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Objectives: To develop a deep-learning model for supervised classification of myocardial iron overload (MIO) from magnitude T2* multi-echo MR images., Materials and Methods: Eight hundred twenty-three cardiac magnitude T2* multi-slice, multi-echo MR images from 496 thalassemia major patients (285 females, 57%), labeled for MIO level (normal: T2* > 20 ms, moderate: 10 ≤ T2* ≤ 20 ms, severe: T2* < 10 ms), were retrospectively studied. Two 2D convolutional neural networks (CNN) developed for multi-slice (MS-HippoNet) and single-slice (SS-HippoNet) analysis were trained using 5-fold cross-validation. Performance was assessed using micro-average, multi-class accuracy, and single-class accuracy, sensitivity, and specificity. CNN performance was compared with inter-observer agreement between radiologists on 20% of the patients. The agreement between patients' classifications was assessed by the inter-agreement Kappa test., Results: Among the 165 images in the test set, a multi-class accuracy of 0.885 and 0.836 was obtained for MS- and SS-Hippo-Net, respectively. Network performances were confirmed on external test set analysis (0.827 and 0.793 multi-class accuracy, 29 patients from the CHMMOTv1 database). The agreement between automatic and ground truth classification was good (MS: κ = 0.771; SS: κ = 0.614), comparable with the inter-observer agreement (MS: κ = 0.872, SS: κ = 0.907) evaluated on the test set., Conclusion: The developed networks performed classification of MIO level from multiecho, bright-blood, and T2* images with good performances., Key Points: Question MRI T2* represents the established clinical tool for MIO assessment. Quality control of the image analysis is a problem in small centers. Findings Deep learning models can perform MIO staging with good accuracy, comparable to inter-observer variability of the standard procedure. Clinical relevance CNN can perform automated staging of cardiac iron overload from multiecho MR sequences facilitating non-invasive evaluation of patients with various hematologic disorders., Competing Interests: Compliance with ethical standards. Guarantor: The scientific guarantor of this publication is Dr Filippo Cademartiri. Conflict of interest: The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article. Statistics and biometry: One of the authors (Antonella Meloni) has significant statistical expertise. Informed consent: Written informed consent was obtained from all subjects (patients) in this study. Ethical approval: Institutional Review Board approval was obtained. Study subjects or cohorts overlap: The image data used in the study represents part of the MIOT/eMIOT database, which was previously involved in several studies of thalassemia major patients with different scientific objectives. Methodology: Retrospective Observational Performed at one institution, (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Background: No study has assessed myocardial T1 and T2 values in patients with beta-thalassemia intermedia (β-TI)., Purpose: To assess the prevalence of myocardial involvement in β-TI patients by T2* relaxometry and native T1 and T2 mapping and to determine the correlation of myocardial relaxation times with demographic and clinical parameters., Study Type: Prospective matched-cohort study., Subjects: 42 β-TI patients (27 females, 39.65 ± 12.32 years), enrolled in the Extension-Myocardial Iron Overload in Thalassaemia Network, and 42 age- and sex-matched healthy volunteers (27 females, 40.01 ± 11.36 years) and thalassemia major (TM) patients (27 females, 39.27 ± 11.57 years)., Field Strength/sequence: 1.5 T/multi-echo gradient echo, modified Look-Locker inversion recovery, multi-echo fast-spin-echo, cine balanced steady-state-free precession, and late gadolinium enhancement (LGE) sequences., Assessment: Hepatic, pancreatic, and left ventricular (LV) T2* values, LV native T1 and T2 values, biventricular ejection fractions and volumes, and presence and extent of replacement myocardial fibrosis., Statistical Tests: Comparisons between two groups were performed with two-sample t tests, Wilcoxon's signed rank tests, or χ 2 testing. Correlation analysis was performed using Pearson's or Spearman's test. P < 0.05 was considered statistically significant., Results: β-TI patients had significantly higher LV T2 values than healthy subjects (56.84 ± 4.03 vs. 52.46 ± 2.50 msec, P < 0.0001) and significantly higher LV T1 values than TM patients (1018.32 ± 48.94 vs. 966.66 ± 66.47 msec, P < 0.0001). In β-TI, female gender was associated with significantly increased LV T1 (P = 0.041) and T2 values (P < 0.0001), while splenectomy and presence of regular transfusions were associated with significantly lower LV T1 values (P = 0.014 and P = 0.001, respectively). In β-TI patients, all LV relaxation times were significantly correlated with each other (T2*-T1: P = 0.003; T2*-T2: P = 0.003; T1-T2: P < 0.0001). Two patients with a reduced LV T2* also had a reduced LV T1, while only one had a reduced LV T2. Three patients had a reduced LV T1 but a normal LV T2*; 66.7% of the patients had an increased LV T2. All LV relaxation times were significantly correlated with pancreas T2* values (T2*: P = 0.033; T1: P < 0.0001; T2: P = 0.014). No LV relaxation time was associated (P > 0.05) with hepatic iron concentration, biventricular function parameters, or LGE presence., Conclusion: The combined use of all three myocardial relaxation times has potential to improve sensitivity in the detection of early/subclinical myocardial involvement in β-Tl patients., Level of Evidence: 2 TECHNICAL EFFICACY: Stage 2., (© 2024 International Society for Magnetic Resonance in Medicine.)

