Publications (20)96.94 Total impact
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Article: Transfusional iron overload in children with sickle cell anemia on chronic transfusion therapy for secondary stroke prevention.
American Journal of Hematology 10/2011; · 4.67 Impact Factor -
Article: International reproducibility of single breathhold T2* MR for cardiac and liver iron assessment among five thalassemia centers.
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ABSTRACT: To examine the reproducibility of the single breathhold T2* technique from different scanners, after installation of standard methodology in five international centers. Up to 10 patients from each center were scanned twice locally for local interstudy reproducibility of heart and liver T2*, and then flown to a central MR facility to be rescanned on a reference scanner for intercenter reproducibility. Interobserver reproducibility for all scans was also assessed. Of the 49 patients scanned, the intercenter reproducibility for T2* was 5.9% for the heart and 5.8% for the liver. Local interstudy reproducibility for T2* was 7.4% for the heart and 4.6% for the liver. Interobserver reproducibility for T2* was 5.4% for the heart and 4.4% for the liver. These data indicate that T2* MR may be developed into a widespread test for tissue siderosis providing that well-defined and approved imaging and analysis techniques are used.Journal of Magnetic Resonance Imaging 08/2010; 32(2):315-9. · 2.70 Impact Factor -
Article: Iron chelation therapy: you gotta have heart.
Blood 03/2010; 115(12):2333-4. · 9.90 Impact Factor -
Article: Effect of transfusional iron intake on response to chelation therapy in beta-thalassemia major.
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ABSTRACT: The success of chelation therapy in controlling iron overload in patients with thalassemia major is highly variable and may partly depend on the rate of transfusional iron loading. Using data from the 1-year phase III study of deferasirox, including volumes of transfused red blood cells and changes in liver iron concentration (LIC) in 541 patients, the effect of iron loading on achieving neutral or negative iron balance was assessed in patients receiving different doses of deferasirox and the comparator deferoxamine. After dose adjustment, reductions in LIC after 1 year of deferasirox or deferoxamine therapy correlated with transfusional iron intake. At a deferasirox dose of 20 mg/kg per day, neutral or negative iron balance was achieved in 46% and 75% of patients with the highest and lowest transfusional iron intake, respectively; 30 mg/kg per day produced successful control of iron stores in 96% of patients with a low rate of transfusional iron intake. Splenectomized patients had lower transfusional iron intake and greater reductions in iron stores than patients with intact spleens. Transfusional iron intake should be monitored on an ongoing basis in thalassemia major patients, and the rate of transfusional iron loading should be considered when choosing the appropriate dose of an iron-chelating agent. This study is registered at http://clinicaltrials.gov as NCT00061750.Blood 02/2008; 111(2):583-7. · 9.90 Impact Factor -
Article: Multi-center transferability of a breath-hold T2 technique for myocardial iron assessment.
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ABSTRACT: Cardiac iron overload is the leading cause of death in thalassemia major and is usually assessed using myocardial T2* measurements. Recently a cardiovascular magnetic resonance (CMR) breath-hold T2 sequence has been developed as a possible alternative. This cardiac T2 technique has good interstudy reproducibility, but its transferability to different centres has not yet been investigated. The breath-hold black blood spin echo T2 sequence was installed and validated on 1.5T Siemens MR scanners at 4 different centres across the world. Using this sequence, 5-10 thalassemia patients from each centre were scanned twice locally within a week for local interstudy reproducibility (n = 34) and all were rescanned within one month at the standardization centre in London (intersite reproducibility). The local interstudy reproducibility (coefficient of variance) and mean difference were 4.4% and -0.06 ms. The intersite reproducibility and mean difference between scanners were 5.2% and -0.07 ms. The breath-hold myocardial T2 technique is transferable between Siemens scanners with good intersite and local interstudy reproducibility. This technique may have value in the diagnosis and management of patients with iron overload conditions such as thalassemia.Journal of Cardiovascular Magnetic Resonance 02/2008; 10:11. · 3.72 Impact Factor -
Article: Pediatric iron overload.
Clinical advances in hematology & oncology: H&O 09/2007; 5(8):601-2. -
Article: Improved transverse relaxation rate measurement techniques for the assessment of hepatic and myocardial iron content.
