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Background The aim of this study is to evaluate whether adenocarcinomas of the esophagogastric junction (AEG) are better staged as cancers of the esophagus (TNM-EC) or stomach (TNM-GC) according to the 8th edition of the UICC classification. Methods A single-center cohort of 246 patients operated on for AEG type II was staged according to the 8th edition of the UICC classification for esophageal and stomach cancer. Kaplan-Meier and univariate Cox regression analyses were performed to investigate the impact on survival. Results For AEG type II TNM-EC classified most of the patients (n = 126; 51.2%) to UICC stage IIIC and IVA while TNM-GC more evenly distributed the patients over the stages. Hazard ratios increased in between all stages in a stepwise manner except between stage IA and IIA for TNM-EC and between stage IIB and IIIA for TNM-GC. Survival curves for TNM-GC demonstrated significant differences between all four major UICC stages, while in TNM-EC no significant difference between stage I and II was found. When comparing the area under the curves of both staging systems a marginal superiority for TNM-EC was found. Conclusion Neither the esophageal nor the stomach staging system is flawless in predicting survival in AEG type II. A marginal superiority of the TNM-EC was found in discriminating survival rates after three and five years. However, the advantage of the TNM-GC lies in the division of the N3 category into N3a and N3b. We therefor suggest a similar division in future TNM-EC classifications to improve its prognostic value.

// Karl-Frederick Karstens 1 , Eugen Bellon 1 , Adam Polonski 1 , Gerrit Wolters-Eisfeld 1 , Nathaniel Melling 1 , Matthias Reeh 1 , Jakob R. Izbicki 1 and Michael Tachezy 1 1 Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg Eppendor, Hamburg, Germany Correspondence to: Karl-Frederick Karstens, email: k.karstens@uke.de Keywords: neural cell adhesion molecule L1-like protein (CHL1); gastrointestinal stroma tumor (GIST); survival; prognosis; serum Received: December 31, 2019 Accepted: March 03, 2020 Published: March 31, 2020 ABSTRACT Introduction: Diagnosis of gastrointestinal stroma tumors (GIST) is based on the histological evaluation of tissue specimens. Reliable systemic biomarkers are lacking. We investigated the local expression of the neural cell adhesion molecule L1-like protein (CHL1) in GIST and determined whether soluble CHL1 proteoforms could serve as systemic biomarkers. Material and Methods: Expression of CHL1 was analyzed in primary tumor specimens and metastases. 58 GIST specimens were immunohistochemically stained for CHL1 on a tissue microarray (TMA). Systemic CHL1 levels were measured in sera derived from 102 GIST patients and 91 healthy controls by ELISA. Results were statistically correlated with clinicopathological parameters. Results: CHL1 expression was detected in GIST specimens. Reduced tissue expression was significantly associated with advanced UICC stages ( p = 0.036) and unfavorable tumor localization ( p = 0.001). CHL1 serum levels are significantly elevated in GIST patients ( p < 0.010). Elevated CHL1 levels were significantly associated with larger tumors ( p = 0.023), advanced UICC stage ( p = 0.021), and an increased Fletcher score ( p = 0.041). Moreover, patients with a higher CHL1 serum levels displayed a significantly shortened recurrence free survival independent of other clinicopathological variables. Conclusion: Local CHL1 expression and serum CHL1 levels show a reverse prognostic behavior, highlighting the relevance of proteolytic shedding of the molecule. The results of the study indicate a potential role of serum CHL1 as a diagnostic and prognostic marker in GIST.

Diverting esophagectomies in cases of benign esophageal perforations remain rare but potentially life saving procedures. Usually, an esophagostoma and a feeding jejunostomy or gastrostomy are created, and patients are given time to recover from the emergency situation. However, little is known about morbidity and mortality as well as the optimal timing for a staged reconstruction. Patients with benign esophageal perforations were selected from our retrospective database. Perforations in esophageal malignancies were excluded to avoid bias on patients’ general outcome. Clinical parameters and especially, the influence of the nutritional status indicated by the BMI (Body Mass Index) as well as serum albumin levels (g/l) were analyzed. A total of 24 patients with diverting esophagectomies were identified. Of these, 13 (54.2%) patients received a staged reconstruction after a median of 143.0 days. Patients presenting for their staged reconstruction demonstrated a significantly decreased level of their BMI (p = 0.026) as compared to their prior hospitalization. Interestingly, the relative decrease of BMI (8.5 kg/m2 vs. 4.3 kg/m2) and albumin levels (6.5 g/l vs. 0.0 g/l) was significantly different in patients with or without anastomotic leaks between both surgeries (p = 0.021; p = 0.034, respectively). In addition, higher rates of overall complications were associated with an increased rate of malnutrition. The relative amount of malnutrition indicated by BMI or serum albumin levels influences the rate of anastomotic leaks and general complications in patients with staged reconstruction after diverting esophagectomy for non-malignant esophageal perforations. Hence, reconstruction should be done as fast as possible to reduce the amount of malnutrition and a frequent assessment of the nutritional status must be done during recovery from the emergency surgery.

