Search

Intestinal ganglionic cells in the adult enteric nervous system (ENS) are continually exposed to stimuli from the surrounding microenvironment and need at times to respond to disturbed homeostasis following acute intestinal injury. The kinase DCLK1 and intestinal Dclk1-positive cells have been reported to contribute to intestinal regeneration. Although Dclk1-positive cells are present in adult enteric ganglia, their cellular identity and response to acute injury have not been investigated in detail. Here, we reveal the presence of distinct Dclk1-tdTom+/CD49b+ glial-like and Dclk1-tdTom+/CD49b− neuronal cell types in adult myenteric ganglia. These ganglionic cells demonstrate distinct patterns of tracing over time yet show a similar expansion in response to elevated serotonergic signaling. Interestingly, Dclk1-tdTom+ glial-like and neuronal cell types appear resistant to acute irradiation injury-mediated cell death. Moreover, Dclk1-tdTom+/CD49b+ glial-like cells show prominent changes in gene expression profiles induced by injury, in contrast to Dclk1-tdTom+/CD49b− neuronal cell types. Finally, subsets of Dclk1-tdTom+/CD49b+ glial-like cells demonstrate prominent overlap with Nestin and p75NTR and strong responses to elevated serotonergic signaling or acute injury. These findings, together with their role in early development and their neural crest-like gene expression signature, suggest the presence of reserve progenitor cells in the adult Dclk1 glial cell lineage. NEW & NOTEWORTHY The kinase DCLK1 identifies glial-like and neuronal cell types in adult murine enteric ganglia, which resist acute injury-mediated cell death yet differ in their cellular response to injury. Interestingly, Dclk1-labeled glial-like cells show prominent transcriptional changes in response to injury and harbor features reminiscent of previously described enteric neural precursor cells. Our data thus add to recently emerging evidence of reserve cellular plasticity in the adult enteric nervous system.

Purpose Surgical oncologists are frequently confronted with the question of expected long-term prognosis. The aim of this study was to apply machine learning algorithms to optimize survival prediction after oncological resection of gastroesophageal cancers. Methods Eligible patients underwent oncological resection of gastric or distal esophageal cancer between 2001 and 2020 at Heidelberg University Hospital, Department of General Surgery. Machine learning methods such as multi-task logistic regression and survival forests were compared with usual algorithms to establish an individual estimation. Results The study included 117 variables with a total of 1360 patients. The overall missingness was 1.3%. Out of eight machine learning algorithms, the random survival forest (RSF) performed best with a concordance index of 0.736 and an integrated Brier score of 0.166. The RSF demonstrated a mean area under the curve (AUC) of 0.814 over a time period of 10 years after diagnosis. The most important long-term outcome predictor was lymph node ratio with a mean AUC of 0.730. A numeric risk score was calculated by the RSF for each patient and three risk groups were defined accordingly. Median survival time was 18.8 months in the high-risk group, 44.6 months in the medium-risk group and above 10 years in the low-risk group. Conclusion The results of this study suggest that RSF is most appropriate to accurately answer the question of long-term prognosis. Furthermore, we could establish a compact risk score model with 20 input parameters and thus provide a clinical tool to improve prediction of oncological outcome after upper gastrointestinal surgery.

Purpose Perioperative systemic treatment has significantly improved the outcome in locally advanced esophagogastric cancer. However, still the majority of patients relapse and die. Data on the optimal treatment after relapse are limited, and clinical and biological prognostic factors are lacking. Methods Patients with a relapse after neoadjuvant/perioperative treatment and surgery for esophagogastric cancer were analyzed using a prospective database. Applied treatment regimens, clinical prognostic factors and biomarkers were analyzed. Results Of 246 patients 119 relapsed. Among patients with a relapse event, those with an early relapse (p 6 months). OS after relapse was longer in patients with a microsatellite-unstable (MSI) tumor. Systemic treatment was initiated in 87 patients (73% of relapsed pat.); among those OS from the start of first-line treatment was inferior in patients with an early relapse with 6.9 vs. 10.0 months (p = 0.037). In 27 patients (23% of relapsed pat.), local therapy (irradiation or surgical intervention) was performed due to oligometastatic relapse, resulting in a prolonged OS in comparison to patients without local therapy (median OS 35.2 months vs. 7.8 months, p Conclusion Patients relapsing after multimodal treatment have a heterogeneous prognosis depending on the relapse-free interval (if systemic treatment applied), extent of metastatic disease as well as MSI status. The benefit of additional local intervention after relapse should be addressed in a randomized trial.

Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. Funding: German Research Foundation (DFG).

Background: Recurrence after resection of pancreatic cancer occurs in up to 80% of patients in the first 2 years after complete resection. While most patients are not eligible for surgical treatment due to disseminated disease, a certain group of patients can be evaluated for re-resection of local recurrence. This review summarizes the current literature on surgical treatment of recurrent pancreatic cancer and potential prognostic factors. Summary: Re-resection of recurrent pancreatic cancer provides a significant survival benefit to selected patients with acceptable procedure-related mortality. Median overall survival after re-resection of recurrent pancreatic cancer is up to 28 months. The most relevant clinical parameters associated with a prognostic benefit are young patient age (10 months), and preoperative chemotherapy before re-resection. Molecular markers are currently under investigation and might help to improve patient selection in the future. Key Message: Re-resection of recurrent pancreatic cancer is safe and feasible in experienced hands. Selected patients benefit from surgical treatment, but future studies are needed to identify reliable prognostic markers predicting survival.

Background Malnutrition is associated with poor survival in pancreatic cancer patients. Nutritional scores show great heterogeneity diagnosing malnutrition. The aim of this study was to find the score best suitable to identify patients with malnutrition related to worse survival after surgery for pancreatic ductal adenocarcinoma (PDAC). This study represents a follow‐up study to the prospective NURIMAS Pancreas trial that evaluated short term impact of nutritional score results after surgery. Methods Risk of malnutrition was evaluated preoperatively using 12 nutritional assessment scores. Patients were followed‐up prospectively for at least 3 years. Patients at risk for malnutrition were compared with those not at risk according to each score using Kaplan–Meier survival statistics. Results A total of 116 patients receiving a PDAC resection in curative intent were included. Malnutrition according to the Subjective Global Assessment score (SGA), the Short Nutritional Assessment Questionnaire (SNAQ), and the INSYST2 score was associated with worse overall survival (SGA: at‐risk: 392 days; not at‐risk: 942 days; P = 0.001; SNAQ: at‐risk: 508 days; not at‐risk: 971 days; P = 0.027; INSYST2: at‐risk: 538 days; not at risk: 1068; P = 0.049). In the multivariate analysis, SGA (hazard ratio of death 2.16, 95% confidence interval 1.34–3.47, P = 0.002) was associated with worse overall survival. Conclusions Malnutrition as defined by the Subjective Global Assessment is independently associated with worse survival in resected PDAC patients. The SGA should be used to stratify PDAC patients in clinical studies. Severely malnourished patients according to the SGA profit from intensified nutritional therapy should be evaluated in a randomized controlled trial.

