Current literature on BEST for slow-flow malformations, though limited, includes valuable insights from case reports and retrospective case series7,8,9 conducted on mixed patient groups encompassing both pediatric and adult populations. Our study exclusively focuses on a pediatric population, employing a prospective design to evaluate the effectiveness and patient outcomes of BEST in treating slow-flow malformations.
This prospective observational study was conducted at the tertiary care Interdisciplinary Vascular Anomalies Center at the University Hospital Halle (Saale), Germany. The aim of the study was to evaluate the efficacy and safety of BEST in pediatric patients undergoing treatment for slow-flow malformations.
The study was approved by the Institutional Review Board of the Martin-Luther-University Halle-Wittenberg (approval number 2019-150). Written informed consent was obtained from all patients and/or legal guardians prior to their enrollment in the study.
A total of 30 pediatric patients (under age 18) were recruited between 2020 and 2021, with follow-up continuing until December 2024 (mean follow-up period of 25 months). Eligibility criteria included undergoing at least one BEST treatment session and having an MRI both before the first treatment and at follow-up. Patients were excluded from the study if they did not attend the follow-up assessment, if follow-up MRI imaging was unavailable or if MRI evaluation was not feasible (e.g., due to artifacts or incomplete protocol). Diagnosis of simple or combined venous malformations was based on patient history, ultrasound, magnetic resonance imaging (MRI), and clinical examination findings. Collected demographic data included age, sex, and details of prior treatments.
Patients received one or more BEST treatments. Before the intervention, laboratory tests including creatinine, C-reactive protein, complete blood count, liver function tests, D-dimer, and fibrinogen levels were obtained. If the patient's history or current clinical presentation suggested pulmonary disease, a pulmonology consultation was obtained, and further investigations such as chest X-ray were performed as recommended by the pulmonologist. All interventions were performed under general anesthesia. First, color-coded duplex sonography was performed. In cases of direct application of bleomycin, ultrasound-guided puncture was performed and contrast agent (Imeron 300; Bracco Imaging Deutschland GmbH, Konstanz, Germany) was applied. Correct needle positioning was then confirmed under fluoroscopy to rule out connections to the deep venous system and estimate the required bleomycin volume for intralesional injection based on visualized lesion size (Fig. 1a). For larger and complex malformations, systemic bleomycin application adapted to the bodyweight was also considered.
The following BEST treatment consisted of three main steps: (1) electrode positioning, (2) intravenous or intralesional Bleomycin infusion (or intralesional injection for smaller lesions), and (3) application of short electric pulses for reversible electroporation. Following the latest guidelines for electrochemotherapy, after an intravenous short infusion, a waiting period of 8 minutes allowed for adequate distribution of Bleomycin in the bloodstream and monitoring for any immediate adverse reactions. If Bleomycin was injected directly into the lesion, the waiting time was reduced to 1-3 min. The maximum bleomycin dose was limited to 1 mg/5 kg body weight per intervention and <5 mg/kg body weight cumulative dose in case of multiple treatment sessions. The maximum Bleomycin concentration was 0.25 mg/ml for both intravenous and intralesional application. Depending on size and location of the malformation, different electrode types were used, including adjustable hexagonal or linear electrodes, finger electrodes, or needle electrodes (Fig. 1b). Electric pulses were applied using an electrical pulse generator (Cliniporator VITAE; IGEA SpA, Carpi, Italy). For each treatment session, the anatomical location of the lesion, the number of electroporation cycles, and the administered Bleomycin dose were documented. Complications were recorded, graded and classified as either temporary or permanent according to the CIRSE classification system.
Treatment outcomes were assessed using MRI-based volumetry. To ensure measurement reliability, MRI scans followed a standardized protocol, with measurements performed by a radiologist with five years of experience in vascular malformation imaging and subsequently verified by an independent radiologist with over 20 years of experience. Equatorial and polar diameters of the slow-flow malformations were measured in T2-weighted short-tau inversion recovery (STIR) fat saturated sequences. Volumes were calculated using the rotational ellipsoid formula , where is the equatorial diameter and is the polar diameter. The pre-treatment volume served as the baseline for all subsequent measurements. MRI scans were performed at each follow-up visit. Based on these volumetric measurements, absolute and relative volume reductions were calculated. Absolute volume reduction was defined as the difference between the baseline and follow-up volumes. Relative volume reduction was calculated as the percentage decrease relative to the baseline volume to ensure comparability between patients with markedly different lesion sizes.
At follow-up (minimum 3 months after the preceding BEST session), patients underwent MR imaging, clinical examination and were questioned regarding changes in their symptoms or complications which occurred during the follow-up period. Clinical response was classified into the following categories: Complete symptom resolution, symptom improvement, no change or symptom worsening/new symptoms. Persistent clinical symptoms were considered an indication for additional BEST sessions with a minimum interval of 3 months between treatments.