Background and aimsEndoscopic resection has been established as curative therapy for superficial cancer arising from Barrett’s oesophagus (BE); recurrences are very rare. Based on a case series with unusual and massive early recurrences, we analyse the issue of tumour cell reimplantation.MethodsThis hypothesis was developed on the basis of two out of seven patients treated by circumferential (n=6) or nearly circumferential (n=1) en bloc and R0 endoscopic resection of T1 neoplastic BE. Subsequently, a prospective histocytological analysis of endoscope channels and accessories was performed in 2 phases (cytohistological analysis; test for cell viability) in 22 different oesophageal carcinoma patients undergoing endoscopy. Finally, cultures from two oesophageal adenocarcinoma cell lines were incubated with different triamcinolone concentrations (0.625–10 mg/mL); cell growth was determined on a Multiwell plate reader.ResultsCancer regrowth in the two suspicious cases (male, 78/71 years) occurred 7 and 1 months, respectively, after curative tumour resection. Subsequent surgery showed advanced tumours (T2) with lymph node metastases; one patient died. On cytohistological examinations of channels and accessories, suspicious/neoplastic cells were found in 4/10 superficial and in all 5 advanced cancers. Further analyses in seven further advanced adenocarcinoma cases showed viable cells in two channel washing specimens. Finally, cell culture experiments demonstrated enhanced tumour cell growth by triamcinolone after 24 hours compared with controls.ConclusionsTumour cell reimplanation from contaminated endoscopes and accessories is a possible cause of local recurrence after curative endoscopic therapy for superficial Barrett carcinoma; also, corticosteroid injection could have promoted tumour regrowth in these cases.

Introduction. Current modalities to predict tumor recurrence and survival in esophageal cancer are insufficient. Even in lymph node-negative patients, a locoregional and distant relapse is common. Hence, more precise staging methods are needed. So far, only the CellSearch system was used to detect circulating tumor cells (CTC) with clinical relevance in esophageal cancer patients. Studies analyzing different CTC detection assays using advanced enrichment techniques to potentially increase the sensitivity are missing. Methods. In this single-center, prospective study, peripheral blood samples from 90 esophageal cancer patients were obtained preoperatively and analyzed for the presence of CTCs by Magnetic Cell Separation (MACS) enrichment (combined anti-cytokeratin and anti-epithelial cell adhesion molecules (EpCAM)), with subsequent immunocytochemical staining. Data were correlated with clinicopathological parameters and patient outcomes. Results. CTCs were detected in 25.6% (23/90) of the patients by combined cytokeratin/EpCAM enrichment (0&ndash, 150 CTCs/7.5 mL). No significant correlation between histopathological parameters and CTC detection was found. Survival analysis revealed that the presence of more than two CTCs correlated with significantly shorter overall survival (OS) and progression-free survival (PFS). Conclusion. With the use of cytokeratin as an additional enrichment target, the CTC detection rate in esophageal cancer patients can be elevated and displays the heterogeneity of cytokeratin (CK) and EpCAM expression. The presence of &gt, 2CTCs correlated with a shorter relapse-free and overall survival in a univariate analysis, but not in a multivariate setting. Moreover, our results suggest that the CK7/8+/EpCAM+ or CK7/8+/EpCAM&minus, CTC subtype does not lead to an advanced tumor staging tool in non-metastatic esophageal cancer (EC) patients.

Background: The prognostic impact of circumferential resection margin (CRM) involvement in resected esophageal cancer (EC) is controversial discussed. The College of American Pathologists (CAP) and the Royal College of Pathologists (RCP) provide 2 different definitions of CRM involvement. The aim of this systematic review was to evaluate the clinical significance of CRM involvement on patients' survival following esophagectomy due to EC. Methods: PubMed, Science Direct, and Google scholar were searched for studies analyzing the clinical impact of CRM in EC. Summary: A total of 28 studies analyzed the prognostic effect of a positive CRM in EC. A wide range of CRM involvement (8.6-83.1%) was reported. Both available meta-analyses found a significant association between a positive CRM and patients' survival irrespective of RCP (OR 2.52 [95% CI 1.96-3.25; p < 0.001]) or CAP (OR 4.02 [95% CI 2.25-7.20; p < 0.001]) criteria. The influence of neoadjuvant therapy on the CRM remains unclear. Key Messages: CRM involvement is a useful parameter for EC patients' prognosis. The application of CAP criteria should be preferred since patients with a poor prognosis can be identified more sufficiently. Neoadjuvant therapy and en bloc transthoracic esophagectomy show favorable results for achievement of negative CRM.

