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Purpose: This study explored the association between triglyceride-glucose (TyG), TyG index with body mass index (TyG-BMI), triglyceride/high-density lipoprotein cholesterol ratio (TG/HDL-C), metabolic score for insulin resistance (IR) (METS-IR) and the risk of esophageal cancer., Methods: A total of 388,900 participants from the United Kingdom Biobank from 2006 to 2010 were included. Fine-Gray models, restricted cubic spline (RCS), and receiver operating characteristic (ROC) curves were used to assess the association between the four IR surrogates and the risk of esophageal cancer, specifically, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC)., Results: Ten years after recruitment, 0.16% (95%CI 0.11-0.26%) had esophageal cancer and 4.17% (95%CI 3.86-4.46%) are deceased. For each standard deviation increase in the TyG index, TyG-BMI, TG/HDL-C, and METS-IR, the risk of EAC increased by Hazard ratios (HR)1.16, 1.37, 1.08, and 1.36, respectively (all P < 0.05), while the risk of ESCC decreased by HRs 0.80, 0.67, 0.77, and 0.65, respectively. RCS analysis indicated that most relationships were nonlinear (P < 0.05). ROC curves showed that METS-IR had a more robust diagnostic efficacy than TyG, TyG-BMI, and TG/HDL-C., Conclusion: TyG index, TyG-BMI, TG/HDL-C, and METS-IR were closely associated with the risk of EAC and ESCC. Additionally, METS-IR surpassed the other three IR indices in predicting and diagnosing the risks of EAC and ESCC. The METS-IR is expected to become a more effective metric for identifying populations at early risk of esophageal cancer and for improving risk stratification., (© 2024. The Author(s).)

Objective: To establish the life expectancy burden of esophago-gastric cancer by analyzing years of life lost (YLL) for a Western patient population after treatment of early esophageal (EAC) or early gastric (GAC) adenocarcinoma., Background: For patients with early EAC or GAC, the short-term prognosis after surgical resection is very good. Little data is available regarding long-term prognosis when compared to the general population., Methods: Two hundred and fourteen patients with pT1 EAC (n = 112) or GAC (n = 102) were included in the study. Patients with EAC underwent transthoracic en-bloc esophagectomy; those with GAC had total or subtotal gastrectomy with D2-lymphadenectomy. Surviving patients had a median follow-up of approximately 14 years. YLL was calculated using average life expectancy data from Germany., Results: Patients with EAC were younger (median age 61 years) than those with GAC (66 years) (p = 0.031). The male:female ratio was 10:1 for EAC and 3:2 for GAC (p < 0.001). Multivariate survival analysis showed the age of the patients ≥60 years and the existence of lymph node metastasis was associated with poor prognosis. The median YLL for all patients who died over follow-up was 8.0 years. For patients under 60 years, it was approximately 20 years, and for older patients, approximately 5 years (p < 0.001) without difference in tumor stage between these age cohorts. YLL did not differ for GAC vs. EAC., Conclusion: After surgical resection, the prognostic burden as measured by YLL is relevant for all patients with early esophageal and gastric adenocarcinomas and especially for younger patients. Reasons for YLL need further studies., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The question of the ideal neoadjuvant therapy for locally advanced esophagogastric adenocarcinoma has not been answered to date. Multimodal treatment has become a standard treatment for these adenocarcinomas. Currently, perioperative chemotherapy (FLOT) or neoadjuvant chemoradiation (CROSS) is recommended., Methods: A monocentric retrospective analysis compared long-term survival after CROSS versus FLOT. The study enrolled patients with adenocarcinoma of the esophagus (EAC) or the esophagogastric junction type I or II undergoing oncologic Ivor-Lewis esophagectomy between January 2012 and December 2019. The primary objective was to determine the long-term outcome in terms of overall survival. The secondary objectives were to determine differences regarding the histopathologic categories after neoadjuvant treatment and the histomorphologic regression., Results: The findings showed no survival advantage for one or the other treatment in this highly standardized cohort. All the patients underwent open (CROSS: 9.4% vs. FLOT: 22%), hybrid (CROSS: 82% vs. FLOT: 72%), or minimally invasive (CROSS: 8.9% vs. FLOT: 5.6%) thoracoabdominal esophagectomy. The median post-surgical follow-up period was 57.6 months (95% confidence interval [CI] 23.2-109.7 months), and the median survival was longer for the CROSS patients (54 months) than for the FLOT patients (37.2 months) (p = 0.053). The overall 5-years survival was 47% for the entire cohort (48% for the CROSS and 43% for the FLOT patients). The CROSS patients showed a better pathologic response and fewer advanced tumor stages., Conclusion: The improved pathologic response after CROSS cannot be translated into longer overall survival. To date, the choice of which neoadjuvant treatment to use can be made only on the basis of clinical parameters and the patient's performance status., (© 2023. The Author(s).)

