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.

摘要 淋巴管肌瘤病(LAM)是一种进行性的、女性为主的囊性肺肿瘤，由 结节性硬化症复合体基因突变导致机制靶点的结构性激活 雷帕霉素(MTOR)途径。在西罗莫司的多中心国际LAM疗效试验中，mTOR抑制与 西罗莫司被证明能稳定LAM患者的肺功能下降和改善生活质量。然而， 西罗莫司的治疗是抑制而不是诱导缓解，并不是所有的LAM患者都受益，以及 在LAM进行持久的疾病控制需要长期接触药物。西罗莫司治疗的这些局限性 强调在LAM中探索新疗法的迫切需要。荷尔蒙的影响，特别是雌激素，是 被认为在LAM中起致病作用，由以下观察表明：症状性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，以及 绝经前LAM患者肺功能下降快于绝经后LAM患者。虽然 目前的LAM指南建议，在LAM中，激素类药物的经验性使用在过去是常见的 反对其常规使用，等待做得好的对照试验的结果。我们认为钥匙不见了 在先前对激素类药物在LAM中的疗效的研究中，成分一直被鉴定为 最有可能受益的LAM患者。我们对大约300名LAM患者进行了基于调查的研究 收集有关患者人口统计、临床病史的信息，包括是否存在月经周期 相关的呼吸道症状变异(MCRV)和LAM的当前治疗。这项研究的主要发现 研究结果如下：1)近1/3的LAM患者出现MCRV；2)西罗莫司治疗出现MCRV 3)患有MCRV的LAM患者报告西罗莫司治疗后症状改善的可能性较小 与没有MCRV的患者相比，4)MCRV的患者在治疗后更有可能报告改善 使用激素类药物治疗的患者与没有MCRV的患者进行比较。我们假设自我报告的MCRV是 与可测量的周期性肺活量变化、更快的疾病进展和不理想的 LAM患者对西罗莫司的反应。为了验证我们的假设，我们将进行以下工作 具体目的：确定MCRV对LAM患者疾病进展速度的影响。成功 我们项目的完成将加强我们对月经期间荷尔蒙变化的影响的了解。 循环对LAM患者肺功能的影响，提供疾病进展的自然病史以及对 西罗莫司治疗有无MCRV的LAM患者，并建立MCRV作为一种新的预后和 LAM中的预测性标记。该项目意义重大，因为它将把MCRV确立为一项独特的措施， 可以确定可能从激素治疗中受益的LAM患者亚群，并提供 对于在LAM中进行激素类药物的关键试验来说，这是必要且充分的信息。