Objectives : This multicenter, retrospective, population-based, matched-cohort study compared clinical characteristics and magnetic resonance imaging (MRI) findings, including hepatic, pancreatic, and cardiac iron levels and cardiac function, between 135 adult regularly transfused thalassemia intermedia (TI) patients (44.73 ± 12.16 years, 77 females) and 135 age- and sex-matched thalassemia major (TM) patients (43.35 ± 9.83 years, 77 females), enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. Methods: The MRI protocol included the quantification of hepatic, pancreatic, and cardiac iron levels (R2* technique), the assessment of biventricular function parameters (cine images), and the detection of replacement myocardial fibrosis (late gadolinium enhancement technique). Results: Age, sex, frequency of splenectomy and chelation, and serum ferritin levels were not significantly different ( p > 0.05) between the two groups, but TI patients started regular transfusions significantly later ( p < 0.0001) and showed significantly lower pre-transfusion hemoglobin levels ( p = 0.005). No difference was found in hepatic iron levels ( p = 0.853). TI patients exhibited significantly lower pancreatic R2* values ( p < 0.0001), also correcting for the duration of regular transfusions, and significantly lower cardiac R2* values ( p < 0.0001). In the receiver operating characteristic analysis, pancreatic iron was the strongest discriminator between the two diseases. Left and right ventricular end-diastolic volume indexes were significantly higher in TI than in TM patients ( p = 0.003 and p = 0.046, respectively), but the correction for the duration of regular transfusions removed the disease-specific differences ( p > 0.05). Left ventricular (LV) mass index was significantly higher in TI ( p = 0.049), while no difference ( p > 0.05) was found in biventricular ejection fractions and replacement myocardial fibrosis. Conclusions: TI patients showed lower pancreatic and cardiac iron burden and more pronounced LV hypertrophy. These differences could not be explained by the different duration of the transfusional regimen.

We evaluated the prevalence and the clinical associations of liver steatosis (LS) in patients with transfusion-dependent thalassaemia (TDT). We considered 301 TDT patients (177 females, median age = 40.61 years) enrolled in the Extension-Myocardial Iron Overload in Thalassaemia Network, and 25 healthy subjects. Magnetic resonance imaging was used to quantify iron overload and hepatic fat fraction (FF) by T2* technique and cardiac function by cine images. The glucose metabolism was assessed by the oral glucose tolerance test (OGTT). Hepatic FF was significantly higher in TDT patients than in healthy subjects (median value: 1.48% vs. 0.55%; p = 0.013). In TDT, hepatic FF was not associated with age, gender, serum ferritin levels or liver function parameters, but showed a weak inverse correlation with high-density lipoprotein cholesterol. The 36.4% of TDT patients showed LS (FF >3.7%). Active hepatitis C virus (HCV) infection, increased body mass index and hepatic iron were independent determinants of LS. A hepatic FF >3.53% predicted the presence of an abnormal OGTT. Hepatic FF was not correlated with cardiac iron, biventricular volumes or ejection fractions, but was correlated with left ventricular mass index. In TDT, LS is a frequent finding, associated with iron overload, increased weight and HCV, and conveying an increased risk for the alterations of glucose metabolism., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Cardiac involvement in sickle beta thalassemia (Sβ-thal) patients has been poorly investigated. We aimed to evaluate cardiac function and myocardial iron overload by cardiovascular magnetic resonance (CMR) in patients with Sβ-thal. One-hundred and eleven Sβ-thal patients consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network were studied and compared with 46 sickle cell anemia (SCA) patients and with 111 gender- and age- matched healthy volunteers. Cine images were acquired to quantify biventricular function. Myocardial iron overload (MIO) was assessed by the T2* technique, while macroscopic myocardial fibrosis was evaluated by the late gadolinium enhancement (LGE) technique. In Sβ-thal and SCA patients, the morphological and functional CMR parameters were not significantly different, except for the left atrial area and left ventricular (LV) stroke volume, indexed by body surface area ( p = 0.023 and p = 0.048, respectively), which were significantly higher in SCA patients. No significant differences between the two groups were found in terms of myocardial iron overload and macroscopic myocardial fibrosis. When compared to healthy subjects, Sβ-thal patients showed significantly higher bi-atrial and biventricular parameters, except for LV ejection fraction, which was significantly lower. The CMR analysis confirmed that Sβ-thal and SCA patients are phenotypically similar. Since Sβ-thal patients showed markedly different morphological and functional indices from healthy subjects, it would be useful to identify Sβ-thal/SCA-specific bi-atrial and biventricular reference values.