Background Gastric and esophageal cancers are malignant diseases with rising importance in Western countries. To improve oncologic outcome after surgery, it is essential to understand the relevance of germline mutations. The aim of the study was to identify and distinguish clinically relevant single-nucleotide polymorphisms (SNPs). Patients and Methods In total, 190 patients with curative oncological resections of gastric and distal esophageal adenocarcinomas at Heidelberg University Hospital were eligible for this study. Outcome differences were determined for each SNP by analysis of clinical variables, survival, and mRNA expression levels. Results Significant survival differences were found on univariate analysis for usual prognostic variables (such as pTNM) and for six SNPs. On multivariate survival analysis, the SNPs rs12268840 (intron variant of MGMT, p = 0.045) and rs9972882 (intron variant of STARD3 and eQTL of PGAP3, p = 0.030) were independent and significant survival predictors along with R status and pT/pN category. Group TT of rs12268840 had the highest rate of second primary carcinoma (30.4%, p = 0.0003), lowest expression of MGMT based on cis-eQTL analysis in normal gastroesophageal tissue (p = 1.99 × 10−17), and worst oncologic outcome. Group AA of rs9972882 had the highest rate of distant metastases pM1 (42.9%, p = 0.0117), highest expression of PGAP3 (p = 1.29 × 10−15), and worst oncologic outcome. Conclusions Two intron variant SNPs of MGMT and STARD3 were identified that were significant survival predictors and may influence tumor biology. The data indicate that DNA methylation (MGMT) and malfunction of GPI anchoring (PGAP3) are distinct mechanisms that are relevant for tumor progression and relapse.

Background & Aims Immune checkpoint inhibitors have limited efficacy in many tumors. We investigated mechanisms of tumor resistance to inhibitors of programmed cell death–1 (PDCD1, also called PD-1) in mice with gastric cancer, and the role of its ligand, PD-L1. Methods Gastrin-deficient mice were given N-methyl-N-nitrosourea (MNU) in drinking water along with Helicobacter felis to induce gastric tumor formation; we also performed studies with H/K-ATPase-hIL1B mice, which develop spontaneous gastric tumors at the antral–corpus junction and have parietal cells that constitutively secrete interleukin 1B. Mice were given injections of an antibody against PD-1 or an isotype control before tumors developed, or anti–PD-1 and 5-fluorouracil and oxaliplatin, or an antibody against lymphocyte antigen 6 complex locus G (also called Gr-1), which depletes myeloid-derived suppressor cells [MDSCs]), after tumors developed. We generated knock-in mice that express PD-L1 specifically in the gastric epithelium or myeloid lineage. Results When given to gastrin-deficient mice before tumors grew, anti–PD-1 significantly reduced tumor size and increased tumor infiltration by T cells. However, anti–PD-1 alone did not have significant effects on established tumors in these mice. Neither early nor late anti–PD-1 administration reduced tumor growth in the presence of MDSCs in H/K-ATPase-hIL-1β mice. The combination of 5-fluorouracil and oxaliplatin reduced MDSCs, increased numbers of intra-tumor CD8+ T cells, and increased the response of tumors to anti–PD-1; however, this resulted in increased tumor expression of PD-L1. Expression of PD-L1 by tumor or immune cells increased gastric tumorigenesis in mice given MNU. Mice with gastric epithelial cells that expressed PD-L1 did not develop spontaneous tumors, but they developed more and larger tumors after administration of MNU and H felis, with accumulation of MDSCs. Conclusions In mouse models of gastric cancer, 5-fluorouracil and oxaliplatin reduce numbers of MDSCs to increase the effects of anti–PD-1, which promotes tumor infiltration by CD8+ T cells. However, these chemotherapeutic agents also induce expression of PD-L1 by tumor cells. Expression of PD-L1 by gastric epithelial cells increases tumorigenesis in response to MNU and H felis, and accumulation of MDSCs, which promote tumor progression. The timing and site of PD-L1 expression is therefore important in gastric tumorigenesis and should be considered in design of therapeutic regimens.

Background Gastric cancer is one of the most frequent malignancies worldwide. Angiogenic growth factors play a crucial role in mediating the crosstalk between cancer cells and the surrounding microenvironment. In this exploratory study, we investigate the impact of angiogenic proteins within the tumor cell or stroma compartment on survival of patients with gastric cancer. Materials and methods In 29 patients, tumor and stromal compartments were separated using laser capture microdissection. Angiogenic protein expression was measured using a bead-based immunoassay and correlated with tumor stage and overall survival. Results Overall survival was significantly shorter in patients with a high stroma concentration of vascular endothelial growth factor (VEGF)-A (23.5 (±17.6) versus 33.6 (±21.0) mo; P = 0.009) and stem cell factor (22.2 (±18.5) versus 33.6 (±21.8) mo; P = 0.01) compared with patients with a low stroma concentration. High stromal VEGF-D showed a trend toward worse survival (26.8 (±22.0) versus 37.2 (±19.0) mo; P = 0.09). We did not observe any significant correlation between tumor-specific expression of angiogenic cytokines and survival. Conclusions This translational study highlights the difference in clinical impact between tumor and stromal expression of angiogenic proteins. Compartment-specific concentrations of VEGF-A and stem cell factor affect the clinical prognosis and help to identify the best therapy for patients with gastric cancer.

