4.4.6 Other Project Information Component: Project Summary/Abstract This project will validate our new high-transition-temperature (high-Tc;operating at 77?K, cooled by liquid nitrogen) superconducting magnetic susceptometer as the most clinically effective means for monitoring iron overload in patients who require chronic red blood cell transfusion. Transfusional iron overload is an orphan disease that develops in patients who require regular blood transfusions for treatment of a variety of refractory anemias that are themselves orphan disorders, including sickle-cell disease, thalassemia major (Cooley's anemia), Diamond-Blackfan anemia, aplastic anemia, pure red cell aplasia, hypoplastic and myelodysplastic disorders. In the United States, the number of anemic patients with transfusional iron overload is estimated to be less than 50,000. Without iron-chelating therapy, potentially lethal amounts of iron accumulate in these patients. Treatment with a chelating agent capable of sequestering iron and permitting its excretion from the body provides a means of managing transfusional iron overload that can prolong survival and avert or ameliorate iron-induced organ damage. Optimal management of patients requires careful monitoring of body iron to prevent iron-induced toxicity while avoiding adverse effects of excessive chelator administration. Our laboratories originally developed low-transition-temperature (low-Tc;operating at 4?K, cooled by liquid helium) superconducting quantum interference device (SQUID) susceptometry as a clinical method for quantitation of hepatic iron stores. The safety, ease, rapidity and comfort of magnetic measurements have made frequent, serial investigations technically feasible and practically acceptable to patients. Recently, we have made a series of technological breakthroughs and instrumental innovations that have made possible replacement, redesign and refinement of the elements of the low-Tc susceptometer, operating at 4?K in liquid helium, with components able to function at 77?K in liquid nitrogen. The proposed Phase 2 clinical studies are designed to test the hypothesis that measurements of hepatic iron stores with our new high-Tc susceptometer are clinically superior to all other available methods and to supply essential data needed for FDA approval of the medical device. The proposed project has three specific aims: (1) to calibrate the high-Tc susceptometer with results of biochemical analysis of tissue from liver explants from adult and pediatric patients undergoing liver transplantation and from clinically indicated liver biopsy;and (2) to prospectively validate the high-Tc susceptometer with results of biochemical analysis of tissue from liver explants from adult and pediatric patients and from clinically indicated liver biopsy;and (3) to prospectively compare measurements of hepatic iron concentration by the high-Tc susceptometer with (i) estimates derived from liver magnetic resonance imaging (MRI) relaxation rates (R2, R2*, signal intensity ratios), (ii) with determinations of serum ferritin, and (iii) with histopathological examination, using biochemical analysis of liver storage iron concentrations as the reference standard.
|Brittenham, Gary M (2011) Iron-chelating therapy for transfusional iron overload. N Engl J Med 364:146-56|