Swallowing dysfunction following radiation to the rat mylohyoid muscle is associated with sensory neuron injury.

Radiation-based treatments for oropharyngeal and hypopharyngeal cancers result in impairments in swallowing mobility, but the mechanisms behind the dysfunction are not clear. The purpose of this study was to determine if we could establish an animal model of radiation-induced dysphagia in which mechanisms could be examined. We hypothesized that 1) radiation focused at the depth of the mylohyoid muscle would alter normal bolus transport and bolus size and 2) radiation to the mylohyoid muscle will induce an injury/stress-like response in trigeminal sensory neurons whose input might modulate swallow. Rats were exposed to 48 or 64 Gy of radiation to the mylohyoid given 8 Gy in 6 or 8 fractions. Swallowing function was evaluated by videofluoroscopy 2 and 4 wk following treatment. Neuronal injury/stress was analyzed in trigeminal ganglion by assessing activating transcription factor (ATF)3 and GAP-43 mRNAs at 2, 4, and 8 wk post treatment. Irradiated rats exhibited decreases in bolus movement through the pharynx and alterations in bolus clearance. In addition, ATF3 and GAP-43 mRNAs were upregulated in trigeminal ganglion in irradiated rats, suggesting that radiation to mylohyoid muscle induced an injury/stress response in neurons with cell bodies that are remote from the irradiated tissue. These results suggest that radiation-induced dysphagia can be assessed in the rat and radiation induces injury/stress-like responses in sensory neurons.NEW & NOTEWORTHY Radiation-based treatments for head and neck cancer can cause significant impairments in swallowing mobility. This study provides new evidence supporting the possibility of a neural contribution to the mechanisms of swallowing dysfunction in postradiation dysphagia. Our data demonstrated that radiation to the mylohyoid muscle, which induces functional deficits in swallowing, also provokes an injury/stress-like response in the ganglion, innervating the irradiated muscle.

Cytokine and Growth Factor Response in a Rat Model of Radiation Induced Injury to the Submental Muscles.

Submental muscles (i.e., mylohyoid and geniohyoid) play a vital role during swallowing, protecting the airway from ingested material. To design therapies to reduce the functional deficits associated with radiation treatment relies in part on our understanding of the changes in the cytokine and growth factor response that can impact muscle function. The purpose of this study is to quantify changes in the inflammatory, pro-fibrotic, and pro-angiogenic factors following 48 Gy of fractionated radiation to the mylohyoid muscle. We hypothesized that (1) irradiation will provoke increases in TGF-1ß and MMP-2 mRNA in the mylohyoid muscle; and (2) muscles surrounding the target location (i.e., geniohyoid and digastric muscles) will exhibit similar alterations in their gene expression profiles. Rats were exposed to 6 fractions of 8 Gy using a 6 MeV electron beam on a clinical linear accelerator. The highest dose curve was focused at the mylohyoid muscle. After 2- and 4-weeks post-radiation, the mylohyoid, geniohyoid, and digastric muscles were harvested. Expression of TNF-α, IFNγ, IL-1ß, IL-6, TGF-1ß, VEGF, MMP-2, and MMP-9 mRNA was analyzed via PCR and/or RT-PCR. TGF-1ß, MMP-2, and IL-6 expression was upregulated in the irradiated mylohyoid compared to non-irradiated controls. No notable changes in TNF-α, IFNγ, and IL-1ß mRNA expression were observed in irradiated muscles. Differing expression profiles were found in the surrounding muscles post-radiation. Results demonstrated that irradiation provokes molecular signals involved in the regulation of wound healing, which could lead to fibrosis or atrophy in the swallowing muscle after radiation.

A simple knowledge-based tool for stereotactic radiosurgery pre-planning.

We studied the dosimetry of single-isocenter treatment plans generated to treat a solitary intracranial lesion using linac-based stereotactic radiosurgery (SRS). A common metric for evaluating SRS plan quality is the volume of normal brain tissue irradiated by a dose of at least 12 Gy (V12), which is important because multiple studies have shown a strong correlation between V12 and incidence of radiation necrosis. Unrealistic expectations for values of V12 can lead to wasted planning time. We present a model that estimates V12 without having to construct a full treatment plan. This model was derived by retrospectively analyzing 50 SRS treatment plans, each clinically approved for delivery using circular collimator cone arc therapy (CAT). Each case was re-planned for delivery via dynamic conformal arc therapy (DCAT), and then scaling arguments were used to extend dosimetric data to account for different prescription dose (PD) values (15, 18, 21, or 24 Gy). We determined a phenomenological expression for the total volume receiving at least 12 Gy (TV12) as a function of both planning target volume (PTV) and PD: T V 12 / 1 c c = n ∗ P D / 1 G y + d ∗ P T V / 1 c c a ∗ P D / 1 G y c , where a , c , n , d are fit parameters, and a separate set of values is determined for each plan type. In addition, we generated a sequence of plots to clarify how the relationship between conformity index (CI) and TV12 depends on plan type (CAT vs DCAT), PTV, and PD. These results can be used to suggest realistic plan parameters and planning goals before the start of treatment planning. In the absence of access to more sophisticated pre-planning tools, this model can be locally generated and implemented at relatively low cost with respect to time, money, and expertise.