Background and aimsThe gastric epithelium undergoes continuous turnover. Corpus epithelial stem cells located in the gastric isthmus serve as a source of tissue self-renewal. We recently identified the transcription factor Mist1 as a marker for this corpus stem cell population that can give rise to cancer. The aim here was to investigate the regulation of the Mist1+ stem cells in the response to gastric injury and inflammation.MethodsWe used Mist1CreERT;R26-Tdtomato mice in two models of injury and inflammation: the acetic acid-induced ulcer and infection with Helicobacter felis. We analysed lineage tracing at both early (7 to 30 days) and late (30 to 90 days) time points. Mist1CreERT;R26-Tdtomato;Lgr5DTR-eGFP mice were used to ablate the corpus basal Lgr5+ cell population. Constitutional and conditional Wnt5a knockout mice were used to investigate the role of Wnt5a in wound repair and lineage tracing from the Mist1+ stem cells.ResultsIn both models of gastric injury, Mist1+ isthmus stem cells more rapidly proliferate and trace entire gastric glands compared with the normal state. In regenerating tissue, the number of traced gastric chief cells was significantly reduced, and ablation of Lgr5+ chief cells did not affect Mist1-derived lineage tracing and tissue regeneration. Genetic deletion of Wnt5a impaired proliferation in the gastric isthmus and lineage tracing from Mist1+ stem cells. Similarly, depletion of innate lymphoid cells, the main source of Wnt5a, also resulted in reduced proliferation and Mist1+ isthmus cell tracing.ConclusionGastric Mist1+ isthmus cells are the main supplier of regenerated glands and are activated in part through Wnt5a pathway.

Background Based on two benchmark studies perioperative chemotherapy (CTx) has become standard treatment for locally advanced esophagogastric adenocarcinoma (EGA) in Europe. However, only half of the patients in both studies actually received postoperative CTx (aCTx). Thus, we evaluated the prognostic impact of preoperative CTx (nCTx) and aCTx combined versus nCTx alone. Furthermore, we aimed to identify subgroups potentially beneficial of aCTx and factors associated with its non-administration. Methods We retrospectively analyzed 299 consecutive patients with EGA, who underwent complete resection (all M0, R0) after nCTx in our institution and were eligible for aCTx. Patients with and without aCTx were compared regarding clinicopathological data, treatment, morbidity, and long-term prognosis. Results 129 patients (43.1%) did not receive aCTx. Administration of aCTx did not significantly improve overall (OS) and recurrence free survival (RFS) (median OS: 78.2 months vs. not reached, p = 0.331; RFS: 43.3 vs. 41.1 months, p = 0.118), but was an independent positive predictor of RFS (HR 1.6 95%CI 1.1–2.5, p = 0.024). aCTx improved RFS in non-intestinal tumors (p = 0.023) and patients receiving FLOT regimen (p = 0.038). By logistic regression analysis factors predictive of non-administration of aCTx were older age (>65 years: OR 3.2, p = 0.028), longer hospital stay (15–28 days: OR 2.6, p = 0.001; >28 days: OR 5.2, p Conclusion Advanced age, histopathologic non-response, and prolonged convalescence due to postoperative morbidity lead to omission of aCTx. However, this study could not provide evidence to support the beneficial role of aCTx in perioperative chemotherapy regimens for a selected patient collective with EGA and excellent prognosis.

The enteric neurotransmitter acetylcholine governs important intestinal epithelial secretory and immune functions through its actions on epithelial muscarinic Gq-coupled receptors such as M3R. Its role in the regulation of intestinal stem cell function and differentiation, however, has not been clarified. Here, we find that nonselective muscarinic receptor antagonism in mice as well as epithelial-specific ablation of M3R induces a selective expansion of DCLK1-positive tuft cells, suggesting a model of feedback inhibition. Cholinergic blockade reduces Lgr5-positive intestinal stem cell tracing and cell number. In contrast, Prox1-positive endocrine cells appear as primary sensors of cholinergic blockade inducing the expansion of tuft cells, which adopt an enteroendocrine phenotype and contribute to increased mucosal levels of acetylcholine. This compensatory mechanism is lost with acute irradiation injury, resulting in a paucity of tuft cells and acetylcholine production. Thus, enteroendocrine tuft cells appear essential to maintain epithelial homeostasis following modifications of the cholinergic intestinal niche., Acetylcholine regulates intestinal epithelial secretion via muscarinic Gq-coupled receptors but its role in cell differentiation is unclear. Here, the authors show that Prox1-positive endocrine cells are sensors for the cholinergic intestinal niche and can trigger increased differentiation of enteroendocrine DCLK1-positive tuft cells.

Background & Aims Enterochromaffin-like (ECL) cells in the stomach express gastrin/cholecystokinin 2 receptor CCK2R and are known to expand under hypergastrinemia, but whether this results from expansion of existing ECL cells or increased production from progenitors has not been clarified. Methods We used mice with green fluorescent protein fluorescent reporter expression in ECL cells (histidine decarboxylase [Hdc]-green fluorescent protein), as well as Cck2r- and Hdc-driven Tamoxifen inducible recombinase Cre (Cck2r-CreERT2, Hdc-CreERT2) mice combined with Rosa26Sor-tdTomato (R26-tdTomato) mice, and studied their expression and cell fate in the gastric corpus by using models of hypergastrinemia (gastrin infusion, omeprazole treatment). Results Hdc-GFP marked the majority of ECL cells, located in the lower third of the gastric glands. Hypergastrinemia led to expansion of ECL cells that was not restricted to the gland base, and promoted cellular proliferation (Ki67) in the gastric isthmus but not in basal ECL cells. Cck2r-CreERT2 mice marked most ECL cells, as well as scattered cell types located higher up in the glands, whose number was increased during hypergastrinemia. Cck2r-CreERT2+ isthmus progenitors, but not Hdc+ mature ECL cells, were the source of ECL cell hyperplasia during hypergastrinemia and could grow as 3-dimensional spheroids in vitro. Moreover, gastrin treatment in vitro promoted sphere formation from sorted Cck2r+Hdc- cells, and increased chromogranin A and phosphorylated- extracellular signal-regulated kinase expression in CCK2R-derived organoids. Gastrin activates extracellular signal-regulated kinase pathways in vivo and in vitro, and treatment with the Mitogen-activated protein kinase kinase 1 inhibitor U0126 blocked hypergastrinemia-mediated changes, including CCK2R-derived ECL cell hyperplasia in vivo as well as sphere formation and chromogranin A expression in vitro. Conclusions We show here that hypergastrinemia induces ECL cell hyperplasia that is derived primarily from CCK2R+ progenitors in the corpus. Gastrin-dependent function of CCK2R+ progenitors is regulated by the extracellular signal-regulated kinase pathway.

Background Delayed gastric emptying (DGE) occurs in up to 40% of patients after esophageal resection and prolongs recovery and hospital stay. Surgically pyloroplasty does not effectively prevent DGE. Recently published methods include injection of botulinum toxin (botox) in the pylorus and mechanical interventions as preoperative endoscopic dilatation of the pylorus. The aim of this study was to investigate the efficacy of those methods with respect to the newly published Consensus definition of DGE. Methods A systematic literature search using CENTRAL, Medline, and Web of Science was performed to identify studies that described pre- or intraoperative botox injection or mechanical stretching methods of the pylorus in patients undergoing esophageal resection. Frequency of DGE, anastomotic leakage rates, and length of hospital stay were analyzed. Outcome data were pooled as odd’s ratio (OR) or mean difference using a random-effects model. Risk of bias was assessed using the Robins-I tool for non-randomized trials. Results Out of 391 articles seven retrospective studies described patients that underwent preventive botulinum toxin injection and four studies described preventive mechanical stretching of the pylorus. DGE was not affected by injection of botox (OR 0.87, 95% confidence interval [CI] 0.37–2.03, P = 0.75), whereas mechanical stretching resulted in significant reduction of DGE (OR 0.26, 95% CI 0.14–0.5, P Conclusion Mechanical stretching of the pylorus, but not injection of botox reduces DGE after esophageal cancer resection. A newly developed consensus definition should be used before the conduction of a large-scale randomized-controlled trial.

In this study, protein profiling was performed on gastric cancer tissue samples in order to identify proteins that could be utilized for an effective diagnosis of this highly heterogeneous disease and as targets for therapeutic approaches. To this end, 16 pairs of postoperative gastric adenocarcinomas and adjacent non-cancerous control tissues were analyzed on microarrays that contain 813 antibodies targeting 724 proteins. Only 17 proteins were found to be differentially regulated, with much fewer molecules than the numbers usually identified in studies comparing tumor to healthy control tissues. Insulin-like growth factor-binding protein 7 (IGFBP7), S100 calcium binding protein A9 (S100A9), interleukin-10 (IL‐10) and mucin 6 (MUC6) exhibited the most profound variations. For an evaluation of the proteins’ capacity for discriminating gastric cancer, a Receiver Operating Characteristic curve analysis was performed, yielding an accuracy (area under the curve) value of 89.2% for distinguishing tumor from non-tumorous tissue. For confirmation, immunohistological analyses were done on tissue slices prepared from another cohort of patients with gastric cancer. The utility of the 17 marker proteins, and particularly the four molecules with the highest specificity for gastric adenocarcinoma, is discussed for them to act as candidates for diagnosis, even in serum, and targets for therapeutic approaches.

Minimally invasive oesophagectomy (MIO) for oesophageal cancer may reduce surgical complications compared with open oesophagectomy. MIO is, however, technically challenging and may impair optimal oncological resection. The aim of the present study was to assess if MIO for cancer is beneficial.A systematic literature search in MEDLINE, Web of Science and CENTRAL was performed and randomized controlled trials (RCTs) comparing MIO with open oesophagectomy were included in a meta-analysis. Survival was analysed using individual patient data. Random-effects model was used for pooled estimates of perioperative effects.Among 3219 articles, six RCTs were identified including 822 patients. Three-year overall survival (56 (95 per cent c.i. 49 to 62) per cent for MIO versus 52 (95 per cent c.i. 44 to 60) per cent for open; P = 0.54) and disease-free survival (54 (95 per cent c.i. 47 to 61) per cent versus 50 (95 per cent c.i. 42 to 58) per cent; P = 0.38) were comparable. Overall complication rate was lower for MIO (odds ratio 0.33 (95 per cent c.i. 0.20 to 0.53); P 0.010) mainly due to fewer pulmonary complications (OR 0.44 (95 per cent c.i. 0.27 to 0.72); P 0.010), including pneumonia (OR 0.41 (95 per cent c.i. 0.22 to 0.77); P 0.010).MIO for cancer is associated with a lower risk of postoperative complications compared with open resection. Overall and disease-free survival are comparable for the two techniques.Oesophagectomy for cancer is associated with a high risk of complications. A minimally invasive approach might be less traumatic, leading to fewer complications and may also improve oncological outcome. A meta-analysis of randomized controlled trials comparing minimally invasive to open oesophagectomy was performed. The analysis showed that the minimally invasive approach led to fewer postoperative complications, in particular, fewer pulmonary complications. Survival after surgery was comparable for the two techniques.Oesophagectomy for cancer is associated with a high risk of complications. A minimally invasive approach might be less traumatic, leading to fewer complications and may also improve oncological outcome. A meta-analysis of randomized controlled trials comparing minimally invasive to open oesophagectomy was performed. The analysis showed that the minimally invasive approach led to fewer postoperative complications, in particular, fewer pulmonary complications. Survival after surgery was comparable for the two techniques.

IntroductionThe only curative treatment for most gastric cancer is radical gastrectomy with D2 lymphadenectomy (LAD). Minimally invasive total gastrectomy (MIG) aims to reduce postoperative morbidity, but its use has not yet been widely established in Western countries. Minimally invasivE versus open total GAstrectomy is the first Western multicentre randomised controlled trial (RCT) to compare postoperative morbidity following MIG vs open total gastrectomy (OG).Methods and analysisThis superiority multicentre RCT compares MIG (intervention) to OG (control) for oncological total gastrectomy with D2 or D2+LAD. Recruitment is expected to last for 2 years. Inclusion criteria comprise age between 18 and 84 years and planned total gastrectomy after initial diagnosis of gastric carcinoma. Exclusion criteria include Eastern Co-operative Oncology Group (ECOG) performance status >2, tumours requiring extended gastrectomy or less than total gastrectomy, previous abdominal surgery or extensive adhesions seriously complicating MIG, other active oncological disease, advanced stages (T4 or M1), emergency setting and pregnancy.The sample size was calculated at 80 participants per group. The primary endpoint is 30-day postoperative morbidity as measured by the Comprehensive Complications Index. Secondary endpoints include postoperative morbidity and mortality, adherence to a fast-track protocol and patient-reported quality of life (QoL) scores (QoR-15, EUROQOL EuroQol-5 Dimensions-5 Levels (EQ-5D), EORTC QLQ-C30, EORTC QLQ-STO22, activities of daily living and Body Image Scale). Oncological endpoints include rate of R0 resection, lymph node yield, disease-free survival and overall survival at 60-month follow-up.Ethics and disseminationEthical approval has been received by the independent Ethics Committee of the Medical Faculty, University of Heidelberg (S-816/2021) and will be received from each responsible ethics committee for each individual participating centre prior to recruitment. Results will be published open access.Trial registration numberDRKS00025765., publishedVersion