Purpose: Diagnosis and treatment of gastric and gastroesophageal junction cancer have undergone many critical changes during the last two decades. We addressed the question of how clinical reality outside of clinical trials has changed for gastric and gastroesophageal junction cancer patients in a European center for upper gastrointestinal surgery., Methods: In this retrospective cohort study, patients undergoing (sub)total gastrectomy for gastric or gastroesophageal junction adenocarcinoma between 1996 and 2017 in a tertiary upper gastrointestinal center were included. The time was divided into a) before (1996-2006) (pre-CTx) and b) after (2006-2017) (CTx) the MAGIC trial. Data were comprehensively analyzed for demographics, tumor stage, perioperative treatment, surgery, histopathology, and survival rates (SR)., Results: 737 patients (32% female) underwent gastrectomy, 255 patients in the pre-CTx era and 482 patients in the CTx era. The median age was 65 years and the median follow-up was 27.5 months for surviving patients. Around 16.9% of patients received neoadjuvant treatment in the pre-CTx era versus 46.3% in the CTx era. The 3-year survival rate (3-YSR) was 46.4% in the pre-CTx and 60.9% in the CTx era (p < 0.001). For pretreated patients, 3-YSR was 39.0% (pre-CTx) versus 55.3% (CTx) (p = 0.168). Survival rate (SR) for locally advanced tumor stages (cT3/cT4) was higher when neoadjuvant therapy was administered (3-YSR: 56.7% vs 40.6%; p = 0.022). There were no significant differences according to sex (p = 0.357), age (p = 0.379), pT category (p = 0.817), pN stage (p = 0.074), cM stage (p = 0.112), Laurén classification (p = 0.158), and SRs (3-YSR: 60.3% vs 59.4%; p = 0.898) between the MAGIC and FLOT regimens., Conclusions: Survival rates have dramatically improved for gastric cancer patients during the last two decades. MAGIC and FLOT regimens showed similar results in the postsurgical follow-up., (© 2023. The Author(s).)

Background: Endoscopic vacuum therapy (EVT) has become an established procedure for the treatment of anastomotic leaks (AL) in upper gastrointestinal surgery. A novel approach is the use of EVT for preventing leaks in high-risk anastomosis. The aim of this study was to analyze the outcome of prophylactic EVT (pEVT) in patients receiving surgical revision of the anastomosis after oncological Ivor-Lewis esophagectomy (ILE) due to AL. Material and methods: Between June 2016 and February 2019, all patients who underwent anastomotic revision after ILE due to a confirmed AL were included. The primary outcome was the success rate of pEVT, which was defined as absence of an AL after revision. Secondary outcome parameters were duration of treatment, inflammatory levels, and ICU/hospital stay. Results: Twenty-one patients underwent anastomotic revision due to an AL. The cause of the AL was ischemia in nine patients (42.9%) and non-ischemia (other) in 12 patients (57.1%). PEVT was performed in 14 patients (66.6%). The overall success rate of pEVT was five out of 14 patients (35.7%). Conclusions: Prophylactic EVT cannot prevent a re-leak in patients with high-risk anastomosis due to surgical revision of an AL after oncological ILE. However, pEVT might help to control the clinical condition of these patients.

