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Purpose/Objective(s): Radiographic lung density changes are observed in most patients after stereotactic body radiation therapy (SBRT) for lung cancer. In this study, we assessed the relationship between SBRT dose and our treatment technique. Follow-up computed tomography (CT) density changes were used as a surrogate for lung injury from SBRT. Materials/Methods: Six patients with non-small cell carcinoma of lung were retrospectively assessed. Patients' 4D CT scans were acquired and the reconstructed phase images were imported into a treatment planning computer. The internal target volume (ITV) for each patient was contoured using 10 to 14 phase image datasets. The planning target volume (PTV) was generated by adding a 5-mm margin to the ITV in lateral and anteriorposterior directions, and a 7.5-mm cranial-caudal margin. The RTOG protocol 0618 was generally followed for PTV dose coverage. A total dose of 48 to 54 Gy (52.33AE2.66 Gy) in 3 to 5 (3.50AE0.84) fractions to the isocenter were prescribed. Seven to 9 coplanar and nonopposing conformal beams (8.50AE0.84 beams) were placed. The convolution dose algorithm with heterogeneity correction was used for dose calculations. Treatments were delivered on alternate days under cone beam CT (CBCT) image guidance. A follow-up PET/CT scan was acquired between 6 and 14 months (8.50AE3.02 month) after SBRT treatment completion. The followup scan then was fused with the original planning CT. The high radiographic density region was contoured to determine the net SBRT-induced volume of lung tissue injury. The minimum dose causing radiographic injury was then determined. Results: The average and standard deviation for ITV, PTV, radiographic injury, and total lung volumes were calculated to be 12.74AE14.70 cm 3 , 49.67AE45.40 cm 3 , 16.49AE13.57 cm 3 , and 3452.00AE235.00 cm 3 , respectively. The average radiographic injury volume to PTV ratio was 32.27AE21.67% (ranging 0% to 62%). The threshold dose responsible for radiographic injury was 10.70AE0.84 Gy, based on the scan acquired at an average of 8.50 months following SBRT. There is a linear relationship between the biological effective doses (BED) with the radiographic injury volumes. Conclusion: Increased CT density changes, a surrogate for damage to the normal lung tissue, was associated with higher BED, and increasing PTV size, with a threshold dose of 10.70 Gy in this study. Therefore, to reduce SBRT-induced lung injury, at least 9 conformal equally weighted beams should be used to distribute dose evenly in normal lung tissue. Further, the noncoplanar and nonopposing conformal beams should be used if possible to minimize the radiographic injury. A study of serial follow-up scans of patients, at regular intervals, is warranted to determine the early and late SBRT-induced lung injuries.

Glia modulate neuronal excitability and seizure sensitivity by maintaining potassium and water homeostasis. A SIK3-regulated gene expression program controls the glial capacity to buffer K+ and water, however upstream regulatory mechanisms are unknown. Here we identify an octopaminergic circuit linking neuronal activity to glial ion and water buffering. Under basal conditions, octopamine functions through the inhibitory octopaminergic GPCR OctβR to upregulate glial buffering capacity, while under pathological K+ stress, octopamine signals through the stimulatory octopaminergic GPCR OAMB1 to downregulate the glial buffering program. Failure to downregulate this program leads to intracellular glia swelling and stress signaling, suggesting that turning down this pathway is glioprotective. In the eag shaker Drosophila seizure model, the SIK3-mediated buffering pathway in inactivated. Re-activation of the glial buffering program dramatically suppresses neuronal hyperactivity, seizures, and shortened lifespan in this mutant. These findings highlight the therapeutic potential of a glial-centric therapeutic strategy for diseases of hyperexcitability.