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ABSTRACT: To develop and validate an optimized respiratory-gated, gradient-echo sampling of free induction decay and echo (GESFIDE) pulse sequence for the simultaneous measurement of R2, R2*, and R2' in the liver or heart. Fifteen subjects (12 thalassemia patients and three normal volunteers) were scanned using an optimized navigator-gated GESFIDE pulse sequence for the measurement of R2, R2*, and R2' in the liver and heart. For imaging the myocardium, dark-blood preparation was used to suppress the blood signal to improve accuracy. The results were compared with those obtained from breath-held GESFIDE and multi-gradient-echo (GRE) scans. Good agreement between breath-held and navigator-gated scans was found for R2, R2*, and R2' values in the liver (slopes = 0.97-0.99, r = 0.997-0.998, P < 0.0001) and for R2* in the heart (slope = 1.02, r = 0.85, P < 0.0001). Both R2* and R2' were closely correlated to R2 in the liver, with correlation factors of 0.998 and 0.994, respectively, but weaker correlations were observed in the heart (r = 0.72 for R2* vs. R2 and r = 0.51 for R2' vs. R2). The improved sequence enables free-breathing measurements of transverse relaxation rates of the myocardium and liver. The method precludes the need for multiple breath-held scans and possible misregistration issues, and may prove most beneficial for imaging young children and patients who may have difficulty with prolonged or repeated breath-holds.Journal of Magnetic Resonance Imaging 07/2007; 26(1):208-14. · 2.70 Impact Factor -
Article: Improved transverse relaxation rate measurement techniques for the assessment of hepatic and myocardial iron content
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ABSTRACT: PurposeTo develop and validate an optimized respiratory-gated, gradient-echo sampling of free induction decay and echo (GESFIDE) pulse sequence for the simultaneous measurement of R2, R2*, and R2′ in the liver or heart.Materials and Methods Fifteen subjects (12 thalassemia patients and three normal volunteers) were scanned using an optimized navigator-gated GESFIDE pulse sequence for the measurement of R2, R2*, and R2′ in the liver and heart. For imaging the myocardium, dark-blood preparation was used to suppress the blood signal to improve accuracy. The results were compared with those obtained from breath-held GESFIDE and multi-gradient-echo (GRE) scans.ResultsGood agreement between breath-held and navigator-gated scans was found for R2, R2*, and R2′ values in the liver (slopes = 0.97–0.99, r = 0.997–0.998, P < 0.0001) and for R2* in the heart (slope = 1.02, r = 0.85, P < 0.0001). Both R2* and R2′ were closely correlated to R2 in the liver, with correlation factors of 0.998 and 0.994, respectively, but weaker correlations were observed in the heart (r = 0.72 for R2* vs. R2 and r = 0.51 for R2′ vs. R2).Conclusion The improved sequence enables free-breathing measurements of transverse relaxation rates of the myocardium and liver. The method precludes the need for multiple breath-held scans and possible misregistration issues, and may prove most beneficial for imaging young children and patients who may have difficulty with prolonged or repeated breath-holds. J. Magn. Reson. Imaging 2007;26:208–214. © 2007 Wiley-Liss, Inc.Journal of Magnetic Resonance Imaging 06/2007; 26(1):208 - 214. · 2.70 Impact Factor -
Article: Current Treatment of Cooley's Anemia
Annals of the New York Academy of Sciences 12/2006; 612(1):286 - 292. · 3.15 Impact Factor -
Article: New advances in iron chelation therapy.
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ABSTRACT: The emergence of new chelators is likely to have a major impact on the treatment of thalassemia major, sickle cell disease and other hematologic disorders for which regular red cell transfusions are required either to correct severe anemia or to prevent major complications of the underlying disease. In comparison with deferoxamine, which requires prolonged parenteral infusion to achieve negative iron balance, orally active chelators offer the promise of easier administration and better compliance. Moreover, the availability of more than one iron chelator opens up the possibility of combination therapy to target iron in specific organs and to enhance overall iron excretion. Long-term studies, employing new technologies to measure tissue iron, are required to determine whether the new chelators will be as safe and effective as deferoxamine in maintaining control of iron stores and preventing iron-induced cardiac disease, the major complication of transfusional iron overload.Hematology 02/2006; · 1.49 Impact Factor -
Article: Seasonal variation of pretransfusion hemoglobin levels in patients with thalassemia major.
