Xenon MRI assessment of response to cystic fibrosis therapies

氙 MRI 评估囊性纤维化治疗的反应

• 批准号: 8253057
• 负责人: Iulian Constantin Ruset
• 金额: $ 21.96万
• 依托单位: XEMED, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-05 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8253057
• 关键词: 4 year old; Acute; Adult; Adverse effects; Albuterol; Ambulatory Care; American; Aminoglycoside Antibiotics; Anesthetics; Antibiotic Therapy; Antibiotics; Biological Markers; Blood; Breathing; Caucasians; Caucasoid Race; Cell membrane; Cessation of life; Chest; Child; Childhood; Chloride Channels; Chronic Obstructive Airway Disease; Clinical; Clinical Trials; Coiled Bodies; Collaborations; Continuous Infusion; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Development; Diagnostic; Disease; Dose; Early treatment; Environmental air flow; Euphoria; Future; Gases; Gene Mutation; Genotype; Guidelines; Helium; Hereditary Disease; Human Subject Research; Image; Imaging Techniques; Imaging technology; Impairment; Individual; Infant; Infection; Infection Control; Inflammation; Inflammatory; Inpatients; Intravenous; Ionizing radiation; Life Expectancy; Lung; Magnetic Resonance Imaging; Methods; Metric; Molecular Abnormality; Monitor; Mucous body substance; Multi-Drug Resistance; Mutation; Nodule; Numbness; Outcome; Outcome Measure; Patients; Performance; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Physical therapy; Population; Property; Protocols documentation; Protons; Pseudomonas aeruginosa; Publishing; Pulmonary Cystic Fibrosis; RF coil; Recommendation; Recruitment Activity; Reporting; Research Infrastructure; Respiratory physiology; Safety; Self Assessment; Severities; Societies; Solubility; Spirometry; Structure of parenchyma of lung; Structure/Function Nuclei; Techniques; Teenagers; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; Treatment Efficacy; VX-770; Work; Xenon; age group; base; children with cystic fibrosis; combat; cystic fibrosis patients; design; dysphoria; early cystic fibrosis; effective therapy; evidence based guidelines; functional restoration; healthy volunteer; imaging modality; lung imaging; novel; patient population; pressure; prevent; response; tool; young adult

DESCRIPTION (provided by applicant): New clinical guidelines for the treatment of exacerbations in cystic fibrosis (CF) were recently published by the American Thoracic Society. Examples of these evidence-based recommendations include not performing synergy testing to combat multi-drug-resistant infections, and using only one daily dose of aminoglycoside antibiotics, which was found equally effective as three. However for six of ten therapies evaluated, there simply was not enough data to make recommendations. These six included inpatient versus outpatient care; simultaneous use of intravenous and inhaled antibiotics; number of antibiotics used to treat pseudomonas aeruginosa; continuous infusion of betalactam antibiotics; and duration of antibiotic treatment. This situation clearly indicates that new tools are needed for evaluating response to therapy in CF, particularly for those involving antibiotics and the treatment of CF exacerbations. Hyperpolarized-gas MRI has been shown to be effective for assessing regional airflow impairment of cystic fibrosis in pediatric and adult patients. To date all hyperpolarized-gas MRI studies in children have employed hyperpolarized helium-3 due to wider access to the required infrastructure. Hyperpolarized xenon-129 (HXe) has been perceived as less appropriate for children due to its solubility in blood and tissues, and concomitant side effects including brief euphoria, dysphoria, and/or numbness. However, state-of-the-art polarization infrastructure is providing HXe polarizations as high as 50%, allowing clinical imaging with modest doses. Furthermore from a diagnostic perspective, the solubility of xenon in tissue and blood is precisely the property that makes it able to interrogate lung tissue inflammation, which may serve as an important biomarker for antibiotic response in cystic fibrosis exacerbations. Our collaboration recently demonstrated simultaneous acquisition of xenon gas-phase and xenon dissolved-phase images in a single breath hold. In one of our "healthy" volunteers, we discovered a previously undiagnosed inflammatory nodule was highly conspicuous on the dissolved phase images. This result suggests that this technique may be sensitive to inflammation. Since inflammation is a primary treatment target in CF, this technique may be well suited to detect response to treatment in patients with CF. We propose to utilize HXe simultaneous gas- and dissolved-phase MRI together with a new dual-nucleus structure-function ventilation imaging protocol, acquiring both proton and HXe images within a single breath hold, to monitor therapeutic response in cystic fibrosis exacerbations. Five patients admitted for a cystic fibrosis exacerbation will be recruited, including at least two children. Patients will be imaged upon initiation of treatment and three weeks after therapy commences. Data will be incorporated into an imaging biomarker for CF and compared with other metrics such as spirometry and patient self-assessments. PUBLIC HEALTH RELEVANCE: New treatments are in Phase 3 clinical trials that target the underlying abnormality in cystic fibrosis (CF) and restore the function of the cell membrane chloride channel that is abnormal in CF. Because these treatments work differently for different CF genotypes, there is a pressing need to develop a technique for the assessment of treatment efficacy, particularly for young children, so that effective treatment can be initiated before lung damage is irreversible. Hyperpolarized xenon (HXe) MRI is a new modality for imaging lung function that does not rely on ionizing radiation, an improvement in safety that is particularly important for children. The proposed study is a vital step toward determining whether HXe MRI could be a useful outcome measure in CF, something that could have tremendous clinical impact in this patient population.

描述（由申请人提供）：美国胸科学会最近发表了治疗囊性纤维化（CF）加重的新临床指南。这些循证建议的例子包括不进行协同试验以对抗多重耐药感染，以及每天只使用一剂氨基糖苷类抗生素，结果发现这与三剂同样有效。然而，在被评估的10种治疗方法中，有6种根本没有足够的数据来提出建议。这六项包括住院病人和门诊病人；静脉注射和吸入抗生素同时使用；用于治疗铜绿假单胞菌的抗生素数量；持续输注倍他坦类抗生素；以及抗生素治疗的持续时间。这种情况清楚地表明，需要新的工具来评估CF治疗的反应，特别是那些涉及抗生素和CF恶化治疗的反应。超极化气体MRI已被证明对评估儿童和成人囊性纤维化患者的局部气流损伤是有效的。迄今为止，所有儿童超极化气体MRI研究都使用超极化氦-3，因为所需的基础设施更容易获得。超极化氙-129 （HXe）被认为不太适合儿童使用，因为它在血液和组织中的溶解性，以及伴随的副作用包括短暂的欣快感、烦躁不安和/或麻木。然而，最先进的偏振基础设施提供高达50%的HXe偏振，允许适度剂量的临床成像。此外，从诊断的角度来看，氙在组织和血液中的溶解度正是使其能够询问肺组织炎症的特性，这可能作为囊性纤维化恶化中抗生素反应的重要生物标志物。我们的合作最近展示了在一次屏气中同时获取氙气相和氙溶解相图像。在我们的一个“健康”志愿者中，我们发现一个以前未诊断的炎症结节在溶解期图像上非常明显。这一结果表明，这种技术可能对炎症很敏感。由于炎症是CF的主要治疗目标，该技术可能非常适合检测CF患者对治疗的反应。我们建议利用HXe同时气相和溶相MRI以及新的双核结构功能通气成像方案，在一次屏气中获得质子和HXe图像，以监测囊性纤维化恶化的治疗反应。将招募5名因囊性纤维化恶化而入院的患者，其中至少包括两名儿童。患者将在治疗开始时和治疗开始后三周进行影像学检查。数据将被纳入CF的成像生物标志物，并与其他指标（如肺活量测定和患者自我评估）进行比较。