Mechanisms Underlying Tongue Muscle Dysfunction and Dysphagia Following Concurrent Chemoradiation Therapy

项目摘要/摘要 同步放化疗(CCRT)是头颈部的一种常用治疗方法。 癌症。化疗起到了放射治疗增敏剂的作用，增强了放射对靶区的影响 头部和颈部组织，并提高肿瘤疗效。由于其治愈率可与外科手术相媲美 器官保存的管理和效益，CCRT已越来越多地被用于各种头部和 宫颈癌治疗效果极佳。然而，这种治疗方式与显著的 头部和颈部的副作用，如口干、痉挛、放射性骨坏死、粘膜炎、排便障碍、 发音困难和吞咽困难，主要是由于肿瘤周围正常组织的辐射效应。 吞咽困难可能特别具有破坏性，因为它显著改变了生活质量，并与 吸入性肺炎风险增加。 虽然肌肉无力和纤维化可能是CCRT后吞咽功能障碍的原因， 很少有研究对这种功能障碍的潜在机制进行研究。辐射 治疗会导致纤维化，因此，在人体组织中已有文献记载 心脏、肺和胸部。然而，在舌头，特别是骨骼肌中， 辐射仍然存在争议。多项翻译研究表明，舌头减少 强度是在辐射后出现的，但这种弱点的原因尚不清楚。四个主要的假设有 有人提出用来解释辐射后骨骼肌的变化：1)细胞的变化 代谢和蛋白质降解，2)卫星细胞浓度和功能改变，3)纤维化和肌肉 萎缩和4)组织再生失败。到目前为止，这些假设中很少有系统性的。 追查到确定病因所需的程度。大多数文献都集中在纤维化方面，但研究 还没有明确地证明CCRT导致肌肉持续纤维化。事实上，唯一的人类 对CCRT后头部和颈部组织进行专门检查的研究没有显示出显著的意义 纤维化症。 大多数研究仅集中在放射治疗的动物模型上，并提供非常高剂量的 非定向辐射，限制了数据的转换价值。为了更好地了解该病的病因 CCRT后肌肉损伤，必须使用适当的剂量，并对组织进行充分分析，以测试各种 肌肉功能障碍的假说。目前的提议试图阐明肌肉的病理生理学。 头颈部同步放化疗后功能障碍的确定治疗 恶毒。这项研究是翻译的，因为它在动物和人类模型中测试了各种假设。

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.