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ABSTRACT: Patients with thalassemia major often report that they do not maintain their usual pretransfusion hemoglobin concentration during the summer season. We collected 3977 pretransfusion hemoglobin values, amount of blood transfused, and intertransfusion intervals for 94 patients with thalassemia major from 4 centers worldwide. We also assessed the hematocrits of blood donors, the hemoglobin content of units transfused in one center, and the local mean monthly temperatures during the periods of data collection. Pretransfusion hemoglobin levels were significantly lower during the summer in all centers except the one center where monthly temperatures have the least variation throughout the year. A similar relationship to temperature was observed for the hematocrits of blood donors and the hemoglobin content of donor units. This study confirms that pretransfusion hemoglobin levels in patients with thalassemia major are lower in the summertime. Possible mechanisms include expansion of plasma volume with resultant hemodilution in the patient and lower hemoglobin content in donor blood.Blood 02/2006; 107(1):355-7. · 9.90 Impact Factor -
Article: 1/T2 and magnetic susceptibility measurements in a gerbil cardiac iron overload model.
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ABSTRACT: To measure the transverse relaxation rate (1/T2) and magnetic susceptibility of the heart in conditions of iron overload by using magnetic resonance (MR) imaging and to correlate these with the tissue iron concentration in a gerbil model. With prior approval by the institutional animal care and use committee, iron overload was induced with one to 15 weekly subcutaneous injections of iron dextran. Nine gerbils had one to five injections, 10 had six to 10, and eight had 13-15. T2 of the whole heart was measured ex vivo (n=27), and the magnetic susceptibility of the tissue was estimated through measurement of the tissue lysate (n=25). The iron level was measured (in milligrams of iron per gram of wet tissue) with chemical analysis after MR imaging. While 1/T2 and magnetic susceptibility are not equivalent measures of the chemically determined tissue iron level, correlations were expected and were identified by using linear regression models. Iron concentration range was 0.28-1.95 mg/g wet tissue. Iron concentration was strongly correlated with 1/T2 (r=0.92, P <.001, and the root of the mean squares error of the linear prediction, epsilonRMS, was 0.17 mg Fe/g wet tissue with a repetition time of 700 msec). Iron concentration also was strongly correlated with magnetic susceptibility (r=0.90, P <.001, epsilonRMS=0.19 mg Fe/g wet tissue). Multiple regression analysis with combined 1/T2 (with repetition time of 700 msec) and magnetic susceptibility data led to a slight increase in r and decrease in epsilon(RMS) (r=0.93, P <.001, epsilonRMS=0.16 mg Fe/g wet tissue). The results of this animal model study demonstrate that 1/T2 and magnetic susceptibility values can be used for estimation of the iron level in the heart.Radiology 03/2005; 234(3):749-55. · 5.73 Impact Factor -
Article: MRI measurement of hepatic magnetic susceptibility-phantom validation and normal subject studies.
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ABSTRACT: A magnetic resonance (MR) imaging method with the potential for assessing hepatic iron overload from measurements of hepatic magnetic susceptibility in vivo is described. Using the blood in the portal and hepatic veins as an internal reference, this technique uses the orientation dependence of signal phase to measure the susceptibility of the liver parenchyma. Computer simulations were done to investigate the requirements on spatial resolution and contrast ratio between the vessels and the background liver tissue for data acquisition. Validation studies were conducted using tube-embedded gel phantoms doped with iron-dextran from 0 to 10 mg Fe/mL to mimic healthy and iron-overloaded livers. The phantom measurements were conducted without motion and flow, under respiration-like oscillatory motion, and with flow. Studies on six normal human subjects demonstrated excellent reproducibility and precision. All images were collected at 1.5 T using a 3D T(1)-weighted turbo field echo sequence for inflow MR angiographies with full flow compensation and capable of cardiac synchronization, navigator gating, and motion correction.Magnetic Resonance in Medicine 01/2005; 52(6):1318-27. · 2.96 Impact Factor -
Article: Iron chelation therapy in sickle-cell disease and other transfusion-dependent anemias.
