Low risk in vivo diagnosis of IPF with optical imaging

利用光学成像对 IPF 进行低风险体内诊断

• 批准号: 9088547
• 负责人: Lida P Hariri
• 金额: $ 17.91万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9088547
• 关键词: Address; Adverse effects; Advisory Committees; Biomedical Engineering; Biometry; Biopsy; Blinded; Bronchoscopy; Budgets; Caliber; Catheters; Cessation of life; Chest; Chronic; Clinical; Clinical Management; Clinical Medicine; Clinical Research; Collaborations; Complement; Data; Decision Making; Detection; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Disease; Disease Progression; Drug Prescriptions; Drug usage; Educational workshop; Elements; Engineering; Enrollment; Environment; Evaluation; Excision; FDA approved; Faculty; Fibrosis; Foundations; Goals; Guidelines; Hamman-Rich syndrome; Heterogeneity; Histology; Hospitalization; Image; Imagery; Interstitial Pneumonia; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Libraries; Lung; Lung diseases; Malignant neoplasm of lung; Medical Imaging; Melissa; Mentors; Mentorship; Methods; Microscope; Microscopic; Microscopy; Morbidity - disease rate; Operative Surgical Procedures; Optical Coherence Tomography; Optics; Pathologist; Pathology; Patient Care; Patients; Peripheral; Pharmaceutical Preparations; Physicians; Pilot Projects; Pirfenidone; Positioning Attribute; Postdoctoral Fellow; Progression-Free Survivals; Pulmonary Fibrosis; Research; Research Design; Research Personnel; Research Training; Resected; Resolution; Resources; Risk; Scientist; Sensitivity and Specificity; Solid; Specialist; Specimen; Structure of parenchyma of lung; Survival Rate; Testing; Therapeutic; Time; Tissues; Training; Translating; Translational Research; Translations; Writing; base; career; career development; cost; diagnostic accuracy; effective therapy; experience; high risk; imaging informatics; improved; in vivo; innovation; instructor; lung imaging; medical schools; minimally invasive; mortality; novel; novel therapeutics; optical imaging; outcome forecast; patient oriented; pre-clinical; public health relevance; response; responsible research conduct; skills; tenure track; tool

 DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a progressive, ultimately fatal form of idiopathic interstitial pneumonitis (IIP), with a 3 year survival rate of 0%. Diagnostic certainty of IPF is critical to patient management and therapeutic decision-making. Two new FDA-approved therapies, pirfenidone and nintedanib, have been shown to slow disease progression in IPF and brought new hope to IPF patients. Due to their high costs, side effects, and documented efficacy only in IPF, pulmonologists only prescribe these drugs to patients with a well- established diagnosis of IPF. Definitive IPF diagnosis can be made by chest CT alone in about half of cases when classic imaging features are present, which must include peripheral honeycombing. When CT does not visualize honeycombing, patients must undergo surgery to resect lung tissue and look for honeycombing microscopically to establish diagnostic certainty of IPF. Unfortunately, surgical lung resection has high risks of associated morbidity and mortality, including provoking further disease progression, and even death. There is a clear clinical need for a low risk method of microscopic IPF diagnosis. In this proposal, we take a hypothesis driven approach to determine whether bronchoscopic optical imaging can serve as a novel, low-risk, non- surgical paradigm for IPF diagnosis without surgery or tissue removal. Optical coherence tomography (OCT) provides rapid 3D visualization of large tissue volumes with microscopic resolutions (< 10 µm, comparable with low-power microscopy) well beyond the capabilities of CT. We have developed ultrathin bronchoscopic OCT catheters and conducted in vivo peripheral lung imaging in patients. We have shown in preliminary studies that endobronchial OCT can detect microscopic honeycombing (< 1 mm diameter) in IPF that is not visible with CT. We hypothesize that minimally invasive bronchoscopic OCT can detect microscopic honeycombing and diagnose IPF with high sensitivity and specificity. In Aim 1, we will develop and validate OCT diagnostic criteria to detect microscopic honeycombing and diagnose IPF. We will create a library of airway- based OCT with matched histology from ex vivo lung specimens from patients with suspected IIP. In Aim 2, we will conduct a pilot clinical study to test the translation of bronchoscopic OCT to identify microscopic honeycombing and diagnose IPF in vivo. If successful, these studies will result in the clinical translation of bronchoscopic OCT imaging as a minimally-invasive method for IPF diagnosis, mitigating the need for surgical diagnostic procedures. This proposal addresses a significant clinical problem in a way not previously achievable, and could lead to major innovations in IPF clinical management and therapeutic decision-making. CANDIDATE Dr. Hariri is an Instructor in Pathology on the tenure track at Harvard Medical School. Her long-term career goal is to become an independent physician-scientist using optical imaging to assess pulmonary disease such as IPF. She has a strong background in optical imaging research through her graduate training as a biomedical engineer and post-doctoral research, and is one of four specialist pulmonary pathologists at MGH. Her prior research experience and clinical knowledge of IIP have optimally positioned her to conduct the proposed studies. Dr. Hariri has spent a significant portion of her research training assessing OCT for disease detection, particularly in lung cancer, in controlled preclinical and ex vivo studies. She is now ready to translate this experience to clinical optical imaging that makes direct impacts on patient care. In order to achieve her long- term career goals, she must obtain further mentoring and experience in the translation of optical imaging to the clinical setting. This proposal will provide her with this essential training, and a solid foundation on which she will build her career as an independent researcher in patient-oriented pulmonary optical imaging. MENTORING ENVIRONMENT AND TRAINING PLAN Dr. Hariri will train in an exceptional environment at MGH with abundant intellectual and collaborative opportunities, and access to all the necessary resources to conduct her research. Her mentors, Drs. Melissa Suter and Andrew Tager, are luminaries in their respective fields of clinical optical imaging and pulmonary fibrosis. Drs. Tager and Suter both have ample mentoring experience, each having mentored 15 post-doctoral trainees, of whom many have obtained K awards or full faculty positions. They have an established mentoring relationship with Dr. Hariri, and ongoing collaborations with one another. They are fully dedicated to supporting Dr. Hariri in this proposal and her transition to independence. In addition, Drs. Brett Bouma and Thomas Colby will serve on Dr. Hariri's research advisory committee and provide further respective expertise in clinical translation of optical imaging and IPF diagnosis. To complement the expertise of her mentors and the proposed research, Dr. Hariri will complete courses in biostatistics, medical imaging informatics, translational research, and clinical study design through Harvard. Through mentorship from Drs. Suter and Tager and workshops/courses held at MGH and Harvard, Dr. Hariri will gain the necessary skills to successfully transition to an independent physician-scientist, including research planning, scientific writing, applying for an R01, laboratory and budget management, responsible conduct of research, and effective mentoring.

