Characteristics, Treatment Patterns and Survival of International Federation of Gynecology and Obstetrics Stage IV Epithelial Ovarian Cancer-A Population-Based Study.

BACKGROUND: The aim of the present study was to describe an unselected population of patients with diagnosis of FIGO stage IV OC. METHODS: Data from 1183 patients were available for analysis. RESULTS: The majority of patients (962/1183, 81.3%) received cancer-directed treatment. The median follow-up time was 3.8 years, and the median overall survival duration was 1.9 years. Notably, patients >80 years had a low overall survival rate (HR of age >80 years vs. ≤50 years was 3.81, 95%-CI [2.76, 5.27], p < 0.0001). The survival rate was best in patients with HGSOC (p < 0.0001). The highest overall survival rate was observed in patients in the group with surgical intervention followed by systemic treatment, with an unadjusted HR of 0.72, 95%-CI [0.59, 0.86], p = 0.007 vs. systemic treatment only. After adjustment for age and histology, survival differences between treatment schemes were smaller (HR 0.81, 95%-CI [0.66, 1.00], p = 0.12). CONCLUSIONS: In this cohort of patients with FIGO stage IV OC, more than 80% of the patients received cancer-directed treatment. Age and high-grade serous histology were determinants for survival. The highest overall survival rate was observed in patients who underwent surgery followed by systemic treatment.

Heterogeneity and Remodeling of Ion Currents in Cultured Right Atrial Fibroblasts From Patients With Sinus Rhythm or Atrial Fibrillation.

Cardiac fibroblasts express multiple voltage-dependent ion channels. Even though fibroblasts do not generate action potentials, they may influence cardiac electrophysiology by electrical coupling via gap junctions with cardiomyocytes, and through fibrosis. Here, we investigate the electrophysiological phenotype of cultured fibroblasts from right atrial appendage tissue of patients with sinus rhythm (SR) or atrial fibrillation (AF). Using the patch-clamp technique in whole-cell mode, we observed steady-state outward currents exhibiting either no rectification or inward and/or outward rectification. The distributions of current patterns between fibroblasts from SR and AF patients were not significantly different. In response to depolarizing voltage pulses, we measured transient outward currents with fast and slow activation kinetics, an outward background current, and an inward current with a potential-dependence resembling that of L-type Ca2+ channels. In cell-attached patch-clamp mode, large amplitude, paxilline-sensitive single channel openings were found in ≈65% of SR and ∼38% of AF fibroblasts, suggesting the presence of "big conductance Ca2+-activated K+ (BK Ca )" channels. The open probability of BK Ca was significantly lower in AF than in SR fibroblasts. When cultured in the presence of paxilline, the shape of fibroblasts became wider and less spindle-like. Our data confirm previous findings on cardiac fibroblast electrophysiology and extend them by illustrating differential channel expression in human atrial fibroblasts from SR and AF tissue.

Piezo1 and BKCa channels in human atrial fibroblasts: Interplay and remodelling in atrial fibrillation.

AIMS: Atrial Fibrillation (AF) is an arrhythmia of increasing prevalence in the aging populations of developed countries. One of the important indicators of AF is sustained atrial dilatation, highlighting the importance of mechanical overload in the pathophysiology of AF. The mechanisms by which atrial cells, including fibroblasts, sense and react to changing mechanical forces, are not fully elucidated. Here, we characterise stretch-activated ion channels (SAC) in human atrial fibroblasts and changes in SAC- presence and activity associated with AF. METHODS AND RESULTS: Using primary cultures of human atrial fibroblasts, isolated from patients in sinus rhythm or sustained AF, we combine electrophysiological, molecular and pharmacological tools to identify SAC. Two electrophysiological SAC- signatures were detected, indicative of cation-nonselective and potassium-selective channels. Using siRNA-mediated knockdown, we identified the cation-nonselective SAC as Piezo1. Biophysical properties of the potassium-selective channel, its sensitivity to calcium, paxilline or iberiotoxin (blockers), and NS11021 (activator), indicated presence of calcium-dependent 'big potassium channels' (BKCa). In cells from AF patients, Piezo1 activity and mRNA expression levels were higher than in cells from sinus rhythm patients, while BKCa activity (but not expression) was downregulated. Both Piezo1-knockdown and removal of extracellular calcium from the patch pipette resulted in a significant reduction of BKCa current during stretch. No co-immunoprecipitation of Piezo1 and BKCa was detected. CONCLUSIONS: Human atrial fibroblasts contain at least two types of ion channels that are activated during stretch: Piezo1 and BKCa. While Piezo1 is directly stretch-activated, the increase in BKCa activity during mechanical stimulation appears to be mainly secondary to calcium influx via SAC such as Piezo1. During sustained AF, Piezo1 is increased, while BKCa activity is reduced, highlighting differential regulation of both channels. Our data support the presence and interplay of Piezo1 and BKCa in human atrial fibroblasts in the absence of physical links between the two channel proteins.

Cardiac fibroblasts : Active players in (atrial) electrophysiology?

Fibrotic areas in cardiac muscle-be it in ventricular or atrial tissue-are considered as obstacles for conduction of the excitatory wave and can therefore facilitate re-entry, which may contribute to the sustenance of cardiac arrhythmias. Persistence of one of the most frequent arrhythmias, atrial fibrillation (AF), is accompanied by enhanced atrial fibrosis. Any kind of myocardial perturbation, whether via mechanical stress or ischemic damage, inflammation, or irregular and high-frequency electrical activity, activates fibroblasts. This leads to the secretion of paracrine factors and extracellular matrix proteins, especially collagen, and to the differentiation of fibroblasts into myofibroblasts. Excessive collagen production is the hallmark of fibrosis and impairs regular impulse propagation. In addition, direct electrical coupling between cardiomyocytes and nonmyocytes, such as fibroblasts and macrophages, via gap junctions affects conduction. Although fibroblasts are not electrically excitable, they express functional ion channels, in particular K+ channels and mechanosensitive channels, some of which could be involved in tissue remodeling. Here, we briefly review these aspects with special reference to AF.