QSM to Guide Iron Chelating Therapy in Transfusional Iron Overload

QSM 指导铁螯合疗法治疗输血铁过量

• 批准号: 10558645
• 负责人: Gary M Brittenham
• 金额: $ 53.13万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558645
• 关键词: Agranulocytosis; Agreement; Auditory; Binding; Biophysics; Biopsy Specimen; Body measure procedure; Breathing; Cells; Chelating Agents; Chemicals; Cirrhosis; Clinical Research; Concentration measurement; Cooley' s anemia; Data; Deposition; Development; Diabetes Mellitus; Disease; Dose; Double-Blind Method; Edema; Error Sources; Erythrocyte Transfusion; Excretory function; FDA approved; Fatty acid glycerol esters; Fibrosis; Gastrointestinal Diseases; Gastrointestinal Hemorrhage; Growth; Heart; Heart failure; Hepatic; Histologic; Histology; Impairment; In Vitro; Iron; Iron Chelating Agents; Iron Chelation; Iron Overload; Kidney Failure; Laboratories; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Magnetic Resonance Imaging; Magnetism; Maps; Measurement; Measures; Methods; Neutropenia; Organ; Pancreas; Patients; Phase; Practice Guidelines; Predisposition; Property; Reference Standards; Refractory anemias; Relaxation; Reporting; Reproducibility; Research; Research Institute; Resources; Safety; Scanning; Sickle Cell Anemia; Signal Transduction; Techniques; Thalassemia; Tissues; Toxic effect; Transfusion; Translating; Variant; Visual impairment; Water; arthropathies; chemical standard; clinical practice; computerized data processing; data acquisition; improved; in vivo; insight; iron chelation therapy; liver biopsy; liver transplantation; programs

The overall objective of this research is to improve the safety of iron-chelating therapy (ICT) in patients with transfusional iron overload by developing accurate non-invasive measurement of the liver iron concentration (LIC), the best measure of the body iron burden in all forms of systemic iron overload. Our scientific premise is that MRI using quantitative susceptibility mapping (QSM) will be free of the inherent interfering factors, particularly fibrosis, that distort current LIC measurements based on R2 (=1/T2) and R2* (=R2+R2') estimates. Transfusional iron overload progressively develops in patients with refractory anemia who undergo regular red blood cell (RBC) transfusion (thalassemia major, sickle-cell disease, and other disorders), because the body lacks any effective means to excrete excess iron. Excess iron from transfused RBCs eventually leads to the formation of circulating non-transferrin-bound iron that is then progressively deposited in the liver, pancreas, heart and other organs, causing cirrhosis, diabetes, heart failure, and other disorders. ICT, which we have developed the practice guideline, can remove excess iron from cells, clear circulating non–transferrin-bound iron, and maintain or return body iron to safe levels. Safe therapy requires careful adjustment of the dose of iron-chelating agents to the body iron burden to optimize iron excretion while avoiding chelator toxicity, including gastrointestinal disorders, auditory and visual impairment, agranulocytosis and neutropenia, arthropathy, growth retardation, and potentially fatal hepatic failure, renal failure, and gastrointestinal hemorrhage. LIC at present is primarily estimated by noninvasive MRI using R2 (=1/T2) and R2* (=R2+R2') techniques that depend upon the contribution of iron to relaxation (R2) and intravoxel dephasing (R2'). A fundamental limitation of the R2 and R2* approaches is that intravoxel contents other than iron, including fibrosis, steatosis and necroinflammation, also alter relaxation. We have the biophysical insight to eliminate the R2 and R2* interfering effects using QSM, which we have developed to measure tissue magnetic properties. QSM is generated from processing the phase, while R2* is determined from the magnitude, of the same gradient echo MRI data without additional scans. Magnetic susceptibility measured by QSM has a simple linear relationship with intravoxel contents in accordance with chemical decomposition, allowing iron quantification without interfering errors from fibrosis, steatosis, necroinflammation and other intravoxel contents. Hence, we conservatively anticipate a >5 fold improvement in the accuracy of LIC measurements using hepatic QSM (hQSM) compared to the current R2 and R2* method. Our research plan has 3 specific aims: Aim 1. Develop hQSM for accurate measurement of LIC without interfering errors. Aim 2. Validate hQSM using histology and chemical measurement of LIC in liver explants. Aim 3. Evaluate hQSM in patients with transfusional iron overload under ICT.

这项研究的总体目标是提高铁螯合疗法(ICT)在慢性前列腺癌患者中的安全性。 开发准确的无创性肝铁浓度测量方法实现输血铁超载 (LIC)，在所有形式的全身性铁超载中，身体铁负荷的最佳衡量标准。我们的科学前提是 使用定量磁化率图(QSM)的MRI将不受固有干扰因素的影响， 尤其是纤维化，这扭曲了基于R2(=1/T2)和R2*(=R2+R2‘)估计的当前LIC测量。 接受常规红色治疗的难治性贫血患者进行性发展为输血铁超载 血细胞(RBC)输注(地中海贫血、镰状细胞病等疾病)，因为身体 缺乏任何有效的方法来排泄多余的铁。输注的红细胞中过量的铁最终会导致 形成循环中的非转铁蛋白结合的铁，然后逐渐沉积在肝脏，胰腺， 心脏和其他器官，引起肝硬变、糖尿病、心力衰竭等疾病。信息和通信技术，我们拥有 开发的实践指南，可以清除细胞中多余的铁，清除循环中的非转铁蛋白结合 铁，并保持或恢复身体铁到安全水平。安全治疗需要仔细调整剂量 铁络合剂给体内铁负荷，优化铁排泄，同时避免螯合剂毒性， 包括胃肠道疾病、听力和视力障碍、粒细胞缺乏症和中性粒细胞减少症， 关节病、生长迟缓和潜在致命的肝功能衰竭、肾功能衰竭和胃肠道疾病 大出血。目前，LIC主要由无创性MRI利用R2(=1/T2)和R2*(=R2+R2‘)来估计。 依赖于铁对松弛(R2)和体素内去相(R2‘)贡献的技术。一个 R2和R2*方法的基本限制是体素内铁以外的含量，包括 纤维化、脂肪变性和坏死性炎症也会改变松弛。我们有生物物理学的洞察力来消除 使用QSM的R2和R2*干扰效应，这是我们为测量组织磁性而开发的。 QSM是通过处理相位而产生的，而R2*是根据其大小确定的 梯度回波MRI数据，无需额外扫描。QSM测量的磁化率具有简单的线性关系 根据化学分解与体素内含量的关系，允许铁的定量 不干扰纤维化、脂肪变性、坏死性炎症和其他体素内内容的错误。因此，我们 保守地预计使用肝脏QSM测量LIC的准确性将提高5倍 (HQSM)与当前的R2和R2*方法进行比较。我们的研究计划有三个具体目标：目标1.发展 HQSM，用于准确测量LIC，无干扰误差。目标2.使用组织学和组织学验证hQSM 肝外植体中LIC的化学测定目的3.评估输血铁患者的hQSM 信息和通信技术下的超负荷。