Introduction: Despite modern multimodal therapeutic regimens, the prognosis of esophageal adenocarcinoma (EAC) is still poor and there is a lack of biological markers estimating the patients' prognosis. Fructose-1,6-biphosphatase (FBP1) is a key enzyme in gluconeogenesis and is associated with tumor initiation in several cancers. Therefore, this study aims to characterize its implication for EAC patients., Methods and Materials: A total of 571 EAC patients who underwent multimodal treatment between 1999 and 2017 were analyzed for FBP1 expression using immunohistochemistry., Results: 82.5% of the EACs show FBP1 expression in the tumor albeit with different intensities categorizing specimens accordingly into score 0 (no expression), score 1 (weak expression), score 2 (moderate expression) and score 3 (strong expression) (score 1 = 25.0%, score 2 = 35.9%, score 3 = 21.5%). Intratumoral FBP1 expression was significantly associated with a better prognosis (p = 0.024). This observation was particularly relevant among patients who received primary surgery without neoadjuvant treatment (p = 0.004). In multivariate analysis, elevated FBP1 expression was an independent biomarker associated with a favorable prognosis., Discussion: Despite being associated with a favorable prognosis, the majority of patients with high FBP1 expression also require individualized therapy options to ensure long-term survival. Recently, it has been shown that the presence of the FBP1 protein increases the sensitivity of pancreatic cancer cells to the bromodomain and extraterminal domain (BET) inhibitor JQ1., Conclusion: We described for the first time the prognostic and possibly therapeutic relevance of FBP1 in EAC. The efficiency of the BET inhibitor in EAC should be verified in clinical studies and special attention should be paid to the effects of neoadjuvant therapy on FBP1 expression., (© 2022. The Author(s).)

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., (© 2021. The Author(s).)

