withdrawn 2017 hrs ehra ecas aphrs solaece expert consensus statement on catheter and surgical ablation of atrial fibrillation

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Safety and efficacy of high-intensity focused ultrasound atop coronary arteries during epicardial catheter ablation

Coronary arterial injury continues to be a limitation of epicardial catheter ablation using currently available energy sources. Application of high intensity focused ultrasound (HIFU) energy may avoid such injury due to its theoretical ability to focus energy beyond the ablation element and create lesions at depth. This study evaluated the safety of HIFU applications delivered directly over the left anterior descending (LAD) artery in an open-chest swine model. Ten swine underwent median sternotomy. A prototype HIFU probe was placed atop the LAD. Forty-three therapies along the LAD (60-seconds/6 watt) were analyzed. Three, 3, and 4 swine were studied at 2, 4, and 8 weeks and subsequently sacrificed. Lesions were scored (0-4) depending on the percent circumferential involvement of arteries. Lesion area increased minimally from 54.5 ± 18.0 mm(2) at 2 weeks to 56.9 ± 20.6 mm(2) at 8 weeks, and depth increased moderately from 13.2 ± 2.5 mm to 15.5 ± 3.4 mm. At 2, 4, and 8 weeks, the mean injury score of the LAD was 0.8 ± 0.3, 1.5 ± 0.9, and 2.0 ± 0.7. No/minimal arterial injury was seen in 64% of all sections. However, a progressive increase in injury resulted in 89% of all sections showing any injury at 8 weeks. One animal developed occlusion of the distal LAD. HIFU has the potential to create deep ventricular lesions with relative sparing of the LAD. The incremental arterial damage noted over time warrants further evaluation to support the viability of focusing ultrasound energy beyond vulnerable critical structures to ablate deeper targets

Variable Presentations and Ablation Sites for Manifest Nodoventricular/Nodofascicular Fibers

Background: Nodofascicular and nodoventricular (NFV) accessory pathways connect the atrioventricular node and the Purkinje system or ventricular myocardium, respectively. Concealed NFV pathways participate as the retrograde limb of supraventricular tachycardia (SVT). Manifest NFV pathways can comprise the anterograde limb of wide-complex SVT but are quite rare. The purpose of this report is to highlight the electrophysiological properties and sites of ablation for manifest NFV pathways. Methods: Eight patients underwent electrophysiology studies for wide-complex tachycardia (3), for narrow-complex tachycardia (1), and preexcitation (4). Results: NFV was an integral part of the SVT circuit in 3 patients. Cases 1 to 2 were wide-complex tachycardia because of manifest NFV SVT. Case 3 was a bidirectional NFV that conducted retrograde during concealed NFV SVT and anterograde causing preexcitation during atrial pacing. NFV was a bystander during atrioventricular node re-entrant tachycardia, atrial fibrillation, atrial flutter, and orthodromic atrioventricular re-entrant tachycardia in 4 cases and caused only preexcitation in 1. Successful NFV ablation was achieved empirically in the slow pathway region in 1 case. In 5 cases, the ventricular insertion was mapped to the slow pathway region (2 cases) or septal right ventricle (3 cases). The NFV was not mapped in cases 5 and 7 because of its bystander role. QRS morphology of preexcitation predicted the right ventricle insertion sites in 4 of the 5 cases in which it was mapped. During follow-up, 1 patient noted recurrent palpitations but no documented SVT. Conclusions: Manifest NFV may be critical for wide-complex tachycardia/manifest NFV SVT, act as the retrograde limb for narrow-complex tachycardia/concealed NFV SVT, or cause bystander preexcitation. Ablation should initially target the slow pathway region, with mapping of the right ventricle insertion site if slow pathway ablation is not successful. The QRS morphology of maximal preexcitation may be helpful in predicting successful right ventricle ablation site

A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours

BACKGROUND: This phase I, open-label, dose-escalation study evaluated the safety, pharmacokinetics and pharmacodynamics of combination therapy with the HDM2 inhibitor SAR405838 and the MEK1/2 inhibitor pimasertib administered orally once daily (QD) or twice daily (BID) in locally advanced or metastatic solid tumours (NCT01985191). METHODS: Patients with locally advanced or metastatic solid tumours with documented wild-type TP53 and RAS or RAF mutations were enroled. A 3 + 3 dose-escalation design was employed. The primary objective was to assess maximum tolerated dose (MTD). RESULTS: Twenty-six patients were treated with SAR405838 200 or 300 mg QD plus pimasertib 60 mg QD or 45 mg BID. The MTD was SAR405838 200 mg QD plus pimasertib 45 mg BID. The most common dose-limiting toxicity was thrombocytopenia. The most frequently occurring treatment-related adverse events were diarrhoea (81%), increased blood creatine phosphokinase (77%), nausea (62%) and vomiting (62%). No significant drug-drug interactions were observed. The biomarkers MIC-1 and pERK were, respectively, upregulated and downregulated in response to study treatment. In 24 efficacy-evaluable patients, one patient (4%) had a partial response and 63% had stable disease. CONCLUSIONS: The safety profile of SAR405838 and pimasertib combined was consistent with the safety profiles of both drugs. Preliminary antitumour activity was observed

A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours

BACKGROUND: This phase I, open-label, dose-escalation study evaluated the safety, pharmacokinetics and pharmacodynamics of combination therapy with the HDM2 inhibitor SAR405838 and the MEK1/2 inhibitor pimasertib administered orally once daily (QD) or twice daily (BID) in locally advanced or metastatic solid tumours (NCT01985191). METHODS: Patients with locally advanced or metastatic solid tumours with documented wild-type TP53 and RAS or RAF mutations were enroled. A 3 + 3 dose-escalation design was employed. The primary objective was to assess maximum tolerated dose (MTD). RESULTS: Twenty-six patients were treated with SAR405838 200 or 300 mg QD plus pimasertib 60 mg QD or 45 mg BID. The MTD was SAR405838 200 mg QD plus pimasertib 45 mg BID. The most common dose-limiting toxicity was thrombocytopenia. The most frequently occurring treatment-related adverse events were diarrhoea (81%), increased blood creatine phosphokinase (77%), nausea (62%) and vomiting (62%). No significant drug-drug interactions were observed. The biomarkers MIC-1 and pERK were, respectively, upregulated and downregulated in response to study treatment. In 24 efficacy-evaluable patients, one patient (4%) had a partial response and 63% had stable disease. CONCLUSIONS: The safety profile of SAR405838 and pimasertib combined was consistent with the safety profiles of both drugs. Preliminary antitumour activity was observed