Menstrual Cycle-Related Symptom Variability as a Prognostic Indicator in Lymphangioleiomyomatosis

月经周期相关症状变异性作为淋巴管平滑肌瘤病的预后指标

• 批准号: 10669246
• 负责人: Nishant Gupta
• 金额: $ 20.25万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669246
• 关键词: Aftercare; Bronchodilator Agents; Case Study; Clinical; Cystic Neoplasm; Data; Disease Progression; Drug Exposure; Enrollment; Estrogens; FRAP1 gene; Female; Female of child bearing age; Future; Genes; Guidelines; Home; Hormonal; Hormonal Change; International; Intuition; Linear Models; Lung Neoplasms; Lung diseases; Luteinizing Hormone; Lymphangioleiomyomatosis; Measurable; Measures; Menstrual cycle; Monitor; Mutation; Outcome; Ovulation Detection; Pathogenicity; Pathway interactions; Patient Outcomes Assessments; Patient Self-Report; Patients; Phenotype; Play; Population; Postmenopause; Pregnancy; Premenopause; Prognostic Marker; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary function tests; Quality of life; Questionnaires; Rare Diseases; Recommendation; Recording of previous events; Registries; Remission Induction; Reporting; Research; Resources; Respiratory Failure; Respiratory Signs and Symptoms; Role; Safety; Series; Sirolimus; Surveys; Symptoms; Techniques; Testing; Therapeutic; Time; Training; Tuberous Sclerosis; Urine; Variant; Woman; age group; demographics; design; disease natural history; disorder control; efficacy study; hormone therapy; improved; information gathering; innovation; novel; novel therapeutics; ovulation time; patient subsets; predictive marker; prognostic; prognostic indicator; pulmonary function; pulmonary function decline; pulmonary symptom; rate of change; response; symptomatic improvement; telehealth

ABSTRACT Lymphangioleiomyomatosis (LAM) is a progressive, female-predominant, cystic lung neoplasm caused by mutations in the tuberous sclerosis complex genes leading to constitutive activation of the mechanistic target of rapamycin (mTOR) pathway. In the Multicenter International LAM Efficacy of Sirolimus trial, mTOR inhibition with sirolimus was shown to stabilize lung function decline and improve quality of life in LAM patients. However, treatment with sirolimus is suppressive rather than remission inducing, does not benefit all LAM patients, and durable disease control in LAM requires long-term drug exposure. These limitations of sirolimus treatment highlight the critical need to explore novel therapies in LAM. Hormonal influences, especially estrogen, are believed to play a pathogenic role in LAM as suggested by the following observations: symptomatic LAM is restricted almost exclusively to females, LAM is exacerbated by exogenous estrogen use and pregnancy, and lung function in premenopausal women with LAM declines faster than that of postmenopausal women. Although the empirical use of hormonal agents in LAM was common in the past, the current LAM Guidelines recommend against their routine use, pending the outcome of well-done controlled trials. We submit that the key missing component in prior studies of the efficacy of hormonal agents in LAM has been the identification of the subset of patients with LAM who are most likely to benefit. We conducted a survey-based study of ~300 LAM patients and gathered information about patient demographics, clinical history including the presence of menstrual cycle associated respiratory symptom variation (MCRV), and current treatment for LAM. The key findings from this study were: 1) MCRV was reported by almost one-third of the patients with LAM, 2) treatment with sirolimus did not impact MCRV, 3) LAM patients with MCRV were less likely to report symptom improvement with sirolimus compared to patients without MCRV, and 4) patients with MCRV were more likely to report improvement after treatment with hormonal agents compared to patients without MCRV. We postulate that self-reported MCRV is associated with measurable cyclical spirometric changes, faster disease progression and suboptimal response to sirolimus in patients with LAM. In order to test our hypothesis, we will pursue the following specific aim: Determine the impact of MCRV on the rate of disease progression in patients with LAM. Successful completion of our project will enhance our understanding of the impact of hormonal changes during the menstrual cycle on lung function in LAM patients, provide the natural history of disease progression as well as response to sirolimus treatment in LAM patients with and without MCRV, and establish MCRV as a novel prognostic and predictive marker in LAM. This project is highly significant as it will establish MCRV as a unique measure that can identify the subpopulation of LAM patients who might benefit from hormonal treatment, and provide information that is both necessary and sufficient to conduct pivotal trials of hormonal agents in LAM.

抽象的 淋巴管平滑肌瘤病 (LAM) 是一种进行性、女性占主导地位的囊性肺肿瘤，由以下原因引起： 结节性硬化症复合体基因的突变导致机械靶点的组成性激活 雷帕霉素 (mTOR) 途径。在西罗莫司的多中心国际 LAM 功效试验中，mTOR 抑制 西罗莫司被证明可以稳定 LAM 患者的肺功能衰退并改善生活质量。然而， 西罗莫司治疗是抑制性的，而不是诱导缓解的，并不能使所有 LAM 患者受益，并且 LAM 的持久疾病控制需要长期药物暴露。西罗莫司治疗的这些局限性 强调探索 LAM 新疗法的迫切需要。荷尔蒙的影响，尤其是雌激素， 据信在 LAM 中发挥致病作用，如下观察结果所示：有症状的 LAM 是 LAM 几乎仅限于女性，外源性雌激素的使用和怀孕会加剧 LAM，并且 患有 LAM 的绝经前女性的肺功能下降速度比绝经后女性更快。虽然 过去在 LAM 中经验性使用激素药物很常见，目前的 LAM 指南建议 反对它们的常规使用，等待良好的对照试验的结果。我们认为钥匙丢失了 先前关于 LAM 中激素药物功效的研究的一个组成部分是确定以下子集： 最有可能受益的 LAM 患者。我们对约 300 名 LAM 患者进行了一项基于调查的研究 收集有关患者人口统计、临床病史（包括月经周期）的信息 相关呼吸道症状变异 (MCRV) 以及 LAM 的当前治疗方法。此项研究的主要发现 研究结果是：1) 近三分之一的 LAM 患者报告了 MCRV，2) 西罗莫司治疗确实 不影响 MCRV，3) 患有 MCRV 的 LAM 患者报告西罗莫司症状改善的可能性较小 与没有 MCRV 的患者相比，4) 患有 MCRV 的患者更有可能在治疗后报告病情有所改善 与没有 MCRV 的患者相比，使用激素药物治疗的患者。我们假设自我报告的 MCRV 是 与可测量的周期性肺活量变化、更快的疾病进展和次优相关 LAM 患者对西罗莫司的反应。为了检验我们的假设，我们将追求以下目标 具体目标：确定 MCRV 对 LAM 患者疾病进展率的影响。成功的 完成我们的项目将增强我们对月经期间荷尔蒙变化影响的了解 LAM 患者肺功能周期，提供疾病进展的自然史以及对 LAM 患者的反应 西罗莫司治疗有或没有 MCRV 的 LAM 患者，并将 MCRV 确立为一种新的预后和治疗方法 LAM 中的预测标记。该项目非常重要，因为它将建立 MCRV 作为一项独特的措施， 可以识别可能受益于激素治疗的 LAM 患者亚群，并提供 对于在 LAM 中进行激素药物的关键试验是必要且充分的信息。