Background: In the recent past tumors of the upper gastrointestinal (GI) tract, e.g. esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC) and gastric adenocarcinoma, have been increasingly characterized by molecular genetics. The resulting subtypes provide potential targets for novel targeted treatment based on the biological characteristics., Objective: This article summarizes the current state of molecular subtyping in all three tumor entities and the individualized treatment strategies derived from these categories are discussed., Material and Methods: A selective literature search was performed focusing on molecular subtyping, current targeted treatment and the impact on the oncological treatment concepts. Databases such as PubMed were used., Results: Based on molecular characteristics ESCC is nowadays categorized into three subtypes. Genetically, at least one subgroup resembles oropharyngeal carcinomas rather than those of the upper GI tract. In contrast, EAC is characterized by its high tumor burden and large chromosomal instability. In gastric carcinoma 4 subtypes are distinguished: 1) Epstein-Barr virus (EBV) positive, 2) microsatellite instability (MSI), 3) genomically stable (GS) and 4) chromosomally unstable (CIN) tumors., Conclusion: To date, only a few targeted therapeutic options have been successfully transferred into daily routine derived from the genetic characterization of the three tumor entities. These include selective ERBB2 inhibition, immunotherapy using PD-L1 inhibition or combined blockade of ERBB2/VEGF., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Abstract: Self-expanding metal stents (SEMSs) in different geometric shapes are an established palliative treatment for malignant tumors of the esophagus. Mechanical properties and stent design have an impact on patient comfort, migration rate, and removability. SEMS with a segmented design (segSEMS) have recently become available on the market, promising new biomechanical properties for stent placement in benign and malignant esophageal diseases. In this study, we evaluated recurrent dysphagia, quality of life as well as technical success and complications for segmented SEMS-implantation in a retrospective study in palliative patients with dysphagia caused by malignant tumors of the esophagus.Between May 2017 and December 2018, patients presented to the interdisciplinary department of endoscopy of the University Hospital Cologne underwent segmented SEMS placement for malignant dysphagia. Patient follow-up was evaluated, and complications were monitored. Quality of life and functional improvement were monitored using the EORTC QLQ-C30 and QLQ-OE18.A total of 20 consecutive patients (16 men, 4 women; mean age: 65.5, range: 46-82) participated in the study and were treated with 20 segSEMS in total. The success rate of stent placement was 100%. Stent migration occurred in 3 patients (15.0%). Insertion of segSEMS immediately lead to a 48.0% reduction of dysphagia in the first 2 months (P < .001). Pain while eating (odynophagia) could also be significantly reduced by 39.6% over the first 2 months (P < .001).Implantation of segSEMS is a feasible and effective treatment for dysphagia in palliative patients with malignant tumors of the esophagus, offering immediate relief of symptoms and gain of physical functions., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Within the framework of the quality initiative of the German Society for General and Visceral Surgery (DGAV) a review article was compiled based on a systematic literature search. Recommendations for the current diagnostics and treatment of esophageal cancer were also elaborated., Methods: The systematic literature search was carried out in March 2019 according to the PRISMA criteria using the MEDLINE databank. The recommendations were formulated based on a consensus in the DGAV., Results and Conclusion: Operations below the currently valid minimum quantity threshold should no longer be carried out. There are many indications that the minimum quantity in Germany should be raised to ≥20 resections/year/hospital in order to comprehensively improve the quality. Prehabilitation programs with endurance, strength and intensive breathing training as well as nutritional therapy improve patient outcome. The current treatment of esophageal cancer is stage-dependent and incorporates endoscopic resection of (sub)mucosal low-risk tumors (T1m1-3 or T1sm1 low risk), primary esophagectomy of submucosal high-risk tumors (T1a), submucosal cancer (T1sm2-3) and T2N0 tumors, multimodal treatment with neoadjuvant chemoradiotherapy or perioperative chemotherapy and operations for advanced stages. Esophagectomy is nowadays carried out in one stage as a so-called hybrid procedure (laparoscopy and muscle-preserving thoracotomy) or as a total minimally invasive operation (laparoscopy and thoracoscopy).

Purpose: Driver mutations are typically absent in esophageal adenocarcinoma (EAC). Mostly, oncogenes are amplified as driving molecular events (including GATA6-amplification in 14% of cases). However, only little is known about its biological function and clinical relevance., Methods: We examined a large number of EAC (n = 496) for their GATA6 amplification by fluorescence in situ hybridization (FISH) analyzing both primary resected (n = 219) and neoadjuvant treated EAC (n = 277). Results were correlated to clinicopathological data and known mutations/amplifications in our EAC-cohort., Results: GATA6 amplification was detectable in 49 (9.9%) EACs of our cohort. We observed an enrichment of GATA6-positive tumors among patients after neoadjuvant treatment (12,3% amplified tumors versus 6,8% in the primary resected group; p = 0.044). Additionally, there was a simultaneous amplification of PIK3CA and GATA6 (p < 0.001) not detectable when analyzing other genes such as EGFR, ERBB2, KRAS or MDM2. Although we did not identify a survival difference depending on GATA6 in the entire cohort (p = 0.212), GATA6 amplification was associated with prolonged overall survival among patients with primary surgery (median overall-survival 121.1 vs. 41.4 months, p = 0.032). Multivariate cox-regression analysis did not confirm GATA6 as an independent prognostic marker, neither in the entire cohort (p = 0.210), nor in the subgroup with (p = 0.655) or without pretreatment (p = 0.961)., Conclusions: Our study investigates the relevance of GATA6 amplification on a large tumor collective, which includes primary resected tumors and the clinically relevant group of neoadjuvant treated EACs. Especially in the pretreated group, we found an accumulation of GATA6-amplified tumors (12.3%) and a frequent co-amplification of PIK3CA. Our data suggest an increased resistance to radio-chemotherapy in GATA6-amplified tumors.

