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Excess iron can be extremely toxic for the body and may cause organ damage in the absence of iron chelation therapy. Preclinical studies on the role of free iron on bone marrow function have shown that iron toxicity leads to the accumulation of reactive oxygen species, affects the expression of genes coding for proteins that regulate hematopoiesis, and disrupts hematopoiesis. These effects could be partially attenuated by iron-chelation treatment with deferasirox, suggesting iron toxicity may have a negative impact on the hematopoietic microenvironment. Iron toxicity is of concern in transfusion-dependent patients. Importantly, iron chelation with deferasirox can cause the loss of transfusion dependency and may induce hematological responses, although the mechanisms through which deferasirox exerts this action are currently unknown. This review will focus on the possible mechanisms of toxicity of free iron at the bone marrow level and in the bone marrow microenvironment.

Myelodysplastic syndromes (MDS) are a group of clonally-acquired blood disorders characterized by ineffective hematopoiesis leading to cytopenias. Red blood cell transfusions are an important component of supportive care in patients with MDS. Prolonged exposure to transfusions can lead to iron overload, which results in iron-induced toxicity caused by the production of reactive oxygen species (ROS). ROS accumulation has detrimental effects also on hematopoietic stem cells and may contribute to MDS progression. The observation that iron chelation improves hematologic parameters and reduces transfusion dependence further indicates that iron overload impairs hematopoiesis. Over the past decade, the mechanisms regulating iron homeostasis and the complex interplay between iron overload and toxicity, ineffective hematopoiesis, and transformation to leukemia have become clearer. In this narrative review, we provide an overview of recent findings pertaining to iron overload in patients with MDS and its effects on hematopoiesis. We also briefly discuss the position of chelation therapy in the context of the new developments.

A number of beta-thalassemia (beta-thal) patients in the course of the disease exhibit ectopic calcification affecting skin, eyes and the cardiovascular system. Clinical and histopathological features have been described similar to those in pseudoxanthoma elasticum (PXE), although different genes are affected in the two diseases. Cultured dermal fibroblasts from beta-thal patients with and without PXE-like clinical manifestations have been compared for parameters of redox balance and for the expression of proteins, which have been already associated with the pathologic mineralisation of soft connective tissues. Even though oxidative stress is a well-known condition of beta-thal patients, our results indicate that the occurrence of mineralized elastin is associated with a more pronounced redox disequilibrium, as demonstrated by the intracellular increase of anion superoxide and of oxidized proteins and lipids. Moreover, fibroblasts from beta-thal PXE-like patients are characterized by decreased availability of carboxylated matrix Gla protein (MGP), as well as by altered expression of proteins involved in the vitamin K-dependent carboxylation process. Results demonstrate that elastic fibre calcification is promoted when redox balance threshold levels are exceeded and the vitamin K-dependent carboxylation process is affected decreasing the activity of MGP, a well-known inhibitor of ectopic calcification. Furthermore, independently from the primary gene defect, these pathways are similarly involved in fibroblasts from PXE and from beta-thal PXE-like patients as well as in other diseases leading to ectopic calcification, thus suggesting that can be used as markers of pathologic mineralisation.

Cardiac damage remains a major cause of mortality among patients with thalassemia major. The detection of a lower cardiac magnetic resonance T2* (CMR-T2*) signal has been suggested as a powerful predictor of the subsequent development of heart failure. However, the lack of worldwide availability of CMR-T2* facilities prevents its widespread use for follow-up evaluations of cardiac function in thalassemia major patients, warranting the need to assess the utility of other possible procedures. In this setting, the determination of left ventricular ejection fraction (LVEF) offers an accurate and reproducible method for heart function evaluation. These findings suggest a reduction in LVEF≥7%, over time, determined by 2-D echocardiography, may be considered a strong predictive tool for the detection of thalassemia major patients with increased risk of cardiac death. The reduction of LVEF≥7% had higher (84.76%) predictive value. Finally, Kaplan-Meier survival curves of thalassemia major patients with LVEF≥7% showed a statistically significant decreased probability of survival for heart disease (p=0.0022). However, because of limitations related to the study design, such findings should be confirmed in a large long-term prospective clinical trial.

Purpose To assess the transferability of the magnetic resonance imaging (MRI) multislice multiecho T2* technique for global and segmental measurement of iron overload in thalassemia patients. Materials and Methods Multiecho T2* sequences were installed on six MRI scanners. Five healthy subjects (n = 30) were scanned at each site; five thalassemia major (TM) patients were scanned at the reference site and were rescanned locally (n = 25) within 1 month. T2* images were analyzed using previously validated software. Results T2* values of healthy subjects showed intersite homogeneity. On TM patients, for global heart T2* values the correlation coefficient was 0.97, coefficients of variation (CoVs) ranged from 0.04–0.12, and intraclass coefficients (ICCs) ranged from 0.94–0.99. The mean CoV and ICC for segmental T2* distribution were 0.198 and 88, respectively. Conclusion The multislice multiecho T2* technique is transferable among scanners with good reproducibility. J. Magn. Reson. Imaging 2009;30:62–68. © 2009 Wiley-Liss, Inc.

Objective. Pain has a critical role in the management of sickle cell disease (SCD). Patients may suffer from several pain syndromes, which may be or not may be associated with other clinical complications, such as anemia, organ failures, and infections. Design. Data for review were identified by using PubMed to search MEDLINE, limiting the search to abstract/articles in English, Italian, French, and Dutch. The key words pain, sickle cell disease, anemia, hemoglobin, hemoglobinopathy, analgesics, opioids, morphine, acetaminophen, paracetamol, nonsteroidal anti-inflammatory drugs, hematology, and quality of life were variously combined in the title, abstract, and key word search list. The abstract database of most hematological congresses and the bibliographies of most relevant articles were also considered. Results. There are two major types of SCD pain: acute and chronic. Sometimes, mixed and neuropathic pain can be also observed. Acute pain is mostly related to vaso-occlusion. Chronic pain may be due to some SCD complications, such as leg ulcers and avascular necrosis. Conclusions. Pain management in the SCD setting needs multidisciplinary approaches, given the several syndromes and the pathogenic mechanisms that are likely involved. Pain management is not standardized and often difficult, so that many patients with SCD are still poorly treated. Further efforts to develop care plans and treatment protocols as well as management guidelines are required.

