Hypoglossal neuropathy in the pathogenesis of radiation associated dysphagia (hRAD)

摘要/摘要 放射相关性吞咽困难(RAD)是生活质量的主要驱动因素，也是潜在威胁生命的生存因素 问题，超过一半的口咽癌患者接受根治性放射治疗(RT) (OPC)。吸入者患肺炎的可能性几乎是非吸入者的5倍。 使癌症幸存者的死亡风险增加42%。长期以来，人们一直认为放射性纤维化 RAD的主要驱动因素，但研究人员的初步工作表明，晚期颅神经病变是主要原因 是导致真正严重的延迟或迟发RAD的因素。临床上发现脑神经病变(失神经) 经过一段功能恢复的“静默期”，放疗后中位数为5-8年。目前还没有早期的指标 为这次受伤负责。识别延迟意味着肌肉萎缩和严重的功能损伤是典型的表现。 在诊断时，限制了治疗潜力。这项工作的长期目标是减少吞咽困难 通过机械和技术上灵活的监控算法来增加负担，这是迈向 个性化管理。我们的中心假设是亚临床舌下神经病很普遍，而且 与HNC生存早期RAD的严重程度和新的无创舌面高密度相关 肌电图(HDSEMG)用于定量功能监测是可行的。建议的目标是 研究是分析金标准针刺舌肌电信号和实验性舌体表面肌电信号作为一种可选的检查方法 在现有的大规模OPC队列和两个临床试验数据集中，这些数据集捕捉到了健壮的纵向吞咽 结果数据：1)评估生存过程中舌下神经病的患病率(诊断， 早期和晚期)口咽放疗后(目标1)；2)肌电检测到的舌下神经病变与 口咽放射治疗前后吞咽功能的时间变化(目标2)；以及3)检查 HDSEMG作为舌下神经病的一种快速、非侵入性定量筛查方法(目标3)。建房 根据MD Anderson OPC患者报告的高度精选的功能数据 (教授)核心和研究人员在舌头非侵入性信号测量方面的记录，我们是独一无二的 定位于实现这些互补的目标。这种高风险/高回报的工作可能会导致实践- 变化。我们期望研究结果能为亚临床舌下神经病是一种 RAD的潜在机制，可以用一种新型的非侵入性设备进行测量。因此，将数据提供给 支持一个新的和可测量的目标(亚临床舌下神经病)，其潜在的巨大影响和 潜在致命的常见毒性-RAD-在快速增长的年轻OPC幸存者群体中。

ABSTRACT/SUMMARY Radiation-associated dysphagia (RAD) is a leading driver of QOL and a potentially life-threatening survivorship issue, afflicting more than half of patients treated with curative radiotherapy (RT) for oropharyngeal cancers (OPC). Aspirators are almost 5-times more likely to develop pneumonia than non-aspirators, and pneumonia confers a 42% increased risk of mortality among cancer survivors. Radiation fibrosis has long been considered the primary driver of RAD, but the investigators’ preliminary work points to late cranial neuropathy as a major contributor to truly severe forms of delayed or late-RAD. Cranial neuropathy (denervation) is clinically detected a median of 5 to 8 years after RT after a “quiet period” of functional recovery. There is currently no early indicator for this injury. Delayed identification means that muscle atrophy and profound functional injury is typically present at the time of diagnosis, limiting therapeutic potential. The long-term goal of this work is to reduce dysphagia burden through mechanistically and technically nimble surveillance algorithms as a major step toward personalized management. Our central hypothesis is that subclinical hypoglossal neuropathy is prevalent and associates with severity of RAD early in HNC survivorship and novel non-invasive lingual high density surface electromyography (HDSEMG) is feasible for quantitative functional surveillance. The objective of the proposed study is to analyze gold-standard needle EMG and experimental HDSEMG of the tongue as an optional procedure in an existing large-scale OPC cohort and two clinical trial datasets that capture robust longitudinal swallowing outcomes data to: 1) estimate prevalence of hypoglossal neuropathy along continuum of survivorship (diagnosis, early, and late) after oropharyngeal radiation (Aim 1); 2) correlate EMG-detected hypoglossal neuropathy and swallowing function over time before and after oropharyngeal radiation (Aim 2); and 3) examine feasibility of HDSEMG as a rapid, non-invasive quantitative screening method for hypoglossal neuropathy (Aim 3). Building upon the highly curated functional data from the MD Anderson OPC Patient-Reported Outcomes/Function (PROF) Core and investigators’ track record of non-invasive signal measurement in the tongue, we are uniquely positioned to accomplish these complementary aims. This high risk/high reward work could lead to practice- change. We expect the outcomes to provide proof of concept that subclinical hypoglossal neuropathy is a mechanism underlying RAD that can be measured with a novel, non-invasive device. Thus, providing data to support a novel and measurable target (subclinical hypoglossal neuropathy) underlying a hugely impactful and potentially deadly common toxicity –RAD– in a fast growing, young OPC survivor population.