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ABSTRACT: Regular red cell transfusion therapy may be life-saving or may reduce complications substantially in several hematological disorders. The inevitable consequence of repeated transfusions is iron loading, which, if untreated, leads to organ failure and death. Chelation therapy with deferoxamine is the standard of care for patients who have transfusional iron overload. The necessity to administer this drug parenterally limits compliance; this has prompted the search for a safe and effective orally-administered chelator. Deferiprone, the first extensively studied orally active chelator, is now licensed for use in Europe for patients who are unable to use deferoxamine effectively or safely. ICL670, a newer oral chelator, is being tested in large clinical trials. Combined therapies, potentially including transfusional methods to reduce iron loading with parenteral and oral chelators, may improve compliance and efficacy in some patients who are transfused chronically.Hematology/Oncology Clinics of North America 12/2004; 18(6):1355-77, ix. · 2.64 Impact Factor -
Article: Complications of beta-thalassemia major in North America.
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ABSTRACT: Treatment of patients with beta-thalassemia major has improved dramatically during the past 40 years; however, the current clinical status of these patients remains poorly characterized. We performed a cross-sectional study of 342 patients in the Registry of the National Institutes of Health-sponsored Thalassemia Clinical Research Network. Evidence of hepatitis C exposure was present in 35% of tested patients, was associated with age, and had a rate of spontaneous viral clearance of 33%. Ferritin levels ranged from 147 to 11 010 ng/mL (median, 1696 ng/mL). Median hepatic iron content was 7.8 mg/g dry weight and 23% of patients had values of 15 mg/g dry weight or higher. No patients 15 years or younger and 5% of patients aged 16 to 24 years had heart disease requiring medication. Ten percent had cirrhosis on biopsy. Endocrinologic complications were common among adults. Seventy-four (22%) patients had recent implantable central venous access devices (CVADs) placed. Among 80 episodes of bacteremia in 38 patients, 90% were attributable to the CVAD. Among 330 patients who had received deferoxamine chelation therapy, 224 (68%) reported no complications. We conclude that hepatitis C, iron-related organ dysfunction, and complications of iron chelation therapy are strongly age-dependent in North American patients with beta-thalassemia.Blood 08/2004; 104(1):34-9. · 9.90 Impact Factor -
Article: Positive heterophile antibody test and massive splenomegaly in an adolescent with previously unsuspected Gaucher disease.
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ABSTRACT: Mild splenomegaly is common in patients with Epstein-Barr virus-associated infectious mononucleosis. Massive splenomegaly, however, is rare and requires further evaluation to exclude other causes. We report an adolescent girl with previously undiagnosed type 1 Gaucher disease who presented with massive splenomegaly. The diagnosis of her underlying condition was hampered by the presence of a positive heterophile antibody test for infectious mononucleosis.Pediatric emergency care 04/2004; 20(3):181-4. · 0.92 Impact Factor -
Article: Thalassemia.