Esophageal cancer (EC) is an aggressive form of cancer, including squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) as two predominant histological subtypes. Accumulating evidence supports the existence of cancer stem cells (CSCs) able to initiate and maintain EAC or ESCC. In this review, we aim to collect the current evidence on CSCs in esophageal cancer, including the biomarkers/characterization strategies of CSCs, heterogeneity of CSCs, and the key signaling pathways (Wnt/β-catenin, Notch, Hedgehog, YAP, JAK/STAT3) in modulating CSCs during esophageal cancer progression. Exploring the molecular mechanisms of therapy resistance in EC highlights DNA damage response (DDR), metabolic reprogramming, epithelial mesenchymal transition (EMT), and the role of the crosstalk of CSCs and their niche in the tumor progression. According to these molecular findings, potential therapeutic implications of targeting esophageal CSCs may provide novel strategies for the clinical management of esophageal cancer.

Single-cell transcriptomics have revolutionized our understanding of the cell composition of tumors and allowed us to identify new subtypes of cells. Despite rapid technological advancements, single-cell analysis remains resource-intense hampering the scalability that is required to profile a sufficient number of samples for clinical associations. Therefore, more scalable approaches are needed to understand the contribution of individual cell types to the development and treatment response of solid tumors such as esophageal adenocarcinoma where comprehensive genomic studies have only led to a small number of targeted therapies. Due to the limited treatment options and late diagnosis, esophageal adenocarcinoma has a poor prognosis. Understanding the interaction between and dysfunction of individual cell populations provides an opportunity for the development of new interventions. In an attempt to address the technological and clinical needs, we developed a protocol for the separation of esophageal carcinoma tissue into leukocytes (CD45+), epithelial cells (EpCAM+), and fibroblasts (two out of PDGFRα, CD90, anti-fibroblast) by fluorescence-activated cell sorting and subsequent RNA sequencing. We confirm successful separation of the three cell populations by mapping their transcriptomic profiles to reference cell lineage expression data. Gene-level analysis further supports the isolation of individual cell populations with high expression of CD3, CD4, CD8, CD19, and CD20 for leukocytes, CDH1 and MUC1 for epithelial cells, and FAP, SMA, COL1A1, and COL3A1 for fibroblasts. As a proof of concept, we profiled tumor samples of nine patients and explored expression differences in the three cell populations between tumor and normal tissue. Interestingly, we found that angiogenesis-related genes were upregulated in fibroblasts isolated from tumors compared with normal tissue. Overall, we suggest our protocol as a complementary and more scalable approach compared with single-cell RNA sequencing to investigate associations between clinical parameters and transcriptomic alterations of specific cell populations in esophageal adenocarcinoma., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

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.

Background: Molecular markers predicting survival in esophageal adenocarcinoma (EAC) are rare. Specifically, in favorable oncologic situations, e.g. nodal negativity or major neoadjuvant therapy response, there is a lack of additional risk factors that serve to predict patients' outcome more precisely. This study evaluated X-linked inhibitor of apoptosis protein (XIAP) as a potential marker improving outcome prediction., Methods: Tissue microarrays from 362 patients that were diagnosed with resectable EAC were included in the study. XIAP was stained by immunohistochemistry and correlated to clinical outcome, molecular markers and markers of the cellular tumor microenvironment., Results: XIAP did not impact on overall survival (OS) in the whole study collective. Subgroup analyses stratifying for common genetic markers (TP53, ERBB2, ARID1A/SWI/SNF) did not disclose any impact of XIAP expression on survival. Detailed subgroup analyses of [1] nodal negative patients, [2] highly T-cell infiltrated tumors and [3] therapy responders to neoadjuvant treatment revealed a significant inverse role of high XIAP expression in these specific oncologic situations; elevated XIAP expression detrimentally affected patients' outcome in these subgroups. [1]: OS XIAP low: 202 months (m) vs. XIAP high: 38 m; [2]: OS 116 m vs. 28.2 m; [3]: OS 31 m vs. 4 m)., Conclusions: Our data suggest XIAP expression in EAC as a worthy tool to improve outcome prediction in specific oncologic settings that might directly impact on clinical diagnosis and treatment of EAC in the future.