Objectives: Iron chelation treatment (ICT) in β-thalassemia major (β-TM) patients undergoing blood transfusions can cause low satisfaction, low compliance, with possible negative consequences on treatment success, patients' wellbeing, and costs. The purpose was to estimate the societal burden attributable to β-TM in terms of direct and indirect costs, health-related quality-of-life (HRQoL), satisfaction and compliance with ICT in patients undergoing transfusions and ICT. Research design and methods: The naturalistic, multicenter, longitudinal Italian-THAIassemia-Cost-&-Outcomes-Assessment (ITHACA) cost-of-illness study was conducted involving patients of any age, on ICT for at least 3 years, who were enrolled at 8 Italian Thalassemia Care Centers. Costs were estimated from the societal perspective, quantified with tariffs, prices, or net earnings valid in 2006. Results: One-hundred and thirty-seven patients were enrolled (median age = 28.3, 3-48 years, 49.6% male) and retrospectively observed for a median of 11.6 months. Mean direct costs were €1242/patient/month, 55.5% attributable to ICT, 33.2% attributable to transfusions. Relevant quantity and quality of productivity was lost. Both physical and mental components of HRQoL were compromised. Little difficulties remembering to take ICT and positive satisfaction with the perceived effectiveness of therapy were declared, but not good levels of satisfaction with acceptance, perception of side effects and burden of ICT. Conclusions: The management of β-TM patients undergoing transfusions and ICT is efficacious, although costly, but overall benefits were not always perceived as optimal by patients. Efforts must be focused to improve patients' acceptance and satisfaction with their therapy; this would contribute to a better compliance and hence an increase in treatment effectiveness and patients' overall wellbeing, with expected improved allocation of human and economic resources. © 2008 Informa UK Ltd.

Thalassemia major is an inherited hemoglobin disorder resulting in a chronic hemolytic anemia. Transfusion therapy together with elevated gastrointestinal absorption of iron determines iron overload, which causes most of the mortality and morbidity associated with the disease. Heart complications represent the leading cause of mortality in this disease, although, because of an improvement in chelation treatment, an important and progressive increase of life expectancy mainly as a result of a reduction in mortality due to cardiac dysfunction has been demonstrated in recent years. Clinical pictures of heart damage range from the involvement of the ventricles to pulmonary hypertension or symptomatic ventricular or supra-ventricular arrhythmias. For this reason, the possibility of having specific recommendations is noteworthy. These recommendations outline the definition, the follow-up and the treatment of the main heart complications in this group of patients. The identification of topics and the nomination of the committee were made on behalf of the Society for the Study of Thalassemia and Hemoglobinopathies (SoSTE). The document obtained the auspices of ANMCO, SIC, SIRM and the Cardiovascular Magnetic Resonance Working Groups of the ANMCO, SIC and SIRM. All recommendations provided in this document have been performed according to the American Cardiology College (ACC) and American Heart Association (AHA) guidelines. Moreover, the recommendations were reviewed by two external referees before the definitive approval.

In human beta-thalassemia, the imbalance between alpha- and non-alpha-globin chains causes ineffective erythropoiesis, hemolysis, and anemia: this condition is effectively treated by an enhanced level of fetal hemoglobin (HbF). In spite of extensive studies on pharmacologic induction of HbF synthesis, clinical trials based on HbF reactivation in beta-thalassemia produced inconsistent results. Here, we investigated the in vitro response of beta-thalassemic erythroid progenitors to kit ligand (KL) in terms of HbF reactivation, stimulation of effective erythropoiesis, and inhibition of apoptosis. In unilineage erythroid cultures of 20 patients with intermedia or major beta-thalassemia, addition of KL, alone or combined with dexamethasone (Dex), remarkably stimulated cell proliferation (3-4 logs more than control cultures), while decreasing the percentage of apoptotic and dyserythropoietic cells (5%). More important, in both thalassemic groups, addition of KL or KL plus Dex induced a marked increase of gamma-globin synthesis, thus reaching HbF levels 3-fold higher than in con-trol cultures (eg, from 27% to 75% or 81%, respectively, in beta-thalassemia major). These studies indicate that in beta-thalassemia, KL, alone or combined with Dex, induces an expansion of effective erythropoiesis and the reactivation of gamma-globin genes up to fetal levels and may hence be considered as a potential therapeutic agent for this disease.

Hepatocellular carcinoma (HCC) frequently complicates hepatic cirrhosis secondary to viral infection or iron overload. Therefore, patients affected by thalassaemia syndromes have a theoretically high risk of developing the tumour. We collected data on patients attending Italian centres for the treatment of thalassaemia. Twenty-two cases of HCC were identified; 15 were male. At diagnosis, the mean age was 45 +/- 11 years and the mean serum ferritin was 1764 +/- 1448 microg/l. Eighty-six percent had been infected by hepatitis C virus. Nineteen of 22 cases were diagnosed after 1993, suggesting that this problem is becoming more frequent with the aging population of thalassaemia patients.

Background: Congenital haemolytic anaemia may be associated with pseudoxanthoma elasticum (PXE)-like clinical manifestations. Methods: The cardiovascular system of 14 homozygous and double heterozygous I²-thalassaemia patients with skin and retinal vessel alterations similar to those in genetic PXE was analysed over a period of 12 years and compared with that of 13 relatives (five sets of parents, one single parent, two thalassaemic brothers), and that of the control group composed of 16, age- and sex-matched, thalassaemic patients. Results: All patients with clinical PXE-like skin lesions exhibited, by light and electron microscopy, dermal alterations and mineralization of elastic fibres identical to those typical of inherited PXE. None of the relatives and none of the control group showed clinical or structural findings of PXE. The follow-up started in 1988. After 12 years of clinical observation, six patients showed dramatic progression of skin involvement, angioid streaks had progressed in two subjects. One patient had recurrent gastrointestinal bleeding and underwent partial stomach removal for gastric artery aneurysm, one underwent colon resection for intestinal infarct, one patient had a transitory ischaemic attack, one died after an intracranial haemorrhage, two patients died from cardiovascular disease and one from neoplasia. Conclusions: Thalassaemic patients with PXE-like skin lesions also manifest PXE-like vessel alterations that progress with time. Considering the severe outcome of these lesions, accurate monitoring should be routinely performed on the cardiovascular system of thalassaemic patients with PXE-like skin manifestations.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common X chromosome-linked hereditary enzymopathy in humans. The authors have developed an amplification refractory mutation system (ARMS) to detect the G6PD Mediterranean mutation (nt. 563 C→T) that is the most frequent among Caucasian population. Methods: Specific forward polymerase chain reaction (PCR) primers, within exon 6 of the G6PD gene, were designed: ARMS M complementary to the mutated DNA sequence and ARMS N complementary to the wild-type DNA. They were paired with a common reverse primer. The new method was validated using known DNA samples from 72 G6PD-deficient patients carrying the G6PD Mediterranean mutation ascertained by the restriction enzyme analysis. The ARMS test was performed on DNA extracted both from blood or saliva samples. Results: The ARMS test showed an excellent reproducibility and a complete concordance with the endonuclease cleavage reference method. At the same time, it is more rapid and less expensive. Conclusions: The described molecular test may be a method of choice to identify the G6PD Mediterranean mutation. It could also be helpful to obtain a definite diagnosis of G6PD Mediterranean heterozygotes, which is not feasible by using red blood cell enzyme activity measurements.

