Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump.

Intracerebral convection-enhanced delivery (CED) of chemotherapeutic agents currently requires an externalized catheter and infusion system, which limits its duration because of the need for hospitalization and the risk of infection. To evaluate the feasibility of prolonged topotecan administration by CED in a large animal brain with the use of a subcutaneous implantable pump. Medtronic Synchromed-II pumps were implanted subcutaneously for intracerebral CED in pigs. Gadodiamide (28.7 mg/mL), with or without topotecan (136 µM), was infused at 0.7 mL/24 h for 3 or 10 days. Pigs underwent magnetic resonance imaging before and at 6 times points after surgery. Enhancement and FLAIR+ volumes were calculated in a semi-automated fashion. Magnetic resonance spectroscopy-based topotecan signature was also investigated. Brain histology was analyzed by hematoxylin and eosin staining and with immunoperoxidase for a microglial antigen. CED of topotecan/gadolinium was well tolerated in all cases (n = 6). Maximum enhancement volume was reached at day 3 and remained stable if CED was continued for 10 days, but it decreased if CED was stopped at day 3. Magnetic resonance spectroscopy revealed a decrease in parenchymal metabolites in the presence of topotecan. Similarly, the combination of topotecan and gadolinium infusion led to a FLAIR+ volume that tended to be larger than that seen after the infusion of gadolinium alone. Histological analysis of the brains showed an area of macrophage infiltrate in the ipsilateral white matter upon infusion with topotecan/gadolinium. Intracerebral topotecan CED is well tolerated in a large animal brain for up to 10 days. Intracerebral long-term CED can be achieved with a subcutaneously implanted pump and provides a stable volume of distribution. This work constitutes a proof of principle for the safety and feasibility for prolonged CED, providing a means of continuous local drug delivery that is accessible to the practicing neuro-oncologist.

Selective ganglionated plexi ablation for paroxysmal atrial fibrillation.

BACKGROUND: Selective ganglionated plexi (GP) ablation guided by high-frequency stimulation has been proposed for the treatment of paroxysmal atrial fibrillation (AF), but the efficacy of the method is not established. OBJECTIVE: This study sought to compare selective ablation of GP identified by high-frequency stimulation with extensive regional ablation targeting the anatomic areas of GP in patients with paroxysmal AF. METHODS: Eighty patients with paroxysmal AF (age 53 +/- 9 years) were randomized to undergo selective GP ablation or regional left atrial ablation at the anatomic sites of GP. For selective GP ablation (n = 40), ablation targets were the sites where vagal reflexes were evoked by high-frequency stimulation. Vagal reflexes were defined as prolongation of the R-R interval by >50% and a concomitant decrease in blood pressure (>20 mm Hg) during AF. The end point of the procedure was failure to reproduce vagal reflexes with repeated high-frequency stimulation. For anatomic ablation, lesions were delivered at the sites of GP clustering. RESULTS: At 13.1 +/- 1.9 months, 42.5% of patients with selective GP and 77.5% of patients with anatomic ablation were free of symptomatic paroxysmal AF (PAF) (P = .02). Parasympathetic denervation was more prominent in patients with anatomic than selective GP ablation, and in patients free of AF compared to these with AF recurrence immediately after ablation, but this trend was abolished at 6 months. CONCLUSION: Selective GP ablation directed by high-frequency stimulation does not eliminate paroxysmal AF in the majority of patients. An anatomic approach for regional ablation at the sites of GP confers better results.

Catheter ablation of left atrial ganglionated plexi for atrial fibrillation.

Radiofrequency ablation of pulmonary vein ostia does not provide complete and long-term elimination of atrial fibrillation. Combining this procedure with local radiofrequency application on sites with strong vagal reflexes results in partial parasympathetic denervation and increases the antiarrhythmic effect. A novel catheter-ablation technique to modify ganglionated plexi in the left atrium was assessed in 58 patients (mean age, 52.1 +/- 1.9 years, 67% male) with drug-refractory atrial fibrillation, which was chronic in 21 (36%; mean duration, 14.3 +/- 2.9 months; range, 5-39 months). The mean left atrial volume was 93.1 +/- 6.1 mL. The patients underwent ablation of 4 areas of ganglionated plexi in the left atrium, with no circumferential ablation of the pulmonary veins; atrial fibrillation ceased immediately in 94.1% of them. Transient vagal bradycardia was seen in 93% of patients. For 7.2 +/- 0.4 months after the procedure, 86.2% of them were free from arrhythmias, and no antiarrhythmic drugs were administered. Ganglionated plexi ablation is an efficient treatment for atrial fibrillation.