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ABSTRACT: New developments in the epidemiology, treatment and prognosis of thalassemia have dramatically altered the approach to the care of affected patients, and these developments are likely to have an even greater impact in the next few years. Demographic changes have required an awareness and understanding of the unique features of thalassemia disorders that were previously uncommon in North America but are now seen more frequently in children and recognized more consistently in adults. New methods for measuring tissue iron accumulation and new drugs to remove excessive iron are advancing two of the most challenging areas in the management of thalassemia as well as other transfusion-dependent disorders. Improved survival of patients with thalassemia has given new importance to adult complications such as endocrinopathies and hepatitis that have a major impact on the quality of life. This chapter describes how these changes are redefining the clinical management of thalassemia. In Section I, Dr. Renzo Galanello describes recent advances in iron chelation therapy. Several new chelators are either licensed in some countries, are in clinical trials or are in the late stages of preclinical development. Some of these iron chelators, such as deferiprone (DFP) and ICL670, are orally active. Others, such as hydroxybenzyl-ethylenediamine-diacetic acid (HBED) and starch deferoxamine, require parenteral administration but may be effective with less frequent administration than is currently required for deferoxamine. Chelation therapy employing two chelators offers the possibility of more effective removal of iron without compromising safety or compliance. Other strategies for chelation therapy may take advantage of the ability of particular chelators to remove iron from specific target organs such as the heart and the liver. In Section II, Dr. Dudley Pennell addresses cardiac iron overload, the most frequent cause of death from chronic transfusion therapy. The cardiac complications related to excessive iron may result from long-term iron deposition in vulnerable areas or may be due to the more immediate effects of nontransferrin-bound iron. Cardiac disease is reversible in some patients with intensive iron chelation therapy, but identification of cardiac problems prior to the onset of serious arrhythmias or congestive heart failure has proven difficult. New methods using magnetic resonance imaging (MRI) have recently been developed to assess cardiac iron loading, and studies suggest a clinically useful relationship between the results using these techniques and critical measures of cardiac function. Measurements such as T2* may help guide chelation therapy in individual patients and may also enhance the assessment of new chelators in clinical trials. The use of MRI-based technology also holds promise for wider application of non-invasive assessment of cardiac iron in the management of patients with thalassemia. In Section III, Dr. Melody Cunningham describes some of the important complications of thalassemia that are emerging as patients survive into adulthood. Hepatitis C infection is present in the majority of patients older than 25 years. However, antiviral therapy in patients with thalassemia has been held back by the absence of large clinical trials and concern about ribavirin-induced hemolysis. More aggressive approaches to the treatment of hepatitis C may be particularly valuable because of the additive risks for cirrhosis and hepatocellular carcinoma that are posed by infection and iron overload. Thrombosis is recognized with increasing frequency as a significant complication of thalassemia major and thalassemia intermedia, and pulmonary hypertension is now the focus of intense study. Risk factors for thrombosis such as splenectomy are being identified and new approaches to anticoagulation are being initiated. Pregnancies in women with thalassemia are increasingly common with and without hormonal therapy, and require a better understanding of the risks of iron overload and cardiac disease in the mother and exposure of the fetus to iron chelators. In Section IV, Dr. Elliott Vichinsky describes the dramatic changes in the epidemiology of thalassemia in North America. Hemoglobin E-beta thalassemia is seen with increasing frequency and poses a particular challenge because of the wide variability in clinical severity. Some affected patients may require little or no intervention, while others need chronic transfusion therapy and may be appropriate candidates for hematopoietic stem cell transplantation. Enhancers of fetal hemoglobin production may have a unique role in Hb E-beta thalassemia since a modest increase in hemoglobin level may confer substantial clinical benefits. Alpha thalassemia is also being recognized with increasing frequency in North America, and newborn screening for Hemoglobin Barts in some states is leading to early detection of Hb H disease and Hb H Constant Spring. New data clarify the importance of distinguishing these two disorders because of the increased severity associated with Hb H Constant Spring. The use of intrauterine transfusions to sustain the viability of fetuses with homozygous alpha thalassemia has created a new population of patients with severe thalassemia and has raised new and complex issues in genetic counseling for parents with alpha thalassemia trait.Hematology 02/2004; · 1.49 Impact Factor -
Article: Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone.
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ABSTRACT: The identification of a safe, orally active iron chelator is critically important for the prevention of morbidity and early death in patients receiving regular red cell transfusions. Based on our findings in a 1-year multicenter, prospective study of the safety and efficacy of deferiprone in patients with thalassemia major, we have extended the treatment period to 4 years. The mean dose of the chelator was 73 mg/kg per day during 531 patient-years. The rates of agranulocytosis (absolute neutrophil count [ANC] < 500 x 10(9)/L) and milder forms of neutropenia (ANC, 500-1500 x 10(9)/L) were 0.2 and 2.8 per 100 patient-years, respectively. Neutropenia occurred significantly more commonly in patients with intact spleens. Gastrointestinal and joint symptoms decreased significantly after the first year of therapy, and led to discontinuation of deferiprone in only one patient in years 2 to 4. The mean alanine aminotransferase (ALT) value of 71 U/L after 4 years of therapy was significantly higher than the baseline value of 61 U/L. Trend analysis showed no increase in the ALT levels or the percentage of patients with ALT levels greater than twice the upper limit of the reference range. Ferritin levels did not change significantly from the values at the time of change from deferoxamine to deferiprone in either the intention-to-treat analysis or in the 84 patients who completed 4 years of therapy. Because of concerns regarding the effectiveness of the studied dose of deferiprone, 47 patients discontinued therapy, whereas 15 patients interrupted therapy because of concerns regarding low iron levels. The results of this study help to define the safety and effectiveness of long-term therapy with deferiprone.Blood 09/2003; 102(5):1583-7. · 9.90 Impact Factor -
Article: Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia.