Summary The risk of developing hepatocellular carcinoma (HCC) in patients with thalassaemia is increased by transfusion-transmitted infections and haemosiderosis. All Italian Thalassaemia Centres use an ad hoc form to report all diagnoses of HCC to the Italian Registry. Since our last report, in 2002, up to December 2012, 62 new cases were identified, 52% of whom were affected by thalassaemia major (TM) and 45% by thalassaemia intermedia (TI). Two had sickle-thalassaemia (ST). The incidence of the tumour is increasing, possibly because of the longer survival of patients and consequent longer exposure to the noxious effects of the hepatotropic viruses and iron. Three patients were hepatitis B surface antigen-positive, 36 patients showed evidence of past infection with hepatitis B virus (HBV). Fifty-four patients had antibodies against hepatitis C virus (HCV), 43 of whom were HCV RNA positive. Only 4 had no evidence of exposure either to HCV or HBV. The mean liver iron concentration was 8 mg/g dry weight. Therapy included chemoembolization, thermoablation with radiofrequency and surgical excision. Three patients underwent liver transplant, 21 received palliative therapy. As of December 2012, 41 patients had died. The average survival time from HCC detection to death was 11·5 months (1·4–107·2 months). Ultrasonography is recommended every 6 months to enable early diagnosis of HCC, which is crucial to decrease mortality.

A rare case of hereditary erythrocyte enzymopathy, namely 6-phosphogluconate dehydrogenase (6PGD) deficiency, was found in an Italian family. The activity of the enzyme was reduced to 35% in the propositus and her mother, but was normal in the other three members of the family. The 6PGD deficiency was associated with a variable reticulocyte count and recurrent increased unconjugated bilirubinemia without anemia in the propositus, while no clinical or hematological symptoms were evident in her mother. Increased levels of erythrocyte pyruvate kinase (PK) activity and reduced glutathione (GSH) were observed, indicating a slight decrease in mean red blood cell (RBC) age and an activation of reducing systems. The episodic hemolytic events with jaundice observed in the propositus may be the result of a defective RBC ability to counteract conditions of marked oxidative stress. In this report the importance of 6PGD estimation for a proper analysis of glucose-6-phosphate dehydrogenase (G6PD) deficiency is also highlighted. In fact in the present study, the presence of 6PGD deficiency could be mistaken for a partial G6PD deficiency if the assay of G6PD activity was performed without correcting for 6PGD activity.

Patients with beta-globin disorders show amelioration of clinical condition by sustained synthesis of fetal haemoglobin in adult life. We report data on a patient with beta(o)-thalassaemia genotype and thalassaemia intermedia clinical phenotype. He received therapy with hydroxyurea (20 mg/kg/d) because of the presence of extramedullary masses causing paraparesis, neurogenic bladder and impotence. During therapy, the patient showed an improved clinical picture and a significant increase in total Hb (from 71.8 to 103.2 g/L) and a gamma/alpha globin synthetic ratio (from 0.39 to 0.68). The myelosuppressive effect of hydroxyurea was revealed by a decrease in CFU-GEMM, BFU-E, and CFU-GM. Therefore hydroxyurea can be effective in the treatment of patients with extramedullary haematopoiesis (EMH) who are not transfusion-dependent and cannot be treated with radiotherapy.

To compare the effectiveness of dark blood (DB) versus bright blood (BB) sequences. To assess the intra and inter-observer variability and inter-study reproducibility between BB versus DB. To evaluate image quality level in the two sequences.In a setting of 138 patients we performed CMR using cardiac gated Gradient-multiecho single breath-hold BB and DB sequences in the middle ventricular septum. Each acquisition was repeated during the same exam. Truncation method was used to account for background noise. Image quality (IQ) was assessed using a 5 point grading scale and image analysis was conducted by 2 experienced observers.Compared with the conventional BB acquisition, the coefficient of correlation and significance of the DB technique was superior for intra-observer reproducibility (p0.001), inter-observer reproducibility (p0.001) and inter-study reproducibility (p0.001). The variability is also lower for DB sequences for T2* values14 ms. Assessment of artifacts showed a superior score for DB versus BB scans (4 versus 3, p0.001).Improvement in terms of inter observer and inter study variability using DB sequences was obtained. The greatest disparity between them was seen in inter-study reproducibility and higher IQ in DB was seen. Study demonstrates better performance of DB imaging compared to BB in presence of comparable effectiveness.

Purpose Myocardial T2* cardiovascular magnetic resonance provides a rapid and reproducible assessment of cardiac iron load in thalassemia patients. Although cardiac involvement is mainly characterized by left ventricular dysfunction caused by iron overload, little is known about right ventricular function. The aim of this study was to assess the relationship between T2* value in myocardium and left–right ventricular volumetric and functional parameters and to evaluate the existing associations between left–right ventricles volumetric and functional parameter, myocardial T2* values and blood ferritin levels. Materials and methods A retrospective analysis of 208 patients with β-thalassemia major and thalassemia intermedia was performed (109 males and 99 females; mean age 37.7 ± 13 years; 143 thalassemia major, 65 thalassemia intermedia). Myocardial iron load was assessed by T2* measurements, and volumetric functions were analyzed using the steady state free precession sequence. Results A significant correlation was observed between EFLV and T2* (p = 0.0001), EFRV and T2* (p = 0.0279). An inverse correlation was present between DVLV and T2* (p = 0.0468), SVLV and T2* (p = 0.0003), SVRV and T2* (p = 0.0001). There was no significant correlation between cardiac T2* and LV–RV mass indices. A significant correlation was observed between T2* and serum ferritin levels (p Conclusion Myocardial iron load assessed by T2* cardiac magnetic resonance is associated with deterioration in left–right ventricular function; this is more evident when T2* values fall below 14 ms. CMR appears to be a promising approach for cardiac risk evaluation in TM patients.

Transfusion and iron chelation treatment have significantly reduced morbidity and improved survival of patients with thalassemia major. However, cardiac disease continues to be the most common cause of death. We report the left-ventricular ejection fraction, determined by echocardiography, in one hundred sixtyeight patients with thalassemia major followed for at least 5 years who received continuous monotherapy with deferoxamine (N = 108) or deferiprone (N = 60). The statistical analysis, using the generalized estimating equations model, indicated that the group treated with deferiprone had a significantly better left-ventricular ejection fraction than did those treated with deferoxamine (coefficient 0.97; 95% CI 0.37; 1.6, p = 0.002). The heart may be particularly sensitive to iron-induced mitochondrial damage because of the large number of mitochondria and its low level of antioxidants. Deferiprone, because of its lower molecular weight, might cross into heart mitochondria more efficiently, improving their activity and, thereby, myocardial cell function. Our findings indicate that the long-term administration of deferiprone significantly enhances left-ventricular function over time in comparison with deferoxamine treatment. However, because of limitations related to the design of this study, these findings should be confirmed in a prospective, randomized clinical trial.

