Differential effects of iron chelators on iron burden and long-term morbidity and mortality outcomes in a large cohort of transfusion-dependent ß-thalassemia patients who remained on the same monotherapy over 10 years.

We conducted a retrospective cohort study on 663 transfusion-dependent ß-thalassemia patients receiving the same iron chelation monotherapy with deferoxamine, deferiprone, or deferasirox for up to 10 years (median age 31.8 years, 49.9 % females). Patients on all three iron chelators had a steady and significant decline in serum ferritin over the 10 years (median deferoxamine: -170.7 ng/mL, P = 0.049, deferiprone: -236.7 ng/mL, P = 0.001; deferasirox: -323.7 ng/mL, P < 0.001) yet had no significant change in liver iron concentration or cardiac T2*; while noting that patients generally had low hepatic and cardiac iron levels at study start. Median absolute, relative, and normalized changes were generally comparable between the three iron chelators. Patients receiving deferasirox had the highest morbidity and mortality-free survival probability among the three chelators, although the difference was only statistically significant when compared with deferoxamine (P = 0.037). On multivariate Cox regression analysis, there was no significant association between iron chelator type and the composite outcome of morbidity or mortality. In a real-world setting, there is comparable long-term iron chelation effectiveness between the three available iron chelators for patients with mild-to-moderate iron overload.

Revisiting iron overload status and change thresholds as predictors of mortality in transfusion-dependent ß-thalassemia: a 10-year cohort study.

Data on iron overload status and change thresholds that can predict mortality in patients with transfusion-dependent ß-thalassemia (TDT) are limited. This was a retrospective cohort study of 912 TDT patients followed for up to 10 years at treatment centers in Italy (median age 32 years, 51.6% female). The crude mortality rate was 2.9%. Following best-predictive threshold identification through receiver operating characteristic curve analyses, data from multivariate Cox-regression models showed that patients with Period Average Serum Ferritin (SF) > 2145 vs ≤ 2145 ng/mL were 7.1-fold (P < 0.001) or with Absolute Change SF > 1330 vs ≤ 1330 ng/mL increase were 21.5-fold (P < 0.001) more likely to die from any cause. Patients with Period Average Liver Iron Concentration (LIC) > 8 vs ≤ 8 mg/g were 20.2-fold (P < 0.001) or with Absolute Change LIC > 1.4 vs ≤ 1.4 mg/g increase were 27.6-fold (P < 0.001) more likely to die from any cause. Patients with Index (first) cardiac T2* (cT2*) < 27 vs ≥ 27 ms were 8.6-fold (P < 0.001) more likely to die from any cause. Similarly, results at varying thresholds were identified for death from cardiovascular disease. These findings should support decisions on iron chelation therapy by establishing treatment targets, including safe iron levels and clinically meaningful changes over time.

'Phenoconversion' in adult patients with ß-thalassemia.

Rate and risk factors for phenoconversion from non-transfusion-dependent ß-thalassemia (NTDT) to transfusion-dependent ß-thalassemia (TDT) during a 10-year follow up of adult patients in Italy.

Multi-Parametric Cardiac Magnetic Resonance for Prediction of Heart Failure Death in Thalassemia Major.

We assessed the prognostic value of multiparametric cardiovascular magnetic resonance (CMR) in predicting death from heart failure (HF) in thalassemia major (TM). We considered 1398 white TM patients (30.8 ± 8.9 years, 725 women) without a history of HF at baseline CMR, which was performed within the Myocardial Iron Overload in Thalassemia (MIOT) network. Iron overload was quantified by using the T2* technique, and biventricular function was determined with cine images. Late gadolinium enhancement (LGE) images were acquired to detect replacement myocardial fibrosis. During a mean follow-up of 4.83 ± 2.05 years, 49.1% of the patients changed the chelation regimen at least once; these patients were more likely to have significant myocardial iron overload (MIO) than patients who maintained the same regimen. Twelve (1.0%) patients died from HF. Significant MIO, ventricular dysfunction, ventricular dilation, and replacement myocardial fibrosis were identified as significant univariate prognosticators. Based on the presence of the four CMR predictors of HF death, patients were divided into three subgroups. Patients having all four markers had a significantly higher risk of dying for HF than patients without markers (hazard ratio (HR) = 89.93; 95%CI = 5.62-1439.46; p = 0.001) or with one to three CMR markers (HR = 12.69; 95%CI = 1.60-100.36; p = 0.016). Our findings promote the exploitation of the multiparametric potential of CMR, including LGE, for better risk stratification for TM patients.

Left ventricular global function index is associated with myocardial iron overload and heart failure in thalassemia major patients.