Treatment options for patients with esophageal cancer are limited and the overall survival is disappointing. While surgical resection remains the only curative treatment option, there is a need for innovative medical therapies to extend patient survival. The tumor microenvironment represents an interesting target for the development of new treatment strategies. The tumor microenvironment consists of different cell types including immune, inflammatory, and stromal cells. In the past two decades many potential targets for the treatment of esophageal cancers were evaluated in preclinical experiments and transferred into clinical trials.In this chapter of the book, we will provide an overview of in vitro data, preclinical animal studies, and translational research on the role of the tumor microenvironment in the development and treatment of esophageal cancer. In particular, we will discuss the impact of inflammatory cytokines like interleukins. Preclinical mouse models with interleukin overexpression develop Barrett lesions in the esophagus and clinical studies have shown an association between an interleukin overexpression in human tumors and shortened overall survival.Beside the inflammatory cells in the tumor microenvironment, recent preclinical studies have shown an important role for stem cells in the development of esophageal carcinoma. In this chapter we summarize the current research on stem cells in the development of esophageal cancer and highlight potential therapeutic options. In addition, we will discuss the role of angiogenesis and anti-angiogenic therapy in the development and treatment of esophageal cancer. In the last section of this chapter, we provide an overview of current clinical trials that investigate the therapeutic potential of the tumor microenvironment.

Background:The only curative treatment for most esophageal cancers is radical esophagectomy. Minimally invasive esophagectomy (MIE) aims to reduce postoperative morbidity, but is not yet widely established. Linear stapled anastomosis is a promising technique for MIE because it is quite feasible even without robotic assistance. Aim of the present study is to compare total MIE with linear stapled anastomosis to open esophagectomy (OE) with circular stapled anastomosis with special regard to postoperative morbidity in an expertise-based randomized controlled trial (RCT).Methods/design:This superiority RCT compares MIE with linear stapled anastomosis (intervention) to OE with circular stapled anastomosis (control) for Ivor-Lewis esophagectomy. It was initiated in February 2019 and recruitment is expected to last for 3 years. For inclusion, patients must be 18 years of age or more with a resectable primary malignancy in the distal esophagus. Participants with tumor localizations above the azygos vein, metastasis or infiltration into adjacent tissue will be excluded. In an expertise-based approach the allocated treatment will only be carried out by the single most experienced surgeon of the surgical center for each respective technique. The sample size was calculated with 20 participants per group for the primary endpoint postoperative morbidity according to comprehensive complication index (CCI) within 30 postoperative days. Secondary endpoints include anastomotic insufficiency, pulmonary complications, other intra- and postoperative outcome parameters such as estimated blood loss, operative time, length of stay, short-term oncologic endpoints, adherence to a standardized fast-track protocol, postoperative pain, and postoperative recovery (QoR-15). Quality of life (SF-36, CAT EORTC QLQ-C30, CAT EORTC QLQ-OES18) and oncological outcomes are evaluated with 60 months follow-up.Discussion:MIVATE is the first RCT to compare OE with circular stapled anastomosis to total MIE with linear stapled anastomosis exclusively for intrathoracic anastomosis. The expertise-based approach limits bias due to heterogeneity of surgical expertise. The use of a dedicated fast-track protocol in both OE and MIE will shed light on the role of the access strategy alone in this setting. The findings of this study will serve to define which approach has the best perioperative outcome for patients requiring esophagectomy.Trial registration: German Clinical Trials Register DRKS00016773. Registered on February 18th, 2019.

Background: The only curative treatment for most esophageal cancers is radical esophagectomy. Minimally invasive esophagectomy (MIE) aims to reduce postoperative morbidity, but is not yet widely established. Linear stapled anastomosis is a promising technique for MIE because it is quite feasible even without robotic assistance. Aim of the present study is to compare total MIE with linear stapled anastomosis to open esophagectomy (OE) with circular stapled anastomosis with special regard to postoperative morbidity in an expertise-based randomized controlled trial (RCT). Methods/design: This superiority RCT compares MIE with linear stapled anastomosis (intervention) to OE with circular stapled anastomosis (control) for Ivor-Lewis esophagectomy. It was initiated in February 2019 and recruitment is expected to last for 3 years. For inclusion, patients must be 18 years of age or more with a resectable primary malignancy in the distal esophagus. Participants with tumor localizations above the azygos vein, metastasis or infiltration into adjacent tissue will be excluded. In an expertise-based approach the allocated treatment will only be carried out by the single most experienced surgeon of the surgical center for each respective technique. The sample size was calculated with 20 participants per group for the primary endpoint postoperative morbidity according to comprehensive complication index (CCI) within 30 postoperative days. Secondary endpoints include anastomotic insufficiency, pulmonary complications, other intra- and postoperative outcome parameters such as estimated blood loss, operative time, length of stay, short-term oncologic endpoints, adherence to a standardized fast-track protocol, postoperative pain, and postoperative recovery (QoR-15). Quality of life (SF-36, CAT EORTC QLQ-C30, CAT EORTC QLQ-OES18) and oncological outcomes are evaluated with 60 months follow-up. Discussion: MIVATE is the first RCT to compare OE with circular stapled anastomosis to total MIE with linear stapled anastomosis exclusively for intrathoracic anastomosis. The expertise-based approach limits bias due to heterogeneity of surgical expertise. The use of a dedicated fast-track protocol in both OE and MIE will shed light on the role of the access strategy alone in this setting. The findings of this study will serve to define which approach has the best perioperative outcome for patients requiring esophagectomy. Trial registration: German Clinical Trials Register DRKS00016773. Registered on February 18th, 2019.

Esophagectomy for oncological reasons is associated with high morbidity, which was intended to be reduced by a minimally invasive approach. Main problem of the minimally invasive approach is the challenge of a safe intrathoracic anastomosis. To address this problem several methods such as a collar anastomosis instead of an intrathoracic anastomosis with poor functional outcome, hybrid techniques with an open approach to the demanding intrathoracic circular stapled anastomosis ore robotic assistance have been used. We demonstrate the minimally invasive linear stapler technique for the intrathoracic esophagogastrostomy, which can be applied quite easily even without robotic assistance.The abdominal part is performed with the patient in French position. After division of the greater omentum along the gastroepiploic arcade and the spleen as well as the perigastric incision of the lesser omentum 6cm from the pylorus a 4,5 cm gastric conduit is created in linear stapler technique. Next an intraabdominal and transhiatal systematic lymphadenectomy is performed. For the thoracic part the patient is repositioned in a left side position. The thoracic lymphadenectomy is completed, and the specimen removed via mini-thoracotomy. For the anastomosis the esophageal stump is incised, and the gastric conduit is opened 5 cm from the oral resection line. Once the stapler is fired and removed the remaining opening is hand-sewn in a modified double-layer technique.The side-to-side esophagogastrostomy in linear stapler technique seems to be a quite easily feasible and safe alternative for the reconstruction after minimally invasive esophagectomy. To confirm this, the method is currently investigated in a randomized controlled trial.