Background: We prospectively evaluated the predictive value of multiparametric cardiac magnetic resonance (CMR) for cardiovascular complications in non-transfusion-dependent β-thalassemia (β-NTDT) patients who started regular transfusions in late childhood/adulthood (neo β-TDT)., Methods: We considered 180 patients (38.25 ± 11.24 years; 106 females). CMR was used to quantify cardiac iron overload, biventricular function, and atrial dimensions, and to detect left ventricular (LV) replacement fibrosis., Results: During a mean follow-up of 76.87 ± 41.60 months, 18 (10.0%) cardiovascular events were recorded: 2 heart failures, 13 arrhythmias (10 supraventricular), and 3 cases of pulmonary hypertension. Right ventricular (RV) end-diastolic volume index (EDVI), RV mass index (MI), LV replacement fibrosis, and right atrial (RA) area index emerged as significant univariate prognosticators of cardiovascular complications. The low number of events prevented us from performing a multivariable analysis including all univariable predictors simultaneously. Firstly, a multivariable analysis including the two RV size parameters (mass and volume) was carried out, and only the RV MI was proven to independently predict cardiovascular diseases. Then, a multivariable analysis, including RV MI, RA atrial area, and LV replacement fibrosis, was conducted. In this model, RV MI and LV replacement fibrosis emerged as independent predictors of cardiovascular outcomes (RV MI: hazard ratio (HR) = 1.18; LV replacement fibrosis: HR = 6.26)., Conclusions: Our results highlight the importance of CMR in cardiovascular risk stratification.

We employed an unsupervised clustering method that integrated demographic, clinical, and cardiac magnetic resonance (CMR) data to identify distinct phenogroups (PGs) of patients with beta-thalassemia intermedia (β-TI). We considered 138 β-TI patients consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network who underwent MR for the quantification of hepatic and cardiac iron overload (T2* technique), the assessment of biventricular size and function and atrial dimensions (cine images), and the detection of replacement myocardial fibrosis (late gadolinium enhancement technique). Three mutually exclusive phenogroups were identified based on unsupervised hierarchical clustering of principal components: PG1, women; PG2, patients with replacement myocardial fibrosis, increased biventricular volumes and masses, and lower left ventricular ejection fraction; and PG3, men without replacement myocardial fibrosis, but with increased biventricular volumes and masses and lower left ventricular ejection fraction. The hematochemical parameters and the hepatic and cardiac iron levels did not contribute to the PG definition. PG2 exhibited a significantly higher risk of future cardiovascular events (heart failure, arrhythmias, and pulmonary hypertension) than PG1 (hazard ratio-HR = 10.5; p = 0.027) and PG3 (HR = 9.0; p = 0.038). Clustering emerged as a useful tool for risk stratification in TI, enabling the identification of three phenogroups with distinct clinical and prognostic characteristics.