MicroRNAs (miRNAs) play key roles in modulating a variety of cellular processes through repression of mRNAs target. The functional relevance of microRNAs has been proven in normal and malignant hematopoiesis. While analyzing miRNAs expression profile in unilineage serum-free liquid suspension unilineage cultures of peripheral blood CD34(+) hematopoietic progenitor cells (HPCs) through the erythroid, megakaryocytic, granulocytic and monocytic pathways, we identified miR-486-3p as mainly expressed within the erythroid lineage. We showed that miR-486-3p regulates BCL11A expression by binding to the extra-long isoform of BCL11A 3'UTR. Overexpression of miR-486-3p in erythroid cells resulted in reduced BCL11A protein levels, associated to increased expression of γ-globin gene, whereas inhibition of physiological miR-486-3p levels increased BCL11A and, consequently, reduced γ-globin expression. Thus, miR-486-3p regulating BCL11A expression might contributes to fetal hemoglobin (HbF) modulation and arise the question as to what extent this miRNA might contribute to different HbF levels observed among β-thalassemia patients. Erythroid cells, differentiated from PB CD34(+) cells of a small cohort of patients affected by major or intermedia β-thalassemia, showed miR-486-3p levels significantly higher than those observed in normal counterpart. Importantly, in these patients, miR-486-3p expression correlates with increased HbF synthesis. Thus, our data indicate that miR-486-3p might contribute to different HbF levels observed among thalassemic patients and, possibly, to the clinical severity of the disease.

β-Thalassemias are a group of hereditary blood disorders characterized by abnormalities in the synthesis of the β hemoglobin (Hb) chains. This disease causes excessive storage of iron in all organs and endocrine glands. Treatment of β-thalassemia major (β-TM) consists of regular blood transfusions, iron chelation and management of secondary complications of iron overload. Endocrine abnormalities are frequently observed. In the last 25 years, the clinical picture of the disease has changed progressively thanks to improvement of treatments. Today, the majority of thalassemic patients reach adult age. The better prognosis and the longer lifespan of affected patients could be responsible for the susceptibility to other concomitant diseases which can manifest during their life. In this context, the possibility and recent literature reports about some cases of malignancy in thalassemic patients open new scenarios for oncoming years. We describe first reports of endocrine malignancies in thalassemic patients.

In β-thalassemia major (β-TM) patients, iron chelation therapy is mandatory to reduce iron overload secondary to transfusions. Recommended first line treatment is deferoxamine (DFO) from the age of 2 and second line treatment after the age of 6 is deferiprone (L1). A multicenter randomized open-label trial was designed to assess the effectiveness of long-term alternating sequential L1-DFO versus L1 alone iron chelation therapy in β-TM patients. Deferiprone 75 mg/kg 4 days/week and DFO 50 mg/kg/day for 3 days/week was compared with L1 alone 75 mg/kg 7 days/week during 5-year follow-up. A total of 213 thalassemia patients were randomized and underwent intention-to-treat analysis. Statistically, a decrease of serum ferritin levels was significantly higher in alternating sequential L1-DFO patients compared with L1 alone patients (p = 0.005). Kaplan-Meier survival analysis for the two chelation treatments did not show statistically significant differences (log-rank test, p = 0.3145). Adverse events and costs were comparable between the groups. Alternating sequential L1-DFO treatment decreased serum ferritin concentration during a 5-year treatment by comparison to L1 alone, without significant differences of survival, adverse events or costs. These findings were confirmed in a further 21-month follow-up. These data suggest that alternating sequential L1-DFO treatment may be useful for some β-TM patients who may not be able to receive other forms of chelation treatment.

5165 Introduction: Most deaths in thalassemia major (TM) result from cardiac complications due to iron overload. No data are available in literature about possible different changes in cardiac and liver iron in TM patients treated with sequential deferiprone–deferoxamine (DFP-DFO) versus deferasirox (DFX). Magnetic Resonance (MR) is the unique non invasive suitable technique to evaluated quantitatively this issue. The aim of this multi-centre study was to assess prospectively in the clinical practice the efficacy of the DFP-DFO vs DFX in a cohort of TM patients by quantitative MR. Methods: Among the first 739 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, 253 patients performed a MR follow up study at 18 ± 3 months according to the protocol. We evaluated prospectively the 25 patients treated with DFP-DFO versus the 44 patients treated with DFX between the 2 MR scans. Myocardial and liver iron concentrations were measured by T2* multislice multiecho technique. Results: The doses of the sequential treatment were DFP 70±14 mg/kg/d for 4 d/w and DFO 42±8 mg/kg/d for 3 d/w, the dose of DFX was 26±6 mg/kg/d. Excellent/good levels of compliance were similar in the 2 groups (DFP-DFO 96% vs DFX 100%; P = 0.36). At baseline the 2 groups were homogeneous for cardiac and liver iron. Among the patients with no significant myocardial iron overload at baseline (global heart T2* 3 20 ms), there were no significant differences between groups to maintain the patients without myocardial iron overload (DFP-DFO 95% vs DFX 96%; P = 1.0). Among the patients with myocardial iron overload at baseline (global heart T2* < 20 ms), only in the DFX group there was a significant improvement in the global heart T2* value (11 ± 5 ms at baseline versus 16 ± 8 at 18 ± 3 months, P = 0.0001) and in the number of segment with a normal T2* value ( P = 0.003). The improvement in the global heart T2* was not significantly difference in the DFP-DFO versus the DFX group (mean difference global heart T2* 2.2 ± 4.1 ms versus 4.6 ± 4.8 P = 0.2). The changes in the mean serum ferritin level were not significantly different between groups. In patients with liver iron overload at baseline (liver T2* < 5.1 ms), the change in the liver T2* was not significant between groups (mean difference liver T2* 0.9 ± 2.1 ms vs 2.4 ± 5.2; P = 0.3). Conclusions: Prospectively in the clinical setting over 15 months we did not find significant differences on cardiac and liver iron by quantitative MRI in TM patients treated with sequential DFP–DFO versus the TM patients treated with DFX. Disclosures: No relevant conflicts of interest to declare.

Thalassaemia and other haemoglobinopathies constitute an important health problem in Mediterranean countries, placing a tremendous emotional, psychological, and economic burden on their National Health systems. The development of new chelators in the most recent years had a major impact on the treatment of thalassaemia and on the quality of life of thalassaemic patients. A new initiative was promoted by the Italian Ministry of Health, establishing a Registry for thalassaemic patients to serve as a tool for the development of cost-effective diagnostic and therapeutic approaches and for the definition of guidelines supporting the most appropriate management of the iron-chelating therapy and a correct use of the available iron-chelating agents. This study represents the analysis of the preliminary data collected for the evaluation of current status of the iron chelation practice in the Italian thalassaemic population and describes how therapeutic interventions can widely differ in the different patients' age groups.