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ABSTRACT: Patients with thalassemia major require lifelong chelation therapy to prevent iron-induced organ damage. The orally active chelator deferiprone has been proposed as an alternative for patients unable or unwilling to use deferoxamine. One report has concluded that deferiprone may worsen hepatic fibrosis in patients with thalassemia, whereas others have found no detrimental effect. A panel of 3 pathologists evaluated 112 coded liver biopsies obtained from 56 patients before and after deferiprone therapy. Fibrosis was scored with the Laennec and Ishak systems. The mean interval between liver biopsies was 3.1 years (range, 1.2-4.9 years). In 11 patients seronegative for hepatitis C, fibrosis scores before and after therapy were 1.12 +/- 1.07 and 0.97 +/- 0.84 (P =.42) with the use of the Ishak system, and 0.71 +/- 0.65 and 0.70 +/- 0.53 (P =.91) with the Laennec system. Among 45 patients seropositive for hepatitis C, fibrosis scores before and after therapy were 1.91 +/- 1.13 and 2.04 +/- 1.30 (P =.43) with the use of the Ishak system and 1.26 +/- 0.73 and 1.35 +/- 0.90 (P =.41) with the Laennec system. When the data set was limited to biopsies that each contained 6 or more portal tracts (31 patients), analysis still showed no significant change in fibrosis with time. With the use of the Laennec system, the fibrosis score did not increase by more than one level in any patients without hepatitis C; it increased by more than one level in 1 patient with hepatitis C; and it did not decrease by more than one level in any of the 56 patients. This analysis of the largest collection of liver biopsies reported to date in patients receiving deferiprone demonstrates no evidence of deferiprone-induced progression of hepatic fibrosis during long-term therapy.Blood 10/2002; 100(5):1566-9. · 9.90 Impact Factor -
Article: Evaluation of iron overload by single voxel MRS measurement of liver T2.
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ABSTRACT: To overcome the difficulty of poor signal-to-noise ratio of magnetic resonance imaging (MRI) in evaluating heavy iron overload by using a single voxel magnetic resonance spectroscopy (MRS) technique. A single voxel STEAM pulse sequence with a minimum TE of 1.5 msec and a sampling volume of 36.6 cm(3) was developed and applied to 1/T2 measurement of the liver in 14 patients with thalassemia whose liver iron concentration was determined through biopsy. The iron level ranged from 0.23 to 37.15 mg Fe/g dry tissue with a median value of 18.06. In all cases, strong MR signals were obtained. 1/T2 was strongly correlated with the liver iron concentration (r = 0.95, P < 0.00005). The single voxel MRS measurement of T2 in liver iron overload overcomes the difficulty of lack of detectable signals in conventional MRI when the iron level is high. There is an excellent correlation between the iron level and 1/T2.Journal of Magnetic Resonance Imaging 04/2002; 15(4):395-400. · 2.70 Impact Factor
Top co-authors
Top Journals
Institutions
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2002–2010
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The Children's Hospital of Philadelphia
- • Department of Radiology
- • Division of General Pediatrics
Philadelphia, PA, USA -
University of Toronto
- Department of Laboratory Medicine and Pathobiology
Toronto, Ontario, Canada
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2004
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Hospital of the University of Pennsylvania
- Department of Pediatrics
Philadelphia, PA, USA -
Dana-Farber Cancer Institute
Boston, MA, USA
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