We assessed the value of pancreatic T2* magnetic resonance imaging (MRI) for predicting cardiac events from a large prospective database of transfusion-dependent thalassemia (TDT) patients. We considered 813 TDT patients (36.47 ± 10.71 years, 54.6% females) enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. MRI was used to measure hepatic, pancreatic, and cardiac iron overload (IO), to assess biventricular function and atrial dimensions, and to detect replacement myocardial fibrosis. The mean follow-up was 50.51 ± 19.75 months. Cardiac complications were recorded in 21 (2.6%) patients: one with heart failure (HF) and 20 with arrhythmias. The single patient who developed HF had, at the baseline MRI, a reduced pancreas T2*. Out of the 20 recorded arrhythmias, 17 were supraventricular. Pancreatic T2* values were a significant predictor of future arrhythmia-related events (hazard ratio = 0.89; p = 0.015). Pancreas T2* remained significantly associated with future arrhythmias after adjusting for any other univariate predictor (age and male sex, diabetes, history of previous arrhythmias, or left atrial area index). According to the receiver-operating characteristic curve analysis for arrhythmias, a pancreas T2* < 6.73 ms was the optimal cut-off value. In TDT, pancreatic iron levels had significant prognostic power for arrhythmias. Regular monitoring and the development of targeted interventions to manage pancreatic IO may help improve patient outcomes.

Psychosocial variables are key factors influencing the delicate equilibrium of chronic patients during crisis time. In this study, we explored distress, anxiety, depression, loneliness, coping strategies, and changes in life habits in 43 beta-thalassemia patients and 86 controls during Covid-19 pandemic. Patients showed higher anxiety levels and a predominant transcendent coping profile compared to controls. Patients significantly differed from controls in outdoor habits. Social isolation and habits changes in uncertain life-threaten situations as Covid-19 pandemic are particularly detrimental in fragile beta-thalassemia patients. Structured support interventions are needed to promote well-being in the Covid-19 era.

Background: Consanguinity increases the incidence of recessive diseases such as beta-thalassaemia major (βTM), one of the most prevalent lethal inherited diseases in the world. Aim: This study aims to identify the frequency of endogamy and consanguinity in two Mediterranean βTM populations and to study the implication of socio-economic factors. Subjects and methods: A trans-sectional study was conducted in 203 Tunisian families and 75 Italian families. Data were collected using a questionnaire completed by patients and parents. Results: Complete endogamy and consanguinity were observed in 82.75% and 62.56% of Tunisian families, respectively. Complete endogamy was found in 90.67% of Italian families, no consanguinity was noted. The low occupation status of Tunisian mothers was associated with an increasing frequency of consanguinity ( p  = .01) and endogamy ( p  = .0003). Consanguinity was associated with low education level ( p  = .012) and low occupation status ( p =.047) of fathers. No significant association was found between endogamy and socio-economic factors in the Italian sample. Conclusions: High consanguinity and endogamy rates in Tunisian families may explain the frequency of βTM in Tunisia. The high endogamy rate in Italian families could also increase the frequency of βTM. Identification of geographical distribution and socio-economic factors leading to endogamy and consanguinity in these populations might help to improve βTM prevention.

We determined the prevalence of incidental extracardiac findings (IEF) at Magnetic Resonance Imaging (MRI) potentially related to anemia and hypoxia in age- and sex-matched populations (N = 318) with thalassemia major (TM) and thalassemia intermedia (TI) enrolled in the Myocardial Iron Overload in Thalassemia network. Overall, IEFs were detected in 33.3% and 25.8% of patients with TI and TM, respectively (P = 0.114). TI and TM patients had elevated but comparable prevalence of renal, splenic and liver cysts, and vertebral hemangiomas while TI patients had a significant higher frequency of extramedullary hematopoiesis (EMH) (15.1% vs 4.4%; P = 0.002). The prevalence of total IEFs increased with advancing age. TI non-transfusion-dependent patients had a significantly lower frequency of renal cysts than TI transfusion-dependent patients (8.8% vs 26.4%; P = 0.005). The prevalence of renal cysts in the thalassemic population was significantly higher than that in the general population (19.2% vs 1.9%; P < 0.0001). Our data on renal cysts indicate a significant higher prevalence of these IEFs compared to the general population, suggesting the role of the inappropriate activation of the hypoxia-inducible factor system linked to the chronic hypoxia. The significant prevalence of IEF in thalassemia patients undergoing MRI for iron quantification should prompt the discussion of the inclusion of IEF in the MRI report.

