Mechanisms Underlying Tongue Muscle Dysfunction and Dysphagia Following Concurrent Chemoradiation Therapy

项目总结/摘要 同步放化疗是头颈部肿瘤的一种常用治疗方法 癌的化疗作为放射治疗增敏剂，增强了放射对靶点的作用 头部和颈部组织，并增加肿瘤学功效。由于其治愈率与外科手术相当， 由于器官保存的管理和效益，CCRT已越来越多地用于各种头部和 颈部癌症，具有良好的疗效。然而，这种治疗方式与显著的 头部和颈部的副作用如口干、牙关紧闭、放射性骨坏死、粘膜炎、味觉障碍， 发音困难和吞咽困难，主要是由于对肿瘤周围正常组织的辐射作用。 吞咽困难可能是特别具有破坏性的，因为它显着改变生活质量，并与 吸入性肺炎的风险增加。 虽然肌无力和纤维化是CCRT后吞咽功能障碍的假定原因， 很少进行研究来研究这种功能障碍的潜在机制。辐射 导致纤维化并因此导致功能降低的治疗已经在人体组织中被记录， 心脏肺和乳房然而，在舌头内，特别是骨骼肌， 辐射仍然存在争议。多项翻译研究表明， 辐射后强度出现，但这种弱点的原因是未知的。四个主要假设有 已被提出来解释骨骼肌的变化后，辐射暴露：1）改变细胞 代谢和蛋白质降解，2）改变卫星细胞浓度和功能，3）纤维化和肌肉 萎缩和4）组织再生失败。到目前为止，这些假设很少被系统地 追踪到确定病因所需的程度。大多数文献都集中在纤维化，但研究 尚未明确证明CCRT导致的肌肉纤维化。事实上，唯一的人类 一项专门检查CCRT后头颈部组织的研究未能证明 纤维化 大多数研究仅关注放射治疗的动物模型，并提供非常高剂量的放射治疗。 非靶向辐射，限制了数据的平移值。为了更好地了解 CCRT后的肌肉损伤，必须应用适当的剂量，并对组织进行充分分析，以测试各种 肌肉功能障碍的假说目前的建议旨在阐明肌肉的病理生理学 在对头部和颈部进行同步放化疗以确定性治疗 恶性肿瘤这项研究是翻译的，因为它测试了动物和人类模型中的各种假设。

Project Summary/Abstract Concurrent chemoradiation therapy (CCRT) is a common treatment modality for head and neck cancers. Chemotherapy acts as a radiation therapy sensitizer, enhancing the effects of radiation on the target head and neck tissues and increasing oncologic efficacy. Due to its comparable cure rates to surgical management and benefit of organ preservation, CCRT has been increasingly utilized for various head and neck cancers with excellent curative results. However, this treatment modality is associated with significant side effects within the head and neck such as xerostomia, trismus, osteoradionecrosis, mucositis, dysgeusia, dysphonia, and dysphagia, primarily due to the radiation effects on normal tissue surrounding the tumor. Dysphagia can be particularly devastating, as it significantly alters quality of life and is associated with increased risk of aspiration pneumonia. Although muscle weakness and fibrosis are putative causes for swallow dysfunction following CCRT, very little research has been performed to study the underlying mechanisms of this dysfunction. Radiation therapy resulting in fibrosis and, therefore, decreased function has been documented in human tissue within the heart, lungs, and breast. However, within the tongue, and, specifically skeletal muscle, the effects of radiation remain controversial. Multiple translational studies have demonstrated that decreased tongue strength occurs after radiation, but the cause of this weakness is unknown. Four predominant hypotheses have been proposed to explain the skeletal muscle changes following radiation exposure: 1) alteration in cellular metabolism and protein degradation, 2) altered satellite cell concentration and function, 3) fibrosis and muscle atrophy and 4) failure of tissue regeneration. To date, few of these hypotheses have been systematically pursued to the degree required to determine etiology. Most of the literature has focused on fibrosis, but studies have yet to definitively demonstrate consistent fibrosis in muscle as a result of CCRT. In fact, the only human study to specifically examine tissue from the head and neck following CCRT failed to demonstrate significant fibrosis. Most studies have focused solely on animal models of radiation therapy and deliver very high doses of non-targeted radiation, limiting the translational value of the data. In order to better understand the etiology of muscle injury following CCRT, proper dosing must be applied and the tissues fully analyzed to test various hypotheses for muscle dysfunction. The current proposal seeks to elucidate the pathophysiology of muscle dysfunction following delivery of concurrent chemoradiation to the head and neck for definitive treatment of malignancy. The study is translational in that it tests the various hypotheses in both animal and human models.