 描述（由申请方提供）：特发性肺纤维化（IPF）是一种进行性、最终致死的特发性间质性肺炎（IIP），3年生存率为0%。IPF的诊断确定性对于患者管理和治疗决策至关重要。FDA批准的两种新疗法吡非尼酮和尼达尼布已被证明可减缓IPF的疾病进展，并为IPF患者带来新的希望。由于这些药物的高成本、副作用和仅在IPF中记录的疗效，肺病学家仅将这些药物处方给具有明确诊断的IPF患者。当存在典型的影像学特征（必须包括外周蜂窝样改变）时，大约一半的病例可以单独通过胸部CT进行IPF的确诊。当CT无法显示蜂窝样改变时，患者必须接受手术切除肺组织，并在显微镜下寻找蜂窝样改变，以确定IPF的诊断确定性。不幸的是，手术肺切除术具有相关发病率和死亡率的高风险，包括引起进一步的疾病进展，甚至死亡。临床上明确需要一种低风险的显微镜下IPF诊断方法。在该提案中，我们采用假设驱动的方法来确定支气管镜光学成像是否可以作为一种新型、低风险、非手术的IPF诊断范例，而无需手术或组织切除。光学相干断层扫描（OCT）提供了大组织体积的快速3D可视化，其显微分辨率（< 10 µm，与低倍显微镜相当）远远超过CT的能力。我们已经开发了支气管镜OCT导管，并在患者体内进行了外周肺成像。我们在初步研究中表明，支气管内OCT可以检测到CT无法观察到的IPF中的显微蜂窝（直径< 1 mm）。我们假设微创支气管镜OCT可以检测显微镜下蜂窝样改变，并以高灵敏度和特异性诊断IPF。在目标1中，我们将开发并验证OCT诊断标准，以检测显微镜下蜂窝样改变并诊断IPF。我们将创建一个基于气道的OCT库，该库具有来自疑似IIP患者的离体肺标本的匹配组织学。在目标2中，我们将进行一项初步临床研究，以测试支气管镜OCT的转换，以识别显微镜下蜂窝样改变并诊断体内IPF。如果成功，这些研究将导致支气管镜OCT成像作为IPF诊断的微创方法的临床转化，减少对外科诊断程序的需求。该提案以以前无法实现的方式解决了一个重大的临床问题，并可能导致IPF临床管理和治疗决策的重大创新。候选人哈里里博士是哈佛医学院终身教职的病理学讲师。她的长期职业目标是成为一名独立的医生-科学家，使用光学成像评估肺部疾病，如IPF。她在光学成像研究方面有很强的背景，通过她的研究生培训作为一个生物医学工程师和博士后研究，是四个专家在MGH肺病理学家之一。她之前的研究经验和IIP的临床知识使她能够最佳地进行拟议的研究。Hariri博士在她的研究培训中花了很大一部分时间来评估OCT在疾病检测中的作用，特别是在对照临床前和体外研究中的肺癌。她现在准备将这一经验转化为对患者护理产生直接影响的临床光学成像。为了实现她的长期职业目标，她必须获得进一步的指导和经验，在翻译的光学成像的临床设置。这一建议将为她提供这一基本培训， 坚实的基础上，她将建立她的职业生涯作为一个独立的研究人员在以病人为导向的肺部光学成像。哈里里博士将在MGH的特殊环境中接受培训，拥有丰富的智力和合作机会，并获得所有必要的资源来进行研究。她的导师Melissa Suter博士和Andrew Tager博士是各自临床光学成像和肺纤维化领域的杰出人物。Tager和Suter博士都有丰富的指导经验，每人指导了15名博士后学员，其中许多人获得了K奖或全职教师职位。他们与哈里里博士建立了指导关系，并不断相互合作。他们将全力支持哈里里博士的这一建议和她向独立过渡。此外，Brett Bouma博士和托马斯科尔比博士将在Hariri博士的研究咨询委员会任职，并在光学成像和IPF诊断的临床翻译方面提供更多各自的专业知识。为了补充她的导师和拟议的研究的专业知识，哈里里博士将通过哈佛完成生物统计学，医学成像信息学，转化研究和临床研究设计课程。Suter和Tager博士的指导以及在MGH和哈佛举办的研讨会/课程，哈里里博士将获得成功过渡到独立的医生科学家的必要技能，包括研究规划，科学写作，申请R 01，实验室和预算管理，负责任的研究行为和有效的指导。