Patients with metachronous malignancies before carcinomas of the upper gastrointestinal tract were analyzed regarding clinical parameters, oncological outcome, and prognosis.We analyzed the data of 1583 patients with gastroesophageal cancer who underwent oncological resections between 2002 and 2018. Of 1583 patients, 172 had a malignant tumor before the upper gastrointestinal cancer (second primary carcinomas) and 1411 without preceding malignancies served as the control group. The analyses were performed between both groups and within the subgroup of second primary carcinomas.Patients with second primary carcinomas were older (P 0.0001), had more comorbidities (P 0.0001), and underwent longer surgical resections (P = 0.0024). They had lower (y)pT-categories (P = 0.0427) and had longer stays in intensive care unit (P = 0.0002) and hospital (P = 0.0018). R0-resection was more frequent (P = 0.0275) while having more surgical complications (P = 0.0378). The median survival was 39.5 mo (primary carcinoma) versus 32.9 mo for (second primary carcinoma) and was not significantly different (P = 0.5359).In the subgroup analysis of second primaries, there were no significant survival differences depending on primary tumor entity (P = 0.4989). pT status (P = 0.0062), pN status (P 0.0001), pM status (P 0.0001), and R-status (P 0.0001) were significant prognostic factors. A time period9 y after the primary cancer could be identified as a novel and beneficial survival factor (P = 0.0496). Most patients with primary colorectal, prostate, hematogenous, or breast cancer had adenocarcinoma, whereas patients with initial otolaryngologic cancers mainly had squamous cell carcinoma.Second primary carcinomas of the upper gastrointestinal tract show distinct clinical and oncological characteristics. Common prognostic factors are applicable, and oncologic resection is recommended.

Treatment options for patients with esophageal cancer are limited and the overall survival is disappointing. While surgical resection remains the only curative treatment option, there is a need for innovative medical therapies to extend patient survival. The tumor microenvironment represents an interesting target for the development of new treatment strategies. The tumor microenvironment consists of different cell types including immune, inflammatory, and stromal cells. In the past two decades many potential targets for the treatment of esophageal cancers were evaluated in preclinical experiments and transferred into clinical trials.In this chapter of the book, we will provide an overview of in vitro data, preclinical animal studies, and translational research on the role of the tumor microenvironment in the development and treatment of esophageal cancer. In particular, we will discuss the impact of inflammatory cytokines like interleukins. Preclinical mouse models with interleukin overexpression develop Barrett lesions in the esophagus and clinical studies have shown an association between an interleukin overexpression in human tumors and shortened overall survival.Beside the inflammatory cells in the tumor microenvironment, recent preclinical studies have shown an important role for stem cells in the development of esophageal carcinoma. In this chapter we summarize the current research on stem cells in the development of esophageal cancer and highlight potential therapeutic options. In addition, we will discuss the role of angiogenesis and anti-angiogenic therapy in the development and treatment of esophageal cancer. In the last section of this chapter, we provide an overview of current clinical trials that investigate the therapeutic potential of the tumor microenvironment.

Gastric and esophageal cancers are dreaded malignancies, with a majority of patients presenting in either a locally advanced or metastatic state. Global incidences are rising and the overall prognosis remains poor. The concept of oligometastasis has been established for other tumor entities and is also proposed for upper gastrointestinal tract cancers. This review article explores metastasis mechanisms on the molecular level, specific to esophageal and gastric adenocarcinoma. Existing data and recent studies that deal with upper gastrointestinal tumors in the oligometastatic state are reviewed. Furthermore, current therapeutic targets in gastroesophageal cancers are presented and discussed. Finally, a perspective about future diagnostic and therapeutic strategies is given.

BACKGROUND The liver is the most common site of colorectal liver metastases (CRLM) and surgical resection improves overall survival in selected patients. Here, we investigate outcomes and relevant prognostic factors after repeated hepatic resections for CRLM. METHODS From a prospective database, 578 patients who underwent 788 resections of colorectal liver metastases were included into this study. In total, 169 patients underwent a second and 41 patients had a third operation due to intrahepatic metastatic recurrence. Univariate and multivariate analyses were performed to determine prognostic risk factors. RESULTS 5-year overall survival was 36.7% (95% CI: 30.2%; 43.2%) and 10-year survival was 20.3% (95% CI: 7.6%; 33.0%) in patients undergoing single resection. In patients undergoing a second or third resection, 5- and 10-year survival rates were 56.6% (95% CI: 45.0%; 68.2%) and 21.9% (95% CI: 6.8%; 37.0%) or 53.2% (95% CI: 32.4%; 74.0%) and 25.4%, respectively. In patients undergoing single resection, established markers (number, size and pattern of CRLM [p = 0.030/0.015/

Only a few studies have analyzed multimodal treatment concepts in the subgroup of signet-ring-cell containing upper gastrointestinal (GI) cancer. Recent retrospective, multicentric data favor primary resection without neoadjuvant chemotherapy for gastric signet-ring-cell containing carcinomas (SRCs). We compared the outcomes of primarily resected carcinomas with neoadjuvantly treated, locally advanced esophagogastric SRCs.A total of 310 patients with esophagogastric SRC-staged cT3/4/Nany/Many from a prospective unicentric database were included in this study; 192 (61.9%) received neoadjuvant therapy (NEO group) and 118 (38.1%) were primarily resected (RES group).Overall, 128 (41.3%) patients presented with adenocarcinoma of the esophagogastric junction (AEG) and 182 (58.7%) presented with gastric cancer. Neoadjuvant therapy was significantly associated with resection in curative intent (NEO: 91.1%; RES: 75.4%; P = 0.001), improved (y)pT category (P = 0.035), improved (y)pN category (P 0.001), and R0 resections (curative intent cohort: 76.0% in NEO vs. 60.7% in RES; P = 0.010), among others, but not with postoperative complications. Overall survival was significantly improved by neoadjuvant treatment {median survival 28.5 months (95% confidence interval [CI] 14.4-39.6) vs. RES: 14.9 months (10.6-17.5); P 0.001}, as well as in subgroups (AEG and gastric tumors, R0-resected patients, and patients with and without relevant comorbidities). Independent prognostic factors were neoadjuvant therapy (hazard ratio [HR] 0.66; P = 0.023), pT4 category (HR 1.71; P = 0.041), pN2 category (HR 1.86; P = 0.013), pN3 category (HR 2.40; P 0.001), pM1 category (HR 1.95; P = 0.003), age 70 years (HR 1.79; P = 0.006), gastric localization (HR 0.69; P = 0.032), American Society of Anesthesiologists classification 3/4 (HR 1.71; P = 0.004), and incomplete resection R1/2 (HR 1.6; P = 0.014).Our results demonstrate a survival advantage for advanced-stage esophagogastric SRC patients by neoadjuvant treatment.