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.

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.

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.

Background: The impact of total minimally invasive esophagectomy (MIE) on early postoperative outcome and patient's survival is a matter of recent discussion., Methods: We performed a 1:2 propensity score-matched comparison of 20 patients who underwent 3D-MIE and high intrathoracic esophagogastrostomy with 40 patients who underwent hybrid esophagectomy (HYBRID) with laparoscopic gastric mobilization and open transthoracic esophagectomy and the same anastomosis for esophageal adenocarcinoma in 2014 and 2015. Matching criteria were tumor localization, age, gender, and neoadjuvant treatment., Results: Both groups did not differ regarding overall postoperative complications (MIE 55% vs. HYBRID 50%, p = 0.715) and anastomotic leakage (MIE 15% vs. HYBRID 5%, p = 0.186). A significant difference was seen regarding the rate of postoperative pneumonia (MIE 5% vs. HYBRID 27.5%; p = 0.040) and the postoperative ICU stay (MIE median 1 day vs. HYBRID median 2 days, p < 0.001). The R0-resection rate was 100% in both groups and median number of dissected lymph nodes was 32 for MIE and 35 for HYBRID (p = 0.236). Significant differences between both groups were noticed for postoperative number of patients with use of opiate demand medication and numeric rating scale for pain (NRSP maximum pain, median) both in favor of the MIE group (MIE 25%, NRSP 2 vs. HYBRID 60%, NRSP 4; p = 0.011, p < 0.001). Overall 2-year survival rate was 85% in both groups., Conclusion: Total minimally invasive esophagectomy is superior to hybrid esophagectomy in regard of postoperative pain and rate of pneumonia. No differences exist for postoperative surgical complications or short-term prognosis.

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.

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.

Purpose: Therapeutic decisions in esophageal adenocarcinomas (EAC) restricted to mucosa (pT1a) or submucosa (pT1b) depend mainly on classic histomorphology-based criteria like tumor grading or lymphovascular invasion with limited success. There is a strong need for reliable pre-therapeutical biomarker-based evaluation also applicable on endoscopically obtained biopsies., Methods: Patients who underwent esophagectomy due to EAC in a high volume center between 1999 and 2016 were included. Tissue microarrays (TMA) were retrospectively established from the formalin-fixed and paraffin-embedded material of the resected specimens and immunohistochemically stained using a monoclonal primary antibody specific for IMP3. IMP3 staining intensity was scored manually according to a 3-tier-scoring system (negative, weak and strong)., Results: 371 EACs were interpretable for analysis. 109 patients (29%) had early invasive (pT1a/pT1b) and 262 patients (71%) locally advanced EAC (> pT2). 259 EACs (70%) revealed positive immunostaining for IMP3 including 167 strongly and 92 weakly positive. Early EAC had significantly lower IMP3 expression compared to advanced tumor stages (p < 0.0001). IMP3 positive pT1 EAC revealed higher levels of lymph node metastases (LNM) (p = 0.0001) and pT1b tumors showed higher rates of IMP3 positivity compared to pT1a (p = 0.007). Subdividing the submucosa in thirds, there was a significant trend for higher IMP3 expression with deeper tumor infiltration from pT1a to pT1b (sm3) (p = 0.0001). There was an association between IMP3 expression and shortened survival in pT1 EAC (p = 0.038)., Conclusions: IMP3 expression correlates with depth of tumor infiltration, rate of LNM and is associated with worse outcome. Thus, IMP3 might be useful for therapeutic decisions in early-invasive EAC.