Aims: Our aim was to evaluate the correlation between myocardial fibrosis detected using the late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) technique and chronic hepatitis C (CHC) in a large, retrospective, multicentre cohort of thalassemia major patients., Methods: LGE images were acquired in 434 thalassemia major patients (233 men, 31 ± 9 years) enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) study. Hepatitis C virus (HCV)-RNA tests were sensitive to detect more than 50  copies/ml., Results: No patient manifested moderate/severe adverse events associated with the use of Gadobutrol. Myocardial fibrosis was detected in 90 (21%) patients. Among the 312 patients tested for HCV-RNA, there was a significant correlation between the presence of myocardial fibrosis and CHC (P = 0.011). Among the 62 patients with myocardial fibrosis tested for HCV-RNA, we found a significantly higher prevalence of diabetes mellitus in CHC patients versus the no-CHC patients (P = 0.049)., Conclusion: Our findings support the use of the LGE CMR approach well tolerated in the thalassemia major patients with CHC. HCV infection can be involved in the pathogenesis of myocardial fibrosis through both myocarditis directly and the pancreas and liver damage with the development of diabetes indirectly. These patients could therefore benefit from cardioactive drugs and therapeutic interventions directed towards the eradication of virus.

Background: The multislice multiecho T2* cardiovascular magnetic resonance (CMR) technique allows to detect different patterns of myocardial iron overload (MIO). The aim of this cross-sectional study was to verify the association between cardiac complications (heart failure and arrhythmias), biventricular dysfunction and myocardial fibrosis with different patterns of MIO in thalassemia major (TM) patients., Methods: We considered 812 TM patients enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network. The T2* value in all the 16 cardiac segments was evaluated., Results: We identified 4 groups of patients: 138 with homogeneous MIO (all segments with T2* < 20 ms), 97 with heterogeneous MIO (some segments with T2* < 20 ms, others with T2* ≥ 20 ms) and significant global heart iron (global heart T2* < 20 ms), 238 with heterogeneous MIO and no significant global heart iron, and 339 with no MIO (all segments with T2* ≥ 20 ms). Compared to patients with no MIO, patients with homogeneous MIO were more likely to have cardiac complications (odds ratio-OR = 2.67), heart failure (OR = 2.54), LV dysfunction (OR = 5.59), and RV dysfunction (OR = 2.26); patients with heterogeneous MIO and significant global heart iron were more likely to have heart failure (OR = 2.38) and LV dysfunction (OR = 2.39)., Conclusions: Cardiac complications, heart failure and dysfunction were correlated with MIO distribution with an increasing risk from the TM patients with no MIO to those with homogeneous MIO. Using a segmental approach, early iron deposit or homogeneous MIO patterns can be characterized to better tailor chelation therapy., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Polymorphisms in the interleukin-28B are important determinants in the spontaneous and drug-induced control of hepatitis C virus infection., Design and Methods: We assessed the association of rs8099917 and rs12979860 polymorphisms with spontaneous viral clearance, severity of liver fibrosis, and response to interferon-monotherapy in 245 thalassemia major patients with hepatitis C virus infection., Results: Ninety-eight patients (40%) had a spontaneous viral clearance while 147 patients (60%) developed a chronic infection. Spontaneous viral clearance was more frequent among patients with the T/T genotype of rs8099917 polymorphism (OR 2.130; P = 0.008) or C/C genotype of rs12979860 polymorphism (OR 2.425; P = 0.001). During observation, 131 patients with chronic infection underwent a liver biopsy; age (OR 1.058; P = 0.01) G/T or G/G genotypes of rs8099917 polymorphism (OR 3.962; P = 0.001), and C/T or T/T genotypes of rs12979860 polymorphism (OR 3.494; P = 0.005) were associated with severe liver fibrosis, independent of liver iron concentration. Finally, T/T genotype of rs8099917 polymorphism (OR 3.014; P = 0.03) or C/C genotype of rs12979860 polymorphism (OR 3.285; P = 0.01), age (OR 0.902; P = 0.001), female gender (OR 3.418; P = 0.01) and 2 or 3 virus C genotypes (OR 4.700; P=0.007) were independently associated with sustained virological response in 114 patients treated with alpha-interferon. Conclusions Polymorphisms in the interleukin-28B are associated with the control of hepatitis C virus infection in thalassemia major patients, and understanding allelic patterns has an important role in determining prognosis and therapeutic management.

The correlation between liver stiffness, measured by transient elastography, liver fibrosis, using the histological METAVIR score, and iron overload, measured by atomic absorption spectrometry was evaluated in 56 homozygous-beta-thalassaemics. Liver stiffness increased proportionally to liver fibrosis staging (r = 0.70; P > 0.001) independently of liver iron concentration (r = 0.01; P = 0.932). The area under the receiver-operating characteristic curve for prediction of cirrhosis was 0.997 (95% confidence interval [CI]: 0.925-1.000) with cut-off of 13 kPa with 100% sensitivity (95% CI: 69.0-100.0) and 95% specificity (95% CI: 84.2-99.3). Transient elastography is a reliable non-invasive tool for diagnosing advanced liver fibrosis in homozygous-beta-thalassaemics, regardless of the degree of iron overload.

