Background: Resistance towards chemotherapy is a major obstacle in the treatment of esophageal squamous cell carcinoma (ESCC). We investigated the role of specific microRNAs in chemotherapy resistance and tumor biology. Methods: We selected three microRNAs from characteristic microRNA signatures of resistant ESCC (hsa-miR-125a-5p, hsa-miR-130a-3p, hsa-miR-1226-3p), and hsa-miR-148a-3p. Effects on chemotherapy, adhesion, migration, apoptosis and cell cycle were assessed in six ESCC cell lines. Target analyses were performed using Western blotting and luciferase techniques. Results: MiR-130a-3p sensitized cells towards cisplatin in 100% of cell lines, miR-148a-3p in 83%, miR-125a-5p in 67%, miR-1226-3p in 50% (p ≤ 0.04). MiR-130a-3p sensitized 83% of cell lines towards 5-FU, miR-148a-3p/miR-125a-5p/miR-1226-3p only 33% (p ≤ 0.015). Several resistance-relevant pathways seem to be targeted on various levels. Bcl-2 was confirmed as a direct target of miR-130a-3p and miR-148a-3p, and p53 as a target of miR-125a-5p. All microRNAs decreased migration and adhesion, except miR-130a-3p, and increased apoptosis. Simultaneous manipulation of two microRNAs exhibited additive sensitizing effects towards cisplatin in 50% (miR-125a-5p/miR-148a-3p), and 75% (miR-148a-3p/miR-130a-3p) of cell lines (p ≤ 0.006). Conclusion: Our data present strong evidence that specific microRNA signatures are responsible for drug resistance and aggressiveness of ESCC. Final functional readout of these complex processes appears to be more important than single microRNA-target interactions.

Background Endoscopic vacuum therapy (EVT) has become a promising option in the management of anastomotic leakage (AL) after esophagectomy. However, EVT is an effortful approach associated with multiple interventions. In this study, we conduct a comparative cost analysis for methods of management of AL. Methods All patients who experienced AL treated by EVT, stent, or reoperation following Ivor Lewis esophagectomy for esophageal cancer were included. Cases that were managed by more than one modality were excluded. For the remaining cases, in-patient treatment cost was collected for material, personnel, (par)enteral nutrition, intensive care, operating room, and imaging. Results 42 patients were treated as follows: EVT n = 25, stent n = 13, and reoperation n = 4. The mean duration of therapy as well as length of overall hospital stay was significantly shorter in the stent than the EVT group (30 vs. 44d, p = 0.046; 34 vs. 53d, p = 0.02). The total mean cost for stent was €33.685, and the total cost for EVT was €46.136, resulting in a delta increase of 37% for EVT vs. stent cost. 75% (€34.320, EVT), respectively, 80% (€26.900, stent) of total costs were caused by ICU stay. Mean pure costs for endoscopic management were relatively low and comparable between both groups (EVT: €1.900, stent: €1.100, p = 0.28). Conclusion Management of AL represents an effortful approach that results in high overall costs. The expenses directly related to EVT and stent therapy were however comparatively low with more than 75% of costs being attributable to the ICU stay. Reduction of ICU care should be a central part of cost reduction strategies.

Background Tracheo- or bronchoesophageal fistula (TBF) occurring after esophagectomy represent a rare but devastating complication. Management remains challenging and controversial. Therefore, the purpose of this study was to evaluate the outcome of different treatment approaches and to propose recommendations for the management of TBF. Methods From 2008 to 2018, 15 patients were treated because of TBF and were analyzed with respect to fistula appearance, treatment strategy (stenting, endoscopic vacuum therapy and/or surgical reintervention) and outcome. Results In each case, the fistula was small, located close to the tracheal bifurcation and associated simultaneously (n = 6, 40%) or metachronously (n = 9, 60%) with an anastomotic leakage. Latter was covered by esophageal stents in six patients which in turn resulted in occurrence of TBF at a later time in five patients. Management of TBF included conservative therapy (n = 3), stenting (n = 6), or suturing (n = 6). Ten patients underwent rethoracotomy. Treatment failure was observed in eight patients (53%). In all patients, treatment was accompanied by progressive sepsis. On the contrary, all seven patients with successful defect closure remained in good general condition. Conclusion Fistula appearance was similar in all patients. Implementation of esophageal stents cannot be recommended because of possibility of TBF at a later time point. Surgery is usually required and should preferably be performed when the patient's condition has been optimized at a single-stage repair. Esophageal diversion can only be recommended in patients with persisting mediastinitis. The key element for successful treatment of TBF, however, is control over sepsis; otherwise, outcome of TBF is devastating.

Many patients with Oesophageal Adenocarcinoma (OAC) do not benefit from chemoradiotherapy treatment due to therapy resistance. To better understand the mechanisms involved in resistance and to find potential biomarkers, we investigated the association of microRNAs, which regulate gene expression, with the response to individual treatments, focusing on radiation. Intrinsic radiation resistance and chemotherapy drug resistance were assessed in eight OAC cell lines, and miRNA expression profiling was performed via TaqMan OpenArray qPCR. miRNAs discovered were either uniquely associated with resistance to radiation, cisplatin, or 5-FU, or were common to two or all three of the treatments. Target mRNA pathway analyses indicated several potential mechanisms of treatment resistance. miRNAs associated with the in vitro treatment responses were then investigated for association with pathologic response to neoadjuvant chemoradiotherapy (nCRT) in pre-treatment serums of patients with OAC. miR-451a was associated uniquely with resistance to radiation treatment in the cell lines, and with the response to nCRT in patient serums. Inhibition of miR-451a in the radiation resistant OAC cell line OE19 increased radiosensitivity (Survival Fraction 73% vs. 87%, p = 0.0003), and altered RNA expression. Pathway analysis of effected small non-coding RNAs and corresponding mRNA targets suggest potential mechanisms of radiation resistance in OAC.