While several trials have compared laparoscopic to open surgery for colon cancer showing similar oncological results, oncological quality of laparoscopic versus open rectal resection is not well investigated. A systematic literature search for randomized controlled trials was conducted in MEDLINE, the Cochrane Library, and Embase. Qualitative and quantitative meta-analyses of short-term (rate of complete resections, number of harvested lymph nodes, circumferential resection margin positivity) and long-term (recurrence, disease-free and overall survival) oncologic results were conducted. Fourteen randomized controlled trials were identified including 3528 patients. Patients in the open resection group had significantly more complete resections (OR 0.70; 95% CI 0.51–0.97; p = 0.03) and a higher number of resected lymph nodes (mean difference − 0.92; 95% CI − 1.08 to 0.75; p

The optimal surgical management of adenocarcinoma of the esophagogastric junction (AEG) is challenging and complex. While Siewert type I tumors are treated according to the algorithm of esophageal cancer the optimal approach for Siewert II/III tumors is still under debate (1). In particular, the best operative approach and the extend of lymph node dissection were investigated in several studies without clear consensus (2,3).

// Susanne Blank 1, * , Henrik Nienhuser 1, * , Lena Dreikhausen 1 , Leila Sisic 1 , Ulrike Heger 1 , Katja Ott 2 and Thomas Schmidt 1 1 Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany 2 Romed Klinikum Rosenheim, 83022 Rosenheim, Germany * These authors contributed equally to this work Correspondence to: Thomas Schmidt, email: Thomas.Schmidt1@med.uni-heidelberg.de Keywords: cytokines, inflammation, prognosis, response, esophageal cancer Received: January 13, 2017 Accepted: April 17, 2017 Published: May 07, 2017 ABSTRACT Background: Esophageal cancer is often marked by aggressive tumor growth and poor prognosis. Patient groups who benefit from perioperative therapy are not yet defined. The tumor microenvironment and circulating factors as possible predictors of response and prognosis gain interest. This study aimed to investigate cytokines in patients’ serum and tumor tissue with regard to response and prognosis. Results: Median survival between SCC and AC was not different (published previously). Lower levels of CCL11 (Eotaxin-1) and CXCL10 (IP-10) in the tumor tissue were associated with a better prognosis ( p = 0.022; p = 0.002). In the AC subgroup higher concentrations of TGF-β3 in serum and corresponding tumor tissue were associated with adverse prognosis ( p = 0.035; p = 0.006). An association with histopathological response was found for IL-12(p70) and CXCL10 in patients’ sera ( p = 0.041; p = 0.032). The tissue levels of TGF-β1 and TGF-β2 were significantly lower in histopathological responders than in nonresponders ( p = 0.033; p = 0.007). A similar trend was seen for TGF-β3, without statistical significance ( p = 0.097). Materials and Methods: Preoperative serum samples and corresponding tumor tissue ( n = 54), only serum ( n = 20) or only tissue ( n = 4) were collected from patients undergoing surgery for cT3/4 esophageal squamous cell cancer (SCC) ( n = 34) and adenocarcinoma (AC) ( n = 44). All samples were taken after neoadjuvant treatment. All patients received perioperative chemo(radio)therapy. Cytokine levels of 17 different cytokines were measured by multiplex immunoassay and correlated with clinicopathological factors. Conclusions: Two chemokines (CCL11 and CXCL10) in posttherapeutic tumor tissue were associated with prognosis in patients with esophageal cancer, lower levels indicating a better prognosis. Lower levels of TGF-β were associated with better response and prognosis in patients with AC.

Zusammenfassung Hintergrund Die onkologische Ösophagektomie ist mit hoher Morbidität verbunden. Mit minimal invasiven Operationsverfahren ist verschiedentlich versucht worden, diese zu reduzieren. Hauptproblem ist dabei die intrathorakale Anastomose. Es existieren verschiedene Techniken, mit dem Problem umzugehen, wie die Anlage einer funktionell problematischen zervikalen Anastomose, die offene Anlage der thorakalen Anastomose (Hybrid-Technik) oder die robotergestützte Anlage der technisch sehr anspruchsvollen Zirkularstapleranastomose. Als minimal invasiv auch ohne Roboterassistenz relativ einfach machbare Alternative zeigen wir die intrathorakale Seit-zu-Seit Ösophagogastrostomie in Linearstapler-Technik. Operationstechnik Der abdominelle Teil erfolgt in French-Lagerung. Nach Dissektion des Omentum majus entlang der gastroepiploischen Arkade und des Milzhilus sowie Trennung des Omentum minus 6 cm präpylorisch wird ein 4,5 cm breiter Magenschlauch in Linearstaplertechnik gebildet. Dann erfolgt die systematische abdominale und transmediastinale Lymphadenekotmie. Nach Umlagerung des Patienten in Links-Seitenlage wird die Lymphadenektomie thorakal komplettiert und das Präparat entfernt. Die Seit-zu-Seit Ösophagogastrostomie beginnt mit der Inzision des Ösophagusstumpfes. Dann wird der Magenschlauch mesonah 5 cm vom oralen Absetzungsrand inzidiert und ein Linearstapler über 3 cm in die beiden Inzisionen eingebracht und abgefeuert. Die verbleibende Öffnung wird mit einer fortlaufenden Naht modifiziert zweireihig quer verschlossen. Diskussion Die Seit-zu-Seit Ösophagogastrostomie in Linearstapler-Technik scheint eine einfache und sichere Alternative für die Rekonstruktion nach minimal invasiver Ösophagektomie zu sein. Die Methode wird aktuell in einer randomisiert kontrollierten Studie untersucht.

