadjuvant chemoradiation (nCRT), respectively, perioperative chemotherapy (pCT). However, it remains unclear which treatment is superior concerning postoperative morbidity. METHODS: In this study, we compared the postsurgical survival (30-day/90-day/1-year mortality) (primary endpoint), treatment response, and surgical complications (secondary endpoints) of patients who either received nCRT (CROSS protocol) or pCT (FLOT protocol) due to esophageal/gastroesophageal adenocarcinoma. Between January 2013 and December 2017, 873 patients underwent Ivor Lewis esophagectomy in our high-volume center. 339 patients received nCRT and 97 underwent pCT. After 1:1 propensity score matching (matching criteria: sex, age, BMI, ASA score, and Charlson score), 97 patients per subgroup were included for analysis. RESULTS: After matching, tumor response (ypT/ypN) did not differ significantly between nCRT and pCT (p = 0.118, respectively, p = 0.174). Residual nodal metastasis occurred more often after pCT (p = 0.001). Postsurgical mortality was comparable within both groups. No patient died within 30 or 90 days after surgery while the 1-year survival rate was 72.2% for nCRT and 68.0% for pCT (p = 0.47). Only grade 3a complications according to Clavien-Dindo were increased after pCT (p = 0.04). There was a trend towards a higher rate of pylorospasm within the pCT group (nCRT: 23.7% versus pCT: 37.1%) (p = 0.061). Multivariate analysis identified pCT, younger age, and Charlson score as independent variables for pylorospasm. CONCLUSION: Both nCRT and pCT are safe and efficient within the multimodal treatment of esophageal/gastroesophageal adenocarcinoma. We did not observe differences in postoperative morbidity. However, functional aspects such as gastric emptying might be more frequent after pCT.

Self-Expanding Metal Stents Versus Endoscopic Vacuum Therapy in Anastomotic Leak Treatment After Oncologic Gastroesophageal Surgery.

BACKGROUND: Anastomotic leak after gastroesophageal surgery is a life-threatening complication. Self-expanding metal stent (SEMS) implantation or endoscopic vacuum therapy (EVT) have been established as alternatives to reoperation. This study compares the outcome of both interventions for anastomotic leak clinical management. METHODS: In this retrospective study, we identified all patients who received SEMS or EVT for anastomotic leaks after oncological gastroesophageal surgery between January 2007 and December 2016. Only patients with type II leaks according to the Esophagectomy Complications Consensus Group were included. Sealing rates, intervention-related complications, demographic characteristics, clinical history, leak characteristics, therapy duration, and in-hospital mortality were analyzed. RESULTS: One hundred eleven patients who received SEMS (n = 76) or EVT (n = 35) were identified and categorized by primary and final treatment. The overall closure rate in the final treatment analysis was 85.7% for EVT and 72.4% for SEMS (p = 0.152). ICU stay ranged from 0 to 60 days (median 6 days) for EVT and from 0 to 295 days (median 9 days) for SEMS (p = 0.704). EVT patients were hospitalized for 19-119 days (median 39 days) and SEMS patients for 13-296 days (median 37 days; p = 0.812). Demographic factors, comorbidities, and surgical parameters did not correlate with treatment or treatment success. CONCLUSIONS: SEMS and EVT show comparable results for anastomotic leak management after oncologic gastroesophageal surgery. No superior outcome could be found for either one of the two treatments options.

Upregulation of miR-17-92 cluster is associated with progression and lymph node metastasis in oesophageal adenocarcinoma.

The occurrence of lymph node metastasis (LNM) and depth of tumour infiltration are significant prognostic factors in oesophageal adenocarcinoma (OAC), however no reliable prognostic biomarkers have been established so far. Aim of this study was to characterize microRNAs (miRs) of OAC patients, who primarily underwent oesophagectomy, in order to identify specific alterations during tumour progression and LNM. MicroRNA array-based quantification analysis of 754 miRs, including tumour specimens of 12 patients with pT2 OAC from three different centres (detection group), was performed. We identified miR-17, miR-19a/b, miR-20a, and miR-106a, showing the best predictive power for LNM. These miRs were validated by quantitative real time-PCR (qRT-PCR) in 43 patients with different tumour stages (pT1: n = 21; pT2: n = 12 and pT3: n = 10) (training group) (p < 0.05), demonstrating that increasing levels of identified miRs were associated with advanced depth of tumour infiltration. These findings were verified in another independent group of 46 pT2 OAC patients (validation group). Quantitative RT-PCR analysis of the miR-panel confirmed these results except for miR-19a (p < 0.05 each). Logistic regression analysis identified miR-17 and miR-20a (p = 0.025 and p = 0.022, respectively) to be independent variables for prediction of LNM. The mathematical prediction model was used in the validation group, and the estimated prognosis was compared to the actual postsurgical follow-up. This comprehensive data demonstrated the importance of miR-17-92 cluster and miR-106a for progression as well as LNM in OAC indicating that those might be feasible prognostic biomarkers.

Somatic alterations in circulating cell-free DNA of oesophageal carcinoma patients during primary staging are indicative for post-surgical tumour recurrence.

Oesophageal cancer (OC) has high mortality. This study aims at determining the feasibility of liquid biopsies for genomic profiling in early stage OC, comparing two different technologies for mutational analysis in circulating cell -free DNA (ccfDNA) and evaluating the clinical impact of these somatic alterations during primary staging. In 25 patients with locally advanced OC, endoscopic tumour biopsies and simultaneous blood samples were taken during primary staging. Genomic DNA from biopsies and ccfDNA were analysed for mutations using a 12 gene panel next-generation sequencing (NGS) assay as well as digital droplet PCR (ddPCR). Genetic data was correlated with patients' outcome. In 21 of the tested biopsies (84%) at least one somatic mutation was detected by NGS. Mutations detected by NGS were detectable by ddPCR with similar allele frequencies. In three out of the 21 patients with proven mutations, the same mutations were also detectable in ccfDNA using NGS (14%). In contrast, ddPCR detected mutations in ccfDNA of five additional patients (8/21, 38%). Post-surgical outcome analysis was performed for those patients who had received complete tumour resection (n = 16). Five of them suffered from an early relapse within the first year after surgery, including four with detectable somatic mutations in ccfDNA during primary staging. Taken together, we showed a higher sensitivity for ddPCR compared to NGS in detecting mutated ccfDNA in OC. Detection of somatically altered ccfDNA during primary staging seems to be indicative for post-surgical tumour recurrence.