Abstract 2157 Introduction: Magnetic Resonance Imaging (MRI) by the T2* technique allows highly reproducible and non invasive quantifications of myocardial iron burden and it is the gold standard for quantifying biventricular function parameters. It is important to determine the appropriate age to start MRI screening, because its high cost. Few data are available in the literature and they are contrasting. So the aim of this study was to address this issue in our paediatric patients with thalassemia major (TM). Methods: We studied retrospectively 72 patients (47 males, 4.2–17.9 years old, mean age 13.03 ± 3.70 years), enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network. Myocardial iron overload was measured by T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Results: The global heart T2* value was 29.7 ± 11.2 ms (range 6.2 – 48.0 ms). No significant correlation was found between global heart T2* value and age (see figure). The global heart T2* value did not show significant differences according to the sex (male 30.2 ± 11.0 ms versus female 28.7 ± 11.8 ms, P=0.568). Sixteen patients (22%) showed an abnormal global heart T2* value ( Conclusion: The MRI screening for both cardiac iron overload and function assessment can be started for TM patients at the age of 7 years. At this age not sedation is generally needed. If the availability of cardiac MRI is low, the serum ferritin levels could be used as a discriminating factor. Disclosures: No relevant conflicts of interest to declare.

Abstract 2150 Introduction. In thalassemia major (TM) patients myocardial iron overload and chronic anemia are the recognized leading causes of cardiomyopathy, but a role can also be played by other factors such as endocrine abnormalities. The aim of this retrospective study was to evaluate if diabetes mellitus (DM) was associated with an higher prevalence and risk of cardiac dysfunction and of heart complications, regardless to the presence of myocardial iron overload. Methods. From a cohort of 957 TM patients who underwent MRI within the MIOT network (Myocardial Iron Overload in Thalassemia), among the patients (N = 358) with no cardiac iron (all cardiac segments with a T2* ≥ 20 ms) we identified 29 patients with DM and 329 patients without DM. The normal values of ejection fraction (EF) normalized by sex and age, obtained in a cohort of 142 TM patients without cardiac disease and iron overload, were used to define left ventricular (LV) and right ventricular (RV) heart dysfunction (EF < mean – 2 standard deviation). Heart failure (HF) was diagnosed by Magnetic Resonance Imaging (MRI) in presence of a LV and/or RV EF lower than 4 standard deviations from the normalized mean value and by a positive history (clinical symptoms, confirmation by physical examination and treatment). Myocardial fibrosis was evaluated by delayed enhancement MRI technique. Results. The prevalence of overall heart dysfunction (LV, RV or both) was higher in patients with DM (44.8%) versus patients without DM (28.3%), with a P-value very close to the statistically significance (P=0.061). In more details, patients with DM presented significantly more biventricular dysfunction (20.7% vs 7.6%, P=0.016). The prevalence of myocardial fibrosis was significantly higher in the DM patients vs the no DM patients (37.5% vs 19.2 %; P=0.033). Cardiac complications occurred with a significantly higher frequency in patients with DM (55.2% vs 15.5%, P Table 1 shows odds ratios (OR) estimating the relationship between diabetes and cardiac involvement. Among cardiac dysfunctions, only the biventricular forms were significantly positively associated with the diabetes. However, the correction for age caused the loss of the significance. The association between DM and myocardial fibrosis became not significant after the correction for age and endocrine co-morbidity. Patients with DM were significantly more likely to have cardiac complications and the results were not affected by the adjustment for age and/or endocrine co-morbidity. Considering separately each cardiac complication, a significant association was found for HF and hyperkinetic arrhythmias. The association between DM and HF resulted not significant after the correction for age. For the hyperkinetic arrhythmias, the OR remained significant after the correction for age and/or endocrine co-morbidity. Conclusion. In TM patients without myocardial iron DM was significantly associated with the presence of cardiac complications globally considered and hyperkinetic arrhythmias. Disclosures: No relevant conflicts of interest to declare.

The effectiveness of deferoxamine (DFO), deferiprone (DFP), or deferasirox (DFX) in thalassemia major was assessed. Outcomes were reported as means±SD, mean differences with 95% CI, or standardized mean differences. Statistical heterogeneity was tested using χ2 (Q) and I2. Sources of bias and Grading of Recommendations Assessment, Development and Evaluation system (GRADE) were considered. Overall, 1520 patients were included. Only 7.4% of trials were free of bias. Overall measurements suggest low trial quality (GRADE). The meta-analysis suggests lower final liver iron concentrations during associated versus monotherapy treatment (p

Increased survival in patients with β thalassaemia major (TM) allowed for several morbidities to manifest. Renal manifestations of the disease and its treatment have been poorly evaluated. There is evidence, mainly from studies in the paediatric population, of tubular dysfunction and glomerular filtration rate abnormalities in this patient population. Long-term outcomes of these changes, however, have not been prospectively investigated. The pathogenesis of these abnormalities could be attributed to iron overload, too aggressive iron removal, and/or the underlying anaemia. These changes seem to be nonprogressive, resolve spontaneously in most part, or may require iron chelator dose modifications. Relative iron depletion may explain renal function changes attributed to chelation therapy; thus, sudden removal of iron or overchelation should be avoided. Future studies should aim to evaluate the natural history of kidney function in TM patients to help understand the mechanisms and long-term sequelae of the observed renal changes.

Myocardial iron overload is the leading cause of death in patients with β-thalassemia major. An intensification monotherapy with deferoxamine (DFO) as well as a combination therapy with DFO and deferiprone (DFP) reduces myocardial iron and improves cardiac function. However, the prognosis for thalassemia major patients with established cardiac disease switched from DFO monotherapy to combined DFP/DFO chelation is unknown. Twenty-eight thalassemia major patients with cardiac disease were enrolled in a prospective study lasting 42 ± 6 months. Fifteen (9 high-ferritin and 6 low-ferritin) were placed on DFP/DFO (DFP, 75 mg/kg t.i.d.; DFO, 40–50 mg/kg over 8–12 h at night 5–7 days/week), while 13 (5 high- and 8 low-ferritin) received DFO alone. No cardiac events were observed among high-ferritin patients on combination therapy, whereas 4 cardiac events ( p = 0.0049), including three deaths, occurred in high-ferritin patients on DFO monotherapy. These findings demonstrate that in thalassemia major patients with well-established cardiac disease combined iron-chelation therapy with DFP/DFO is superior to DFO monotherapy.

ss Open Acce Oral presentation Myocardial fibrosis by delayed enhancement cardiovascular magnetic resonance and HCV infection in thalassemia major patients Alessia Pepe1, Antonella Meloni1, Zelia Borsellino2, Maria Chiara Dell'Amico1, Vincenzo Positano1, Caterina Borgna-Pignatti3, Aurelio Maggio4, Gennaro Restaino5, Francesco Gagliardotto2, Paolo Cianciulli6, Luciano Prossomariti7, Aldo Filosa7, Michele Centra8, Domenico D'Ascola9, Antonella Quarta10, Angelo Peluso11, Antonello Pietrangelo12, Eliana Cracolici13, Massimo Lombardi*1 and Marcello Capra2

Abstract 5165 Introduction: Most deaths in thalassemia major (TM) result from cardiac complications due to iron overload. No data are available in literature about possible different changes in cardiac and liver iron in TM patients treated with sequential deferiprone–deferoxamine (DFP-DFO) versus deferasirox (DFX). Magnetic Resonance (MR) is the unique non invasive suitable technique to evaluated quantitatively this issue. The aim of this multi-centre study was to assess prospectively in the clinical practice the efficacy of the DFP-DFO vs DFX in a cohort of TM patients by quantitative MR. Methods: Among the first 739 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, 253 patients performed a MR follow up study at 18 ± 3 months according to the protocol. We evaluated prospectively the 25 patients treated with DFP-DFO versus the 44 patients treated with DFX between the 2 MR scans. Myocardial and liver iron concentrations were measured by T2* multislice multiecho technique. Results: The doses of the sequential treatment were DFP 70±14 mg/kg/d for 4 d/w and DFO 42±8 mg/kg/d for 3 d/w, the dose of DFX was 26±6 mg/kg/d. Excellent/good levels of compliance were similar in the 2 groups (DFP-DFO 96% vs DFX 100%; P = 0.36). At baseline the 2 groups were homogeneous for cardiac and liver iron. Among the patients with no significant myocardial iron overload at baseline (global heart T2* 3 20 ms), there were no significant differences between groups to maintain the patients without myocardial iron overload (DFP-DFO 95% vs DFX 96%; P = 1.0). Among the patients with myocardial iron overload at baseline (global heart T2* < 20 ms), only in the DFX group there was a significant improvement in the global heart T2* value (11 ± 5 ms at baseline versus 16 ± 8 at 18 ± 3 months, P = 0.0001) and in the number of segment with a normal T2* value (P = 0.003). The improvement in the global heart T2* was not significantly difference in the DFP-DFO versus the DFX group (mean difference global heart T2* 2.2 ± 4.1 ms versus 4.6 ± 4.8 P = 0.2). The changes in the mean serum ferritin level were not significantly different between groups. In patients with liver iron overload at baseline (liver T2* < 5.1 ms), the change in the liver T2* was not significant between groups (mean difference liver T2* 0.9 ± 2.1 ms vs 2.4 ± 5.2; P = 0.3). Conclusions: Prospectively in the clinical setting over 15 months we did not find significant differences on cardiac and liver iron by quantitative MRI in TM patients treated with sequential DFP–DFO versus the TM patients treated with DFX. Disclosures: No relevant conflicts of interest to declare.

Abstract 4267 Introduction: Most deaths in thalassemia major (TM) result from cardiac complications due to iron overload. In thalassaemia available three iron chelation regimes in monotherapy may achieve different changes in cardiac iron and function and liver iron. No data are available in literature about prospective comparisons on cardiac iron and function and liver iron in TM patients treated with deferasirox (DFX) versus deferiprone (DFP) and desferrioxamine (DFO) in monotherapy. Magnetic Resonance (MR) is the unique non invasive suitable technique to evaluated quantitatively this issue. The aim of this multi-centre study was to assess prospectively in the clinical practice the efficacy of the DFX versus DFP and DFO in monoterapy in a large cohort of TM patients by quantitative MR. Methods: Among the first 1135 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, 392 patients performed a MR follow up study at 18 ± 3 months according to the protocol. We evaluated prospectively the 193 TM patients who had been received one chelator alone between the 2 MR scans. We identified 3 groups of patients: 80 treated with DFX, 39 treated with DFP and 74 treated with DFO. Myocardial and liver iron concentrations were measured by T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Results: The dose of DFX was 26±7 mg/kg/d, DFP was 73±13 mg/kg/d and DFO was 41±6 mg/kg for 5.5 d/wk. Excellent/good levels of compliance were similar in the 3 groups (DFX 99%, DFP 95%; DFO 96%, P = 0.6). Among the patients with no significant myocardial iron overload at baseline (global heart T2* ≥ 20 ms) (DFX 54 pts, DFP 30 pts, DFO 53 pts), there were no significant differences in all 3 groups to maintain the patients without significant myocardial iron overload (DFX 98%; DFP 100%; DFO 98%; P=1.0) Among the patients with myocardial iron overload at baseline (global heart T2* < 20 ms) in all 3 groups there was a significant improvement in the global heart T2* value (DFX P=0.001, DFP P=0.015 and DFO P =0.007) and in the number of segment with a normal T2* value (DFX + 2.4 P=0.003, DFP +6.0 P=0.031 and DFO + 2.9 P=0.001); only in the DFP group there was a significant improvement in the right global systolic function (+ 6.8% P = 0.016). The improvement in the global heart T2* was significantly lower in the DFX versus the DFP group (P=0.0026), but it was not significantly different in the DFX versus the DFO group (mean difference global heart T2* 3.5 ± 4.7 ms versus 8.8 ± 8.6 ms and versus 3.7 ± 5.5 ms, respectively; P = 0.90) (see the figure). The changes in the mean serum ferritin level and in the global systolic bi-ventricular function were not significantly different among groups. In patients with liver iron overload at baseline (liver T2* < 5.1 ms), the change in the liver T2* was not significant among groups (mean difference liver T2*DFX 2.1 ± 4.2 ms vs DFO 1.9 ± 3.8 ms vs DFP 1.3 ± 3.3 ms; P = 0.9). Conclusions: Prospectively over 15 months in a large clinical setting of TM patients DFP monotherapy was significantly more effective than DFX in improving myocardial siderosis, no significant differences were found between DFX and DFO monotherapy. Disclosures: No relevant conflicts of interest to declare.

In 1991 Delaitre and Maignien described the first laparoscopic splenectomy, since when a rapid spread of this technique has been observed and the procedure has become the gold standard in the surgical management of benign and malignant haematological diseases. In the present study, the results of the first 30 laparoscopic splenectomies performed at the Division of General Surgery of the S. Eugenio Hospital of Rome are reported. The operations were performed in patients with benign (27 cases) and malignant (3 cases) haematological diseases, treated in the Regional Haematological Centre of the same hospital. The procedures were carried out according to criteria corresponding to those recently described in the guidelines of the European Association for Endoscopic Surgery. As regards the results, two procedures (6.7%) were converted to open surgery. One postoperative haemorrhage was observed, requiring a laparoscopic reoperation for haemostasis. No other major local or general complications were observed. Mortality was nil. The mean postoperative hospital stay was 4.2 days (range: 4-8 days). Medium-term surgical and haematological results were excellent. Laparoscopic splenectomy is the surgical gold standard, but should be performed in advanced centres in close cooperation with a haematology centre. The procedure is indicated in all patients who are candidates for splenectomy, with the sole exception of those affected by portal hypertension or with general contraindications to laparoscopy. In advanced centres, better early and late results can be achieved, in addition to the well-known benefits of the minimally invasive technique, particularly in aesthetic terms, which in younger patients affected by benign haematological pathologies are very important.

