Vosoritide treatment for children with hypochondroplasia: a phase 2 trial.

Background: Hypochondroplasia is a rare autosomal dominant skeletal dysplasia due to activating variants in FGFR3. It presents with disproportionate short stature with a wide range of clinical severity. There are currently no approved medications to treat short stature in children with hypochondroplasia. Vosoritide is a C-type natriuretic peptide analog that was recently approved for improving growth in children with achondroplasia. We aimed to evaluate the safety and efficacy of vosoritide in children with hypochondroplasia. Methods: We conducted a single-arm, phase 2, open-label trial at a single centre in the USA and enrolled 26 children with hypochondroplasia. The trial consists of a 6-month observation period to establish a baseline annualized growth velocity followed by a 12-month intervention period during which vosoritide is administered daily via subcutaneous injection at a dose of 15 µg/kg/day. The trial's co-primary endpoints included the incidence of adverse events and the change from baseline in age-sex standardized annualized growth velocity and height standardized deviation score (SDS) after 12 months of treatment. This trial is registered with ClinicalTrials.gov (NCT04219007). Findings: Twenty-four participants with a mean age of 5.86 years received vosoritide therapy. The first participant was enrolled on August 4, 2020, and the final participant completed the 18-month trial on September 8, 2023. Vosoritide was well tolerated with no treatment-related serious adverse events. Injection site reactions occurred in 83.3% of participants. No participants discontinued therapy due to an adverse event. Annualized growth velocity increased by 2.26 standard deviations (SD) and height SDS increased by 0.36 SD during the treatment period versus the observation period. Hypochondroplasia specific height SDS increased by 0.38 SD. There was a 1.81 cm/year increase in absolute annualized growth velocity. Interpretation: Vosoritide was safe and effective in increasing growth velocity in children with hypochondroplasia. Efficacy was similar to what has been reported in children with achondroplasia. Funding: This study was supported by an investigator-initiated grant from BioMarin Pharmaceutical.

In Vivo Characterization of the Swine Airway Morphometry and Motion Based on Computed Tomographic Imaging During Respiration.

Swine are a commonly used model in translational pulmonary research. However, in vivo airway morphometry during respiration has not been studied in extensive detail using modern imaging tools. Chest computed tomographic was performed in swine (n = 3) at multiple stages of respiration. Morphometric parameters of each airway segment at end-expiration and end-inspiration were compared as well as among matched anatomical regions (proximal and distal; ventral, lateral, and dorsal). Analysis included segment diameter, length, ellipticity, and the bifurcation angle between daughter branches. Deformation of the airway during respiration was qualitatively visualized using a point-to-point deformation map. Comparison of airway generation showed airway diameter and length were larger at end-inspiration in the fourth and seventh generations compared to end-expiration. Bifurcation angle was larger at end-inspiration compared to end-expiration. Analysis by anatomical region showed that length and bifurcation angle were larger at inspiration in the distal airway regions only. Regardless of respiratory phase, the lateral regions had larger diameters and lengths compared to the ventral and dorsal regions at similar generations and proximal regions had larger bifurcation angles. The findings that morphological changes were more prevalent in distal airways during respiration was confirmed by analysis of a deformation map. Compared to human airway models, the relative diameter may be smaller and length may be greater in swine in similar airway generations. This morphometric description of the swine airways during respiration may guide conduct of preclinical translational studies, revealing advantages and limitations of swine models for specific evaluations. Such morphometric parameters may directly determine the suitability of the swine model for the study of lung interventions, in terms of recapitulation of human morphometry dynamics.

Radiofrequency Ablation Duration per Tumor Volume May Correlate with Overall Survival in Solitary Hepatocellular Carcinoma Patients Treated with Radiofrequency Ablation Plus Lyso-Thermosensitive Liposomal Doxorubicin.

PURPOSE: To determine whether burn time per tumor volume (BPV) (min/mL), where burn time is the total time during which radiofrequency (RF) energy is being applied, is correlated with hepatocellular carcinoma (HCC) treatment outcomes using RF ablation and lyso-thermosensitive liposomal doxorubicin (LTLD). MATERIALS AND METHODS: The HEAT study was a double-blind, randomized controlled phase III trial of RF ablation only versus RF ablation + LTLD in patients with HCCs 3-7 cm in diameter. Effect of BPV on progression-free survival and overall survival (OS) was analyzed. RESULTS: BPV demonstrated statistically significant differences between study groups for OS (P = .038, hazard ratio [HR] = 0.85), but not for progression-free survival (P = .389, HR = 1.059). In a separate analysis, treatment groups were independently analyzed to determine the effect of BPV within each individual group. OS improved as BPV increased for patients receiving RF ablation + LTLD (P = .017, HR = 0.836, confidence interval [0.722, 0.968]). This same association was not observed in patients receiving RF ablation only (P = .57, HR = 0.99). CONCLUSIONS: BPV may be a useful metric for RF ablation + LTLD combination therapy for solitary HCC. The analysis suggested that the burn time for the tumor needs to be adjusted depending on the tumor volume. Because this is a post hoc study, the results are only suggestive and need to be confirmed with prospective studies.