We report the long-term effects of deferasirox 10-30 mg/kg/day on cardiac iron overload in a case series of five patients with transfusion-dependent beta-thalassaemia major who underwent up to 5 years of chelation therapy. Iron overload was monitored by multislice multi-echo T2* magnetic resonance imaging (MRI). Overall, T2* MRI showed a decrease from baseline in cardiac iron levels in all patients during treatment with deferasirox (baseline T2* levels 13-24 ms; final T2* levels 21-41 ms). The improvement in T2* values correlated with maintenance of left ventricular ejection fraction (LVEF) [baseline LVEF values 56-61%; final LVEF values 57-70%]. Deferasirox chelation treatment regimen was well tolerated and adherence to the regimen was good. In conclusion, this case series suggests that deferasirox may decrease cardiac iron overload and maintain stable LVEF over the long term. Moreover, it emphasizes the importance of T2* multislice multi-echo MRI in the monitoring of cardiac iron overload.

Iron overload and hepatitis virus C infection cause liver fibrosis in thalassemics. In a monocentric retrospective analysis of liver disease in a cohort of 191 transfusion-dependent thalassemics, in 126 patients who had undergone liver biopsy (mean age 17.2 years; 58 hepatitis virus C-RNA positive and 68 hepatitis virus C-RNA negative) the liver iron concentration (median 2.4 mg/gr dry liver weight) was closely related to serum ferritin levels (R = 0.58; p<0.0001). Male gender (OR 4.12) and serum hepatitis virus C-RNA positivity (OR 11.04) were independent risk factors for advanced liver fibrosis. The majority of hepatitis virus C-RNA negative patients with low iron load did not develop liver fibrosis, while hepatitis virus C-RNA positive patients infected with genotype 1 or 4 and iron overload more frequently developed advanced fibrosis. Hepatitis virus C infection is the main risk factor for liver fibrosis in transfusion-dependent thalassemics. Adequate chelation therapy usually prevents the development of liver fibrosis in thalassemics free of hepatitis virus C-infection and reduces the risk of developing severe fibrosis in thalassemics with chronic hepatitis C.

Objectives: Iron chelation treatment (ICT) in beta-thalassemia major (beta-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 beta-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-THAlassemia-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 euro1242/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 beta-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.

Hemoglobins (Hbs) with high oxygen affinity play a well-known role among the causes of erythrocytosis. In 1996, a new Hb called Hb Hinwil or beta38(C4)Thr-->Asn was described. In carriers, it causes an increase in the number of red blood cells, total Hb, and hematocrit. Here we report the case of a patient, aged 10 months, whom we observed because of severe erythrocytosis. The family history of beta-thalassemia (beta-thal) inheritance, and the evidence in the patient of marked microcytosis, prompted us to perform molecular analysis to detect beta gene mutations that revealed a codon 39 (C>T) (beta0) mutation in the heterozygous state and the presence of the Hb Hinwil mutation on the other allele. We discuss diagnostic, clinical, prognostic, and therapeutic aspects of this rare condition, underlining the extreme difficulty in choosing therapeutic options because of a lack of similar reports in the literature.

High oxidative stress status (OSS) is known to be one of the most important factors determining cell injury and consequent organ damage in thalassaemic patients with secondary iron overload. Using an innovative hydroxylamine 'radical probe' capable of efficiently trapping majority of oxygen-radicals including superoxide we measured, by electron paramagnetic resonance (EPR) spectroscopy, OSS in peripheral blood of 38 thalassaemic patients compared with sex-/age-matched healthy controls. Thalassaemic patients showed sixfold higher EPR values of OSS than controls. Significantly higher EPR values of OSS were observed in those with a severe phenotype (thalassaemia major, transfusion-dependent) with respect to mild phenotype (sickle-cell/beta-thalassaemia, not transfusion-dependent) or thalassaemia intermedia. In patients with thalassaemia major, EPR values of OSS were positively correlated with serum ferritin and with alanine aminotransferase levels. In patients with sickle cell/beta-thalassaemia, there was no correlation between EPR value of OSS and all parameters considered. The type of chelating therapy (desferrioxamine or deferiprone) did not have an effect on EPR value of OSS. In conclusion, EPR 'radical probe' seems to be a valid innovative method to determine total OSS in patients affected by thalassaemia and might be used for evaluating new strategies of chelation, new chelators, or the efficacy of antioxidant formula.

The purpose of this study was to evaluate if the variations of heart magnetic resonance imaging in beta-thalassemia major patients treated with Deferoxamine B mesylate (DF) or Deferiprone (L1) chelation therapy is a useful tool of the indirect myocardial iron content determination. For this reason, a prospective study was carried out. Seventy-two consecutive patients with beta-thalassemia major (35 treated with DF and 37 with L1) were studied. The main outcome results were laboratory parameters including determination of the liver iron concentration (LIC) and magnetic resonance imaging (MRI) of the heart and liver. The heart to muscle signal intensity ratios (HSIRs) were significantly increased in both the DF (t = -2.8; p < 0.01) and L1 (t = -3.1; p < 0.01) groups after one year of treatment No statistically significant difference in the values of HSIRs was present between the two groups at the beginning of treatment (p = 0.25; t = 1.13), and after one year of treatment (p = 0.20; t = 1.28). The HSIR were inversely correlated to the LIC (r = -0.52; p < 0.001) but not with ferritin levels (r = 0.10; p = 0.18). A positive correlation was found between the variation of HSIRs and that of the liver signal intensity ratios (r=0.52; p < 0.001), and a mild correlation (r = 0.40; p < 0.001) was found between the gamma glutamyltransferase (gammaGt) levels and the HSIRs values. Our data confirm that heart MRI is sensitive enough to detect significant variations of the mean HSIR during iron chelation with DF or L1.

Management of thalassemia major has shown substantial clinical and prognostic improvement, suggesting the need for major attention to quality of life. We studied bone health in 25 patients (13 males, 12 females; 15-23 years old) affected by beta-thalassemia major. In all patients, bone mineral density (BMD), biochemical markers of bone and calcium metabolism (calcium, phosphate, magnesium, alkaline phosphatase, urinary calcium, 25-hydroxyvitamin D [25OH-D], 1,25-dihydroxyvitamin D [1,25(OH)2D], parathyroid hormone [PTH]), hematological parameters and gonadal steroids status were assessed and related to each other and to auxological parameters (chronological, statural and bone ages, height, weight, stage of puberty). BMD of the lumbar spine (L1-L4) (g/cm2) and expressed as Z-scores, was assessed by dual energy X-ray absorptiometry. PTH levels were low in seven patients (28%), and in the normal range in 18 (72%). 25OH-D serum levels were normal in 16 patients (64%) and low in nine (36%). 1,25(OH)2D values were reduced in 19 patients (76%) and normal in six (24%). Alkaline phosphatase correlated with bone age delay (r = 0.414; p = 0.039); no other statistically significant correlation was found. Mean BMD values in patients with thalassemia were significantly reduced in comparison with that of age- and sex-matched controls (Z-score: -2.8 +/- 2.0, p <0.001; -3.3 +/- 2.1 in males, and -2.2 +/- 1.9 in females). Twenty-one patients (84%) showed reduced BMD. Overall, BMD reduction was in the osteopenia range in five patients (20%) and in the osteoporosis range in 16 patients (64%). Our data indicate that low BMD is often present in patients with thalassemia, although recognized late, as in the present series. Early diagnosis should be done during childhood, in order to improve the quality of life in adulthood.

Background: In the last years thalassemic patients gained a good improvement in prognosis and life style. However, short stature and hypogonadism are still frequent endocrine problems in this population., Methods: In a group of eleven thalassemic males (14-18 years old), the spontaneous nocturnal endocrine patterns of LH and FSH and plasma gonadotropins in response to GnRH were studied. The profiles were analyzed using a computer program (PULSAR) to determine the secretion pattern (number and amplitude of peaks) and the area under the curve above the secretion baseline (AUC). The endocrine status was compared with liver fibrosis, iron overload and transfusional regimen., Results: A regular and homogeneous transfusion and chelation management often does not prevent pubertal failure; it is related with the degree of liver fibrosis and often it is due to hypothalamic and/or pituitary dysfunction., Conclusions: Spontaneous gonadotropin profiles can be useful to evaluate hypogonadotropic hypogonadism in order to start the correct treatment.