Myocardial fibrosis/necrosis has been documented by histological and Cardiovascular Magnetic Resonance (CMR) studies in patients with hemoglobinopathies.[1][1] The delayed enhancement CMR technique with intravenous administration of gadolinium (Gd) chelates contrast agents is the only validated

Adrenal myelolipoma is an uncommon tumour of the adrenal gland, usually unilateral, frequently associated with hypertension and obesity, with a benign biological behaviour and without hormonal activity, first described in 1905. The neoplasm consists of adipose tissue and myelopoietic cells of the bone marrow. These tumours have a very slow but continued growth and their volume and weight vary significantly from small lesions of a few grams to huge masses weighing up to several kilograms. If symptoms occur, surgery should be performed without delay, especially for large myelolipomas that are at high risk of spontaneous rupture with haemorrhage and life-threatening shock. In this report a case of a 43-year-old male with a 22 x 18 x 9 cm giant myelolipoma, weighing 3500 g and originating from the right adrenal gland is described. The large mass dislocating and compressing the inferior vena cava, was removed surgically. The early postoperative course and the late outcome were favourable without recurrence after 30 months. The different aetiological hypotheses of this rare neoplasm and its clinical features, diagnosis and treatment are discussed.

Iron overload, characterized by excessive iron deposition, occurs commonly in patients with hereditary or refractory anemias such as beta-thalassemia major, sickle cell anemia, and myelodysplastic syndromes, whose anemia is managed with frequent blood transfusions. Without adequate iron chelation therapy, almost all patients with beta-thalassemia will accumulate potentially fatal iron levels. Myocardial siderosis and resulting cardiac complications are among the leading causes of death in such patients. Unfortunately, even with the administration of effective subcutaneous iron chelation therapy with desferrioxamine (DFO), over 50% of patients die before the age of 35 years, largely because of poor compliance with subcutaneous chelation regimens. Recently introduced oral chelation agents, deferiprone and deferasirox, are associated with higher compliance rates, and greater reductions in cardiac iron levels, than those achieved with DFO. This article reviews the pharmacologic properties and clinical efficacy of currently available iron chelation therapies in the management of transfusional chronic iron overload.

A multicentre randomized open-label trial was designed to assess the effectiveness of long-term sequential deferiprone–deferoxamine (DFO–DFP) versus DFP alone to treat thalassaemia major (TM). DFP at 75 mg/kg, divided into three oral daily doses, for 4 d/week and DFO by subcutaneous infusion (8–12 h) at 50 mg/kg per day for the remaining 3 d/week was compared with DFP alone at 75 mg/kg, administered 7 d/week during a 5-year follow-up. The main outcome measures were differences between multiple observations of serum ferritin concentrations. Secondary outcomes were survival analysis, adverse events, and costs. Consecutive thalassaemia patients (275) were assessed for eligibility; 213 of these were randomized and underwent intention-to-treat analysis. The decrease of serum ferritin levels during the treatment period was statistically significant higher in sequential DFP–DFO patients compared with DFP-alone patients (P = 0.005). Kaplan– Meier survival analysis for the two chelation treatments did not show any statistically significant differences (log-rank test, P = 0.3145). Adverse events and costs were comparable between the groups. The trial results show that sequential DFP–DFO treatment compared with DFP alone significantly decreased serum ferritin concentration during treatment for 5 years without significant differences regarding survival, adverse events, or costs.

The prognosis for thalassemia major has dramatically improved in the last two decades. However, many transfusion-dependent patients continue to develop progressive accumulation of iron. This can lead to tissue damage and eventually death, particularly from cardiac disease. Previous studies that investigated iron chelation treatments, including retrospective and prospective non-randomised clinical trials, suggested that mortality, due mainly to cardiac damage, was reduced or completely absent in patients treated with deferiprone (DFP) alone or a combined deferiprone-deferoxamine (DFP-DFO) chelation treatment. However, no survival analysis has been reported for a long-term randomised control trial. Here, we performed a multicenter, long-term, randomised control trial that compared deferoxamine (DFO) versus DFP alone, sequential DFP-DFO, or combined DFP-DFO iron chelation treatments. The trial included 265 patients with thalassemia major, with 128 (48.3%) females and 137 (51.7%) males. No deaths occurred with the DFP-alone or the combined DFP-DFO treatments. One death occurred due to graft versus host disease (GVHD) in a patient that had undergone bone marrow transplantation; this patient was censored at the time of transplant. Only one death occurred with the DFP-DFO sequential treatment in a patient that had experienced an episode of heart failure one year earlier. Ten deaths occurred with the deferoxamine treatment. The main factors that correlated with an increase in the hazard ratio for death were: cirrhosis, arrhythmia, previous episode of heart failure, diabetes, hypogonadism, and hypothyroidism. In a Cox regression model, the interaction effect of sex and age was statistically significant (p-value

In the clinical MRI practice, it is common to assess liver iron overload by T2* multi-echo gradient-echo images. However, there is no full consensus about the best image analysis approach for the T2* measurements. The currently used methods involve manual drawing of a region of interest (ROI) within MR images of the liver. Evaluation of a representative liver T2* value is done by fitting an appropriate model to the signal decay within the ROIs vs. the echo time. The resulting T2* value may depend on both ROI placement and choice of the signal decay model. The aim of this study was to understand how the choice of the analysis methodology may affect the accuracy of T2* measurements. A software model of the iron overloaded liver was inferred from MR images acquired from 40 thalassemia major patients. Different image analysis methods were compared exploiting the developed software model. Moreover, a method for global semiautomatic T2* measurement involving the whole liver was developed. The global method included automatic segmentation of parenchyma by an adaptive fuzzy-clustering algorithm able to compensate for signal inhomogeneities. Global liver T2* value was evaluated using a pixel-wise technique and an optimized signal decay model. The global approach was compared with the ROI-based approach used in the clinical practice. For the ROI-based approach, the intra-observer and inter-observer coefficients of variation (CoVs) were 3.7% and 5.6%, respectively. For the global analysis, the CoVs for intra-observers and inter-observers reproducibility were 0.85% and 2.87%, respectively. The variability shown by the ROI-based approach was acceptable for use in the clinical practice; however, the developed global method increased the accuracy in T2* assessment and significantly reduced the operator dependence and sampling errors. This global approach could be useful in the clinical arena for patients with borderline liver iron overload and/or requiring follow-up studies.

Thalassemia associates anemia and iron overload, two opposite stimuli regulating hepcidin gene expression. We characterized hepatic hepcidin expression in 10 thalassemia major and 13 thalassemia intermedia patients. Hepcidin mRNA levels were decreased in the thalassemia intermedia group which presented both lower hemoglobin and higher plasma soluble transferrin receptor levels. There was no relationship between hepcidin mRNA levels and those of genes controlling iron metabolism, including HFE, hemojuvelin, transferrin receptor-2 and ferroportin. These results underline the role of erythropoietic activity on hepcidin decrease in thalassemic patients and suggest that mRNA modulations of other studied genes do not have a significant impact.

Despite dramatic gains in life expectancy in the desferrioxamine era for thalassemia major patients, the leading cause of death for this young adult’s population remains iron-induced heart failure. For this reason, strategies to reduce heart disease by improving chelation regimens have the highest priority in this phase. These strategies include development of novel oral iron chelators to improve compliance. Oral deferipron was proved more effective than subcutaneous desferrioxamine in removing cardiac iron. The novel oral one-daily chelator deferasirox has been recently commercially available but its long-term efficacy on myocardial iron concentrations and cardiac function is unknown. Aim of this study was to compare in thalassemia major patients the effectiveness of deferasirox, deferipron, and desferrioxamine on myocardial and liver iron concentrations and bi-ventricular function by quantitative magnetic-resonance imaging (MRI). Among the 550 thalassemic subjects enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network between September 2006 and September 2007, we selected patients receiving one chelator alone for longer than one year. MIOT is an Italian network of six MR sites where the cardiac and liver iron status is assessed by validated and homogeneous standard procedures. We identified three groups of patients: 24 treated with deferasirox, 42 treated with deferipron and 89 treated with desferrioxamine. The three groups were matched for gender, Hb pre-transfusion levels, age of starting chelation, and good compliance to the treatment. The deferasirox group was significantly younger (26±7 years) than the deferipron (32±9 years) and desferioxamine group (33±8 years) (P=0.0001) and showed significantly higher mean serum ferritin levels (2516±2106 ng/ml) than the deferipron (1493±1651 ng/ml) and the desferrioxamine group (987±915 ng/ml) (P=0.0001). Myocardial iron concentrations and distribution were measured by MRI T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated by cine-dynamic MRI images. Liver iron concentrations were measured by MR T2* multiecho technique. Written informed consent was obtained from all subjects. The global heart T2* value was significantly higher in the deferipron group (34±11 ms) versus the deferasirox (21±12 ms) and the desferrioxamine group (27±11 ms) (P=0.0001), as showed in Figure A. The T2* in the mid ventricular septum was significantly higher in the deferipron (36 ± 12 ms) versus the deferasirox (20 ± 12 ms) and the desferrioxamine group (28 ± 13 ms) (P = 0.0001). The number of segments with normal T2* value was significantly higher in the deferipron and the desferrioxamine group versus the deferasirox group (14 ± 2 versus 11 ± 6 versus 7 ± 7 segments; P = 0.0001). Among the biventricular function parameters, we found higher left ventricular ejection fractions in the deferipron and the desferrioxamine group versus the deferasirox group (64 ± 7 versus 62 ± 6 versus 58 ± 7 %; P = 0.005), as showed in Figure B. Liver T2* values were significantly higher in the desferrioxamine group versus the deferipron and the deferasirox group (10 ± 9 versus 6 ± 6 versus 5 ± 5 segments; P = 0.002). In conclusion, Oral deferipron seems to be more effective than oral deferasirox and subcutaneous desferrioxamine in removal of myocardial iron with concordant positive effect on left global systolic function. Figure Figure

Studies of the standardized, 3D, 16-segments map of the circumferential distribution of T2* values, of cardiovascular magnetic resonance (CMR) in thalassemia major (TM) and thalassemia intermedia (TI) patients and of electrocardiogram (ECG) changes associated with TM, have been carried out. Similarly, the segment-dependent correction map of the T2* values and the artifactual variations in normal subjects and the T2* correction map to correct segmental measurements in patients with different levels of myocardial iron burden have been evaluated. Cardiovascular magnetic resonance can be a suitable guide to cardiac management in TI, as well as in TM; TI patients show lower myocardial iron burden and more pronounced high cardiac output findings than TM patients. Moreover, it is proposed that, due to its good positive predictive value (PPV) and low cost, ECG can be a suitable guide to orient towards CMR examination in TM cases.

The maintenance of erythrocyte shape and membrane integrity is bound to the modification of deformability and/or permeability. Usually, this features are not investigated with normal laboratory tests. The membrane stiffness, the cell geometry, and the viscoelasticity components are influencing factors on survival and functionality of the erythrocytes. Only few studies have analyzed the viscoelastic characteristics of red blood cells, even less are the studies on patients affected by sickle cell disease (SCD), a pathology characterized by acute and chronic impairment of cell flexibility due to the formation of intracellular sickle haemoglobin (Hb S) polymers. A critical point of SCD is represented by the rheologic alterations of sickle cells determined by the transition from sol to gel of haemoglobin producing a dramatic change in cell viscosity and viscoelastic properties. We have investigated the behaviour of the blood in SCD, from an original rheological point of view, by evaluating the viscoelastic properties of sickle cells in oscillating harmonic sinusoidal mode. A comparison between patients with different severity of the disease, with transfusion dependence (TD) or without transfusion dependence (NTD), has been carried out. This study has confirmed the rheologic impairment of SC blood. The TD patients showed a minor heterogeneneity of rheologic behaviour in comparison with NTD patients, because of the normalizing effect of transfusion. The analysis of viscoelastic properties might be an additional useful tool for monitoring transfusional and pharmacological treatments.

Background Neuroacanthocytosis (NA) denotes a heterogeneous group of diseases that are characterized by nervous system abnormalities in association with acanthocytosis in the patients' blood. The 4.1R protein of the erythrocyte membrane is critical for the membrane-associated cytoskeleton structure and in central neurons it regulates the stabilization of AMPA receptors on the neuronal surface at the postsynaptic density. We report clinical, biochemical, and genetic features in four patients from four unrelated families with NA in order to explain the cause of morphological abnormalities and the relationship with neurodegenerative processes. Case presentation All patients were characterised by atypical NA with a novel alteration of the erythrocyte membrane: a 4.1R protein deficiency. The 4.1R protein content was significantly lower in patients (3.40 ± 0.42) than in controls (4.41 ± 0.40, P < 0.0001), reflecting weakened interactions of the cytoskeleton with the membrane. In patients IV:1 (RM23), IV:3 (RM15), and IV:6 (RM16) the 4.1 deficiency seemed to affect the horizontal interactions of spectrin and an impairment of the dimer self-association into tetramers was detected. In patient IV:1 (RM16) the 4.1 deficiency seemed to affect the skeletal attachment to membrane and the protein band 3 was partially reduced. Conclusion A decreased expression pattern of the 4.1R protein was observed in the erythrocytes from patients with atypical NA, which might reflect the expression pattern in the central nervous system, especially basal ganglia, and might lead to dysfunction of AMPA-mediated glutamate transmission.