Purpose: Esophageal perforations are associated with high morbidity and mortality. Different nonoperative and operative treatment options have been proposed. This study focuses on the impact of different surgical treatments in nonmalignant esophageal perforations and tries to identify predictors of mortality in a single tertiary center over a 15-year period. Methods: From 2002 to 2017, patients with surgically managed esophageal perforation were identified from our database. Patients with esophageal malignancies were excluded. Etiology, clinical data, treatment, and outcome were analyzed. A multivariate logistic regression analysis was performed to investigate the impact on mortality. Results: A total of 72 patients were identified. The majority of perforations were iatrogenic (54.2%) followed by Boerhaave’s syndrome (23.6%). Most ruptures were found in the distal third of the esophagus (59.7%) measuring p < 0.0001) and mortality (p = 0.032). A correlation between an increasing perforation length with sepsis (p = 0.012) was observed. A higher Perforation Severity Score (PSS; OR 4.430; 95% CI 1.143–17.174; p = 0.031) and a higher American Society of Anesthesiologists (ASA) score (OR 2.923; 95% CI 1.011–8.448; p = 0.048) were associated with mortality in multivariate analysis. Conclusion: Esophageal perforations are associated with high mortality, and larger ruptures are associated with worse outcome. Rapid diagnosis and treatment are crucial for patient survival. Hence, PSS and ASA score help to identify high-risk patients. The advantage of surgical management lies in the rapid control of the septic focus in an already critically ill patient. Though, the kind of surgical technique needs to be adjusted to the individual situation.

Background & Aims Unregulated activity of interleukin (IL) 22 promotes intestinal tumorigenesis in mice. IL22 binds the antagonist IL22 subunit alpha 2 (IL22RA2, also called IL22BP). We studied whether alterations in IL22BP contribute to colorectal carcinogenesis in humans and mice. Methods We obtained tumor and nontumor tissues from patients with colorectal cancer (CRC) and measured levels of cytokines by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. We measured levels of Il22bp messenger RNA in colon tissues from wild-type, Tnf–/–, Lta–/–, and Ltb–/– mice. Mice were given azoxymethane and dextran sodium sulfate to induce colitis and associated cancer or intracecal injections of MC38 tumor cells. Some mice were given inhibitors of lymphotoxin beta receptor (LTBR). Intestine tissues were analyzed by single-cell sequencing to identify cell sources of lymphotoxin. We performed immunohistochemistry analysis of colon tissue microarrays from patients with CRC (1475 tissue cores, contained tumor and nontumor tissues) and correlated levels of IL22BP with patient survival times. Results Levels of IL22BP were decreased in human colorectal tumors, compared with nontumor tissues, and correlated with levels of lymphotoxin. LTBR signaling was required for expression of IL22BP in colon tissues of mice. Wild-type mice given LTBR inhibitors had an increased tumor burden in both models, but LTBR inhibitors did not increase tumor growth in Il22bp–/– mice. Lymphotoxin directly induced expression of IL22BP in cultured human monocyte–derived dendritic cells via activation of nuclear factor κB. Reduced levels of IL22BP in colorectal tumor tissues were associated with shorter survival times of patients with CRC. Conclusions Lymphotoxin signaling regulates expression of IL22BP in colon; levels of IL22BP are reduced in human colorectal tumors, associated with shorter survival times. LTBR signaling regulates expression of IL22BP in colon tumors in mice and cultured human dendritic cells. Patients with colorectal tumors that express low levels of IL22BP might benefit from treatment with an IL22 antagonist.

Introduction Reflux promotes esophageal adenocarcinomas (EAC) creating a chronic inflammatory environment. EAC show an increasing incidence in the Western World and median survival rates are still low. The main reasons for poor prognosis despite new multimodal therapies are diagnosis of EACs at an already advanced stage and distant metastases. Hence, we wanted to investigate the presence of systemic inflammatory interleukins (IL) and their impact on patient prognosis. Material and methods Systemic expression levels of pro- and anti-inflammatory markers (IL-2, IL-4, IL-6, IL-10, IL-17A and IL-22) in the sera of 43 EAC patients without neoadjuvant radiochemotherapy were measured by flow cytometric analysis. A correlation to clinicopathological data was performed. Log-rank and Cox regression analysis were used to investigate the impact on patient survival. 43 sera of age and gender matched healthy volunteers were used as controls. Results Increased systemic IL-6 (p = 0.044) and lower IL-17A (p = 0.002) levels were found in EAC patients as opposed to controls. A correlation of IL-10 levels with an increased T stage was found (p = 0.020). Also, systemic IL-10 levels were highly elevated in patients with distant metastasis (p

Pancreatic cancer (PDAC) is one of the leading causes of cancer-related death worldwide. The incidence of PDAC is rising and mortality despite the effort to develop and implement new therapeutic strategies is increasing [1] (The Cancer Statistics Review (2009–2013) online). The major problem to improve individual survival rates is the delayed diagnosis of PDAC. Consequently, the majority of patients have to be excluded from surgical resection due to an already distant spread or locally advancement of the disease. Hence, only 10–20% of PDAC patients are primarily eligible for potential curative surgical approach aiming at a complete oncologic resection of the carcinoma with negative margins (R0). Despite controversies in definition of true R0 resection in PDAC and lessons learned in histological workup of the specimen, tumor-free resection margins still remain the goal of radical operation in PDAC with a reported prolonged survival of 5-year survival rates of up to 25% in selected series [2–7].