Background: The formation of distant metastases constitutes a complex process with a variety of different genes and pathways involved. To improve patient survival, it is necessary to understand the underlying mechanisms of metastasis to allow for targeted intervention. Methods: This review provides an overview of the general concepts of metastasis, focusing on the most important genes and pathways involved and on interventional strategies. Results: Cancer cells undergo different steps to form metastasis: most prominently, local invasion, intravasation, survival in the circulation, arrest at a distant organ site and extravasation, micrometastasis formation, and metastatic colonization. In order to pass these steps, different molecular pathways are of major importance: EGF/RAS/RAF/MEK/ERK, PI3K/Akt/mTOR, HGF/Met, Wnt/β-catenin, and VEGF signaling. The HGF/Met regulator MACC1 and the Wnt signaling target S100A4 have been shown to play a major role in the metastatic process. Each gene and pathway provides an opportunity for therapeutic intervention. Conclusion: Since metastasis represents a highly limiting factor in cancer therapy causing 90% of cancer deaths, it is imperative to reveal the underlying mechanisms. This is fundamental for uncovering prognostic markers and new targeted therapy options.

Introduction: The tight junction molecule Claudin 18.2 is selectively expressed in healthy and malignant gastric epithelial tissue and is a promising therapy target for high Claudin 18.2 expressing adenocarcinomas of the esophagogastric junction and stomach (AEG/S). Methods: This study analyzed the prevalence, characteristics and prognostic impact of Claudin 18.2 expression in primary tumor, lymph node and distant metastasis in a large Caucasian AGE/S cohort with 414 patients. Results: Claudin 18.2 was highly expressed in 17.1% of primary tumors, 26.7% of lymph node metastasis and 16.7% of distant metastasis. High Claudin 18.2 expression in lymph node metastasis and primary tumors correlated significantly (p < 0.001). High expression of Claudin 18.2 was neither associated with histomorphogical subtype, or tumor state, nor with overall survival. Conclusion: In Caucasian AEG/S patients, 17.1% appeared to be eligible for an anti-Claudin 18.2 therapy. Claudin 18.2 expression itself has no impact on prognosis and is not related to any tumor subtype.

The prognostic potential of anti-tumor immune responses is becoming increasingly important in adenocarcinoma of the gastroesophageal junction and stomach (AGE/S) especially regarding the use of immune checkpoint inhibitors. This study analyzes for the first time the prognostic impact of tumor-infiltrating lymphocytes (TILs) and checkpoint inhibitors in a large Caucasian cohort in patients with AGE/S. We screened tissue samples from 438 therapy-naïve patients with AGE/S undergoing surgery between 1992 and 2005, examined in a tissue microarray (TMA) and stained against human CD3, CD4, CD8, PD-1, and PD-L1. Out of 438 tissue samples, 210 were eligible for multivariate analysis. This revealed that high infiltration with CD3⁺, CD4⁺, or CD8⁺ TILs was associated with an increased overall survival in AGE/S patients, which could only be confirmed in multivariate analysis for CD3 (HR: 0.326; p = .023). Independent improved survival was limited to gastric cancer patients and to early tumor stages as long as TILs did not express PD-1 (HR: 1.522; p = .021). Subgroup analyses indicate that TIL-dependent anti-tumor immune response is only effective in gastric cancer patients in early stages of disease in PD-1 negative TILs. Combined analysis of PD-1 and CD3 could serve as a prognostic marker for the clinical outcome of gastric cancer patients and could also be of interest for immunotherapy.

Deregulated Wnt-signaling is a key mechanism driving metastasis in adenocarcinoma of the gastroesophageal junction and stomach (AGE/S). The oncogene S100A4 was identified as a Wnt-signaling target gene and is known to promote metastasis. In this project, we illuminate the role of S100A4 for metastases development and disease prognosis of AGE/S. Five gastric cancer cell lines were assessed for S100A4 expression. Two cell lines with endogenous high S100A4 expression were used for functional phenotyping including analysis of proliferation and migration after stable S100A4 knock-down. The prognostic value of S100A4 was evaluated by analyzing the S100A4 expression of tissue microarrays with samples of 277 patients with AGE/S. S100A4 knock-down induced lower migration in FLO1 and NCI-N87 cells. Treatment with niclosamide in these cells led to partial inhibition of S100A4 and to reduced migration. Patients with high S100A4 expression showed lower 5-year overall and disease-specific survival. In addition, a larger share of patients in the S100A4 high expressing group suffered from metachronous metastasis. This study identifies S100A4 as a negative prognostic marker for patients with AGE/S. The strong correlation between S100A4 expression, metastases development and patient survival might open opportunities to use S100A4 to improve the prognosis of these patients and as a therapeutic target for intervention in this tumor entity.

Esophageal and Gastric Adenocarcinomas (AGE/S) are characterized by early metastasis and poor survival. MACC1 (Metastasis Associated in Colon Cancer 1) acts in colon cancer as a metastasis inducer and is linked to reduced survival. This project illuminates the role and potential for the inhibition of MACC1 in AGE/S. Using 266 of 360 TMAs and survival data of AGE/S patients, we confirm the value of MACC1 as an independent negative prognostic marker in AGE/S patients. MACC1 gene expression is correlated with survival and morphological characteristics. In vitro analysis of lentivirally MACC1-manipulated subclones of FLO-1 and OE33 showed enhanced migration induced by MACC1 in both cell line models, which could be inhibited by the MEK1 inhibitor selumetinib. In vivo, the efficacy of selumetinib on tumor growths and metastases of MACC1-overexpressing FLO-1 cells xenografted intrasplenically in NOG mice was tested. Mice with high-MACC1-expressing cells developed faster and larger distant metastases. Treatment with selumetinib led to a significant reduction in metastasis exclusively in the MACC1-positive xenografts. MACC1 is an enhancer of tumor aggressiveness and a predictor of poor survival in AGE/S. This effect can be inhibited by selumetinib.

Background and study aims Two different techniques for percutaneous endoscopic gastrostomy (PEG) have been developed: classical pull-through and direct puncture techniques. This study compared the complication rate for both techniques in a large retrospective patient cohort. Patients and methods Clinical data from patients who received a PEG in four high-volume centers for endoscopy were included retrospectively between January 2016 and December 2018. Patient characteristics and complication rates were correlated in univariate and multivariate analyses. Results Data from 1014 patients undergoing a PEG insertion by the pull-through technique were compared to 183 patients for whom the direct puncture technique was used. The direct puncture technique was associated with a 50 % reduction in minor and 85.7 % reduction in major complications when compared to the pull-through technique. Multivariate analysis of these data revealed an odds ratio of 0.067 (0.02–0.226; P < 0.001) for major complications in the direct puncture group. Conclusions Compared to the pull-through technique, the direct puncture technique resulted in a significant reduction in complications. Despite the retrospective design of this study, these results suggest that the direct puncture technique may be preferable to improve patient safety.