Clinical outcome in patients with carcinoma of the esophagogastric junction treated with neoadjuvant radiochemotherapy or perioperative chemotherapy: a two-enter retrospective analysis

BACKGROUND: Adenocarcinoma of the esophagogastric junction (AEG) is a rare but rising tumor entity in the Western world. Treatment is complex, as multimodality is key to optimal results. However, trials solely including AEG are rare, and the question if neoadjuvant radiochemotherapy (NRCT) or neoadjuvant/perioperative chemotherapy (NACT) is superior remains unanswered. PATIENTS AND METHODS: Patients with AEG I–III treated between October 2010 and August 2019 at the Ordensklinikum Linz or the Kepler University Hospital were identified either from a monitored tumor registry or by chart review. Time-to-event data were analyzed by Kaplan-Meier product limit estimation. The Kruskal-Wallis test and Fisher’s exact test were used for comparing continuous and categorical data, respectively. RESULTS: A total of 85 patients (median age 63 years; median Charlson Comorbidity Index 3; 98.8% ECOG PS 0–1) were analyzed. Of these, 52 patients received NRCT (81% CROSS protocol) and 33 NACT (65% EOX and 35% FLOT protocol). There was a significantly higher pathological complete response rate in the NRCT group (30 vs. 12%; p = 0.010); distant relapse rates were higher in the NRCT group and local relapse rates were higher in the NACT group (both not significant). These differences, however, did not translate into a different disease-free survival (20 months; 95% CI: 13–34) or overall survival (44 months; 95% CI: 33–NA). Patients >65 years old had the same advantage from treatment as patients <65 years of age. CONCLUSIONS: Although treatment of AEG is complex, the progress documented over the last centuries can be reproduced in our real-life setting. Data regarding the superiority of either type of neoadjuvant/perioperative treatment are sparse. We assume no difference between EOX-based NACT and NRCT

cAMP- and Ca²⁺/calmodulin-dependent protein kinases mediate inotropic, lusitropic and arrhythmogenic effects of urocortin 2 in mouse ventricular myocytes

BACKGROUND AND PURPOSE: Urocortin 2 is beneficial in heart failure, but the underlying cellular mechanisms are not completely understood. Here we have characterized the functional effects of urocortin 2 on mouse cardiomyocytes and elucidated the underlying signalling pathways and mechanisms. EXPERIMENTAL APPROACH: Mouse ventricular myocytes were field-stimulated at 0.5 Hz at room temperature. Fractional shortening and [Ca(2+)](i) transients were measured by an edge detection and epifluorescence system respectively. Western blots were carried out on myocyte extracts with antibodies against total phospholamban (PLN) and PLN phosphorylated at serine-16. KEY RESULTS: Urocortin 2 elicited time- and concentration-dependent positive inotropic and lusitropic effects (EC(50): 19 nM) that were abolished by antisauvagine-30 (10 nM, n = 6), a specific antagonist of corticotrophin releasing factor (CRF) CRF(2) receptors. Urocortin 2 (100 nM) increased the amplitude and decreased the time constant of decay of the underlying [Ca(2+)](i) transients. Urocortin 2 also increased PLN phosphorylation at serine-16. H89 (2 µM) or KT5720 (1 µM), two inhibitors of protein kinase A (PKA), as well as KN93 (1 µM), an inhibitor of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), suppressed the urocortin 2 effects on shortening and [Ca(2+)](i) transients. In addition, urocortin 2 also elicited arrhythmogenic events consisting of extra cell shortenings and extra [Ca(2+)](i) increases in diastole. Urocortin 2-induced arrhythmogenic events were significantly reduced in cells pretreated with KT5720 or KN93. CONCLUSIONS AND IMPLICATIONS: Urocortin 2 enhanced contractility in mouse ventricular myocytes via activation of CRF(2) receptors in a cAMP/PKA- and Ca(2+)/CaMKII-dependent manner. This enhancement was accompanied by Ca(2+)-dependent arrhythmogenic effects mediated by PKA and CaMKII