Aims: The aim of this study was to identify molecular markers predicting depth of tumor infiltration and presence of lymph node metastasis in early esophageal cancer., Methods: Between 1996 and 2004, 67 patients with pT1 esophagus cancer underwent esophagectomy. Resected tumors and lymph nodes were analyzed by immunohistochemistry for tissue infiltration, lymph node metastasis (LNM), micrometastasis and extracapsular lymph node infiltration (ELNI). We focused on MMP-2 (matrix-metalloproteinase-2), TIMP-2 (tissue inhibitor of metalloproteinase-2), PIM-1 and survivin as the most promising marker candidates. The data was correlated with the patients' long term follow-up (median follow-up time 11.4 years)., Results: We found 22 pT1a and 45 pT1b carcinomas. None of the mucosal carcinomas, but 58% (26 patients) of the submucosal carcinomas showed lymph node metastasis or micrometastasis. The rate of LNM positively correlated with the depth of tumor infiltration (23% LNM in sm1 tumors and 82% LNM in sm3 tumors). Low grade PIM-1 expression (<30%) was significantly associated with occurrence of LNM (p=0.034) while high expression TIMP-2 (>70%) were detected in submucosal tumors. Logistic regression analysis revealed PIM-1 and Grading G3 as independent risk factors for LNM (p<0.001). Survival of patients with micrometastasis was comparable to those with LNM (median survival: 5.05 years versus 5.52 years). Patients with ELNI had the worst prognosis (median survival: 1.7 years)., Conclusions: PIM-1 is a promising marker for prediction of lymph node metastasis in early esophagus cancer. Extracapsular lymph node infiltration has an independent worse prognostic impact.

Introduction: This article provides an overview of actual biomarkers with an impact on improvement of diagnosis and treatment of esophageal cancer patients., Areas Covered: Recent literature has been analyzed and provides information regarding the potential role of molecular markers as a diagnostic or prognostic factor in esophageal cancer., Expert Opinion: Until now, the role of molecular markers is far from being firmly established for routine use and is not without obstacles. However, with reliable standardized methods, established cut-off values and promising candidates in marker panels with markers of genetic, epigenetic and proteomic origin might result in a marker tool worthwhile of being validated in large, prospective, randomized trials. Novel validated marker combinations have to be clinically applied to prove their putative role in complementing clinical techniques within the development of better detection concepts of esophageal cancer, improving patients' long-term prognosis by early and purposive therapy within individualized treatment concepts.

Background: There is an increasing trend to include patients with esophageal carcinoma invading the muscularis propria (pT2) in neoadjuvant therapy regimens. But it is unclear which patients have prognostic benefit from this strategy. The aim of this study was to assess the prognosis and prognostic factors in patients with pT2 esophageal adenocarcinoma to further optimize treatment strategies., Methods: Included were patients with pT2 esophageal adenocarcinoma treated operatively at three centers specializing in upper gastrointestinal surgery. There were 159 patients (139 male) without induction therapy; median age was 64.5 years. Survival was analyzed by univariate and multivariate analysis., Results: In 37% of patients (n = 59), no lymph node involvement (pN0) was detected. Overall 5-year survival rate for all patients was 37%; for pN0 patients it was 62%, and for patients with lymph node metastases (pN+) it was 24%. Median number of examined lymph nodes was 26. Extracapsular lymph node involvement (ELNI) was evident in 55 of 100 pN+ patients with a 5-year survival rate of 14%. Patients without ELNI had a 5-year survival rate of 36% (p = 0.041). Results were comparable in all participating hospitals. Thirty-day and 90-day mortality rates of the entire collective were 2.6% and 3.8%, respectively. Multivariate analysis of prognosis revealed the lymph node ratio (p < 0.001) and the pN-ELNI category (p = 0.005) as significant parameters (pN0 hazard ratio 1 [reference]; pN+ without ELNI hazard ratio 2.2, 95% confidence interval: 1.2 to 3.8); pN+ with ELNI hazard ratio 2.5, 95% confidence interval: 1.5 to 4.5)., Conclusions: The prognosis of patients with esophageal adenocarcinoma invading the muscularis propria without lymph node metastasis is very good. However, in this study, about 30% had extracapsular lymph node involvement, which reflects particularly aggressive biological tumor behavior., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)