Background & Aims Enterochromaffin-like (ECL) cells in the stomach express gastrin/cholecystokinin 2 receptor CCK2R and are known to expand under hypergastrinemia, but whether this results from expansion of existing ECL cells or increased production from progenitors has not been clarified. Methods We used mice with green fluorescent protein fluorescent reporter expression in ECL cells (histidine decarboxylase [Hdc]-green fluorescent protein), as well as Cck2r- and Hdc-driven Tamoxifen inducible recombinase Cre (Cck2r-CreERT2, Hdc-CreERT2) mice combined with Rosa26Sor-tdTomato (R26-tdTomato) mice, and studied their expression and cell fate in the gastric corpus by using models of hypergastrinemia (gastrin infusion, omeprazole treatment). Results Hdc-GFP marked the majority of ECL cells, located in the lower third of the gastric glands. Hypergastrinemia led to expansion of ECL cells that was not restricted to the gland base, and promoted cellular proliferation (Ki67) in the gastric isthmus but not in basal ECL cells. Cck2r-CreERT2 mice marked most ECL cells, as well as scattered cell types located higher up in the glands, whose number was increased during hypergastrinemia. Cck2r-CreERT2+ isthmus progenitors, but not Hdc+ mature ECL cells, were the source of ECL cell hyperplasia during hypergastrinemia and could grow as 3-dimensional spheroids in vitro. Moreover, gastrin treatment in vitro promoted sphere formation from sorted Cck2r+Hdc- cells, and increased chromogranin A and phosphorylated- extracellular signal-regulated kinase expression in CCK2R-derived organoids. Gastrin activates extracellular signal-regulated kinase pathways in vivo and in vitro, and treatment with the Mitogen-activated protein kinase kinase 1 inhibitor U0126 blocked hypergastrinemia-mediated changes, including CCK2R-derived ECL cell hyperplasia in vivo as well as sphere formation and chromogranin A expression in vitro. Conclusions We show here that hypergastrinemia induces ECL cell hyperplasia that is derived primarily from CCK2R+ progenitors in the corpus. Gastrin-dependent function of CCK2R+ progenitors is regulated by the extracellular signal-regulated kinase pathway., Graphical abstract

Hintergrund Magenstumpfkarzinome entstehen im Restmagen nach partieller Gastrektomie. Wahrend die Haufigkeit des Magenkarzinoms abnimmt, bleibt die Inzidenz des Magenstumpfkarzinoms aufgrund einer langen Latenzzeit stabil. Nachdem die chirurgische Therapie von Magenulzera durch partielle Gastrektomien an Bedeutung verloren hat, entwickeln sich zunehmend Magenstumpfkarzinome nach onkologischen Resektionen.

The aim of this systematic review and meta-analysis was to compare the oncological and perioperative outcomes of transhiatally extended gastrectomy (TEG) and thoracoabdominal esophagectomy (TAE) for therapy of adenocarcinomas of the esophagogastric junction (AEG) with focus on AEG type II, as the optimal approach for these tumors is still unclear. MEDLINE, EMBASE, and the Cochrane Library (CENTRAL) were searched until July 24, 2018. Studies comparing TAE and TEG for surgical treatment of AEG type tumors have been included. Patient’s baseline and perioperative data have been extracted and meta-analyses have been conducted for the outcomes: number of dissected lymph nodes, R0-resection rate, anastomotic leak rate, postoperative morbidity, and 30-day mortality. Of 6709 articles identified, 8 studies have been included for further analysis. One thousand thirty-four patients underwent TAE, and 1177 patients TEG. No differences were found between the approaches in regard to number of dissected lymph nodes (MD − 0.96; 95% CI − 3.07 to 1.15; p = 0.37), R0-resection rates (OR 0.97; 95% CI 0.57 to 1.63; p = 0.90), anastomotic leak rates (OR 1.13; 95% CI 0.69 to 1.86; p = 0.63), and 30-day mortality (OR 1.53; 95% CI 0.90 to 2.61; p = 0.11). However, a higher rate of postoperative morbidity was found after TAE (OR 1.55; 95% CI 1.12 to 2.14; p = 0.008). The optimal approach to surgical therapy of AEG II still remains unclear. This study identified a significantly higher rate of postoperative morbidity after TAE at comparable surgical outcomes. Due to major limitations concerning the quality of included studies, current data strongly mandates a properly designed randomized controlled trial to identify the optimal surgical approach for AEG type II tumors.

Gastric cancer is one of the most frequent malignancies worldwide. Despite improvements in diagnosis and therapy, the overall prognosis remains poor. In the last decade, several anti-angiogenic drugs for cancer treatment have been approved and lately also introduced to gastric cancer treatment. While the initial trials focused only on unresectable or metastatic cancer, anti-angiogenic treatment is now also investigated in the perioperative and neoadjuvant setting. In this review, an overview of the role of angiogenesis and angiogenic factors in gastric cancer as well as anti-angiogenic treatment of gastric cancer is provided. Findings from in vitro and animal studies are summarized and put in a context with translational data on angiogenesis in gastric cancer. The most important angiogenic factors and their effect in gastric cancer are highlighted and clinical trials including anti-angiogenic drugs are discussed. Finally, an outlook of biomarkers for predicting response to anti-angiogenic treatment is presented, the ongoing trials on this topic are discussed and current challenges of anti-angiogenic therapy are outlined.

Prognostic differences between pTN- and ypTN-categories and the prognostic accuracy of the 8th edition UICC-pTNM- and AJCC-ypTNM-staging-system for esophageal and gastric adenocarcinoma are unclear.We retrospectively analyzed data of 740 patients with esophagogastric adenocarcinoma, who underwent curative surgery (344 after neoadjuvant treatment [NT]) at our institution. Survival analyses were performed according to Kaplan-Meier (log-rank test). Multivariate analyses were performed using the Cox proportional hazard model.Low ypT-categories did not discriminate overall survival (ypT0: reference; ypT1: HR1.0/p = 0.909; ypT2: HR0.9/p = 0.845; ypT3: HR1.5/p = 0.184; ypT4: HR2.8/p = 0.004) and no difference was found between ypN1- and ypN2-disease (ypN0: HR0.4/p 0.001; ypN1: reference; ypN2: HR1.1/p = 0.653; ypN3: HR1.7/p = 0.014). In esophageal adenocarcinoma the UICC-TNM- and AJCC-ypTNM-staging-system was able to predict survival for patients after NT, while in gastric cancer it failed to provide sufficient prognostic information. A simplified staging system provided better stratification after NT and was an independent prognosticator for both esophageal and gastric adenocarcinoma (stage I: reference; stage II: HR2.2/p = 0.005; stage III: HR4.1/p 0.001).Prognostic value of ypTN-categories seems limited. After NT the current UICC/AJCC-staging-system is able to predict survival in esophageal adenocarcinoma, but needs to be reevaluated in gastric cancer patients and modified if needed. A novel simplified staging system might be more practicable for patients after NT.