FIGURE 2. (A) Subtracted image of the diaphragm excursions in the most caudal (inspiratory) and cranial (expiratory) diaphragm positions during tidal breathing in a healthy control. (B) A subtracted image of the diaphragm excursions in the most caudal (inspiratory) and cranial (expiratory) diaphragm positions during tidal breathing in a patient with chronic low back pain. (C) Schematic description of 3 diaphragmatic points (B, C, and D) used for diaphragm excursion calculations. The following 6 distances (in mm) were obtained by measuring the distance between the horizontal baseline in both expiratory and inspiratory diaphragm positions. Diaphragm excursion points: B1 to D1 were derived from the inspiratory diaphragm positions obtained from MRI images; B2 to D2 were derived from expiratory diaphragm positions obtained from respective MRI images. The inspiratory diaphragm position is designated by points B1, C1, and D1. The expiratory diaphragm position is designated by points B2, C2, and D2. Total diaphragm excursion is designated by the distance from the lower to the upper curve along points B1 to B2, C1 to C2, and D1 to D2. Adapted from Kolar et al.

The aim was to describe diaphragmatic behavior during postural limb activities and examine the ventilatory and stabilizing functions of the diaphragm. Thirty healthy subjects were examined in the supine position using a dynamic MRI system assessed simultaneously with specialized spirometric readings. The diaphragmatic excursions (DEs) were measured at three diaphragmatic points in the sagittal plane; the diaphragm positions (DPs) as related to a reference horizontal baseline were determined. Measurements were taken during tidal breathing (TB) and isometric flexion of upper or lower extremities against external resistance together with TB. Mean DE in both upper and lower postural limb activities was greater compared with the TB condition (P < 0.05), with the effect greater for lower limb activities. Inspiratory DPs in the upper and lower extremity activities were lower compared with TB alone (P < 0.01). Expiratory DP was lower only for lower extremity activities (P < 0.01). DP was most affected at the apex of the crescent and crural (posterior) portion of the diaphragm. DEs correlated strongly with tidal volume (Vt) in all conditions. Changes in DEs relative to the initial value were minimal for upper and lower extremities but were related to lower values of Vt (P < 0.03). Significant involvement of the diaphragm in the limb postural activities was found. Resulting DEs and DPs differed from the TB conditions, especially in lower extremity activities. The differences between the percent changes of DEs vs. Vt found for lower extremity activities were confirmed by both ventilatory and postural diaphragm recruitment in response to postural demands.

PURPOSE Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E–mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( P = .02). CONCLUSION Use of BRAF inhibition results in robust and durable responses in BRAF V600E–mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.

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