PURPOSE: The left ventricular global function index (LVGFI) is a comprehensive marker of cardiac performance, integrating LV morphology with global function. We explored the cross-sectional association of LVGFI with myocardial iron overload (MIO), LV ejection fraction (LVEF), myocardial fibrosis, and heart failure (HF) in ß-thalassemia major (TM) patients. METHODS: We considered 1352 adult TM patients (708 females, 32.79 ± 7.16years) enrolled in the Myocardial Iron Overload in Thalassemia Network and 112 healthy subjects (50 females, 32.09 ± 6.08years). LVGFI and LVEF were assessed by cine images and MIO by multislice multiecho T2* technique. Replacement myocardial fibrosis was detected by late gadolinium enhancement technique. RESULTS: LVGFI and LVEF were significantly lower in patients with significant MIO (global heart T2*<20ms) than in patients without MIO and in healthy subjects but were comparable between TM patients without MIO and healthy subjects. In TM, LVGFI was significantly associated with LVEF (R = 0.733; p < 0.0001). Global heart T2* values were significantly associated with both LVGFI and LVEF, but the correlation with LVGFI was significantly stronger (p = 0.0001). Male sex, diabetes mellitus, significant MIO, and replacement myocardial fibrosis were the strongest predictors of LVGFI. Eighty-six patients had a history of HF and showed significantly lower global heart T2* values, LVEF, and LVGFI than HF-free patients. A LVGFI ≤ 44.9% predicted the presence of HF. The LVGFI showed a diagnostic performance superior to that of LVEF (area under the curve: 0.67 vs. 0.62; p = 0.039). CONCLUSION: In TM patients the LVGFI correlates with MIO and provides incremental diagnostic value for HF detection compared with LVEF.

Overall and complication-free survival in a large cohort of patients with ß-thalassemia major followed over 50 years.

We report data on survival and complications for a longitudinal cohort of 709 transfusion-dependent ß-thalassemia major patients (51.1% males) born between 1970 and 1997 and followed through 2020 at seven major centers in Italy. Overall survival probability at 30 years was 83.6% (95%CI: 78.5-89.1) in the oldest birth cohort (1970-1974) compared with 93.3% (95%CI: 88.6-98.3) in the youngest birth cohort (1985-1997) (p = 0.073). Females showed better survival than males (p = 0.022). There were a total of 93 deaths at a median age of 23.2 years with the most frequent disease-related causes being heart disease (n = 53), bone marrow transplant (BMT) complication (n = 10), infection (n = 8), liver disease (n = 4), cancer (n = 3), thromboembolism (n = 2) and severe anemia (n = 1). There was a steady decline in the number of deaths due to heart disease from the year 2000 onwards and no death from BMT was observed after the year 2010. A progressive decrease in the median age of BMT was observed in younger birth cohorts (p < 0.001). A total of 480 (67.7%) patients developed ≥1 complication. Patients in younger birth cohorts demonstrated better complication-free survival (p < 0.001) which was comparable between sexes (p = 0.230). Independent risk factors for death in multivariate analysis included heart disease (HR: 4.63, 95%CI: 1.78-12.1, p = 0.002), serum ferritin >1000 ng/mL (HR: 15.5, 95%CI: 3.52-68.2, p < 0.001), male sex (HR: 2.75, 95%CI: 0.89-8.45, p = 0.078), and splenectomy (HR: 6.97, 95%CI: 0.90-54.0, p < 0.063). Survival in patients with ß-thalassemia major continues to improve with adequate access to care, best practice sharing, continued research, and collaboration between centers.

Prognostic value of multiparametric cardiac magnetic resonance in sickle cell patients.

The aim of this multicenter study was to prospectively assess the predictive value of multiparametric cardiac magnetic resonance (CMR) for cardiovascular complications in sickle cell disease (SCD) patients. Among all patients with hemoglobinopathies consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network, we selected 102 SCD patients (34.38 ± 12.67 years, 49 females). Myocardial iron overload (MIO) was measured by the multislice multiecho T2* technique. Atrial dimensions and biventricular function parameters were quantified by cine images. Late gadolinium enhancement (LGE) images were acquired to detect focal myocardial fibrosis. At baseline CMR, only two patients had significant MIO (global heart T2* < 20 ms). During a mean follow-up of 63.01 ± 24.95 months, 11 cardiovascular events (10.8%) were registered: 3 pulmonary hypertension, 2 supraventricular arrhythmias, 1 heart failure, 1 death for heart failure, 1 pulmonary embolism, 1 peripheral vascular disease, 1 transient ischemic attack, and 1 death after acute chest syndrome. In the multivariate analysis, the independent CMR predictors of cardiovascular events were left ventricular (LV) ejection fraction (hazard ratio-HR = 0.88; p = 0.025) and right ventricular (RV) mass index (HR = 1.09; p = 0.047). According to the receiver-operating characteristic curve analysis for adverse events, an LV ejection fraction < 58.9% and an RV mass index > 31 g/m2 were optimal cut-off values. Reduced left ventricular ejection fraction and increased right ventricular mass index showed a significant prognostic value in patients with SCD. Our data seem to suggest that CMR may be added as a screening tool for identifying SCD patients at high risk for cardiopulmonary and vascular diseases.

Early results of PRO-EPI: PROspective multicenter observational study on elective pelvic nodes irradiation in patients with intermediate/high/very high-risk non-metastatic prostate cancer submitted to radical, adjuvant, or salvage radiotherapy with or without concomitant androgen deprivation therapy.

Simple Summary: Although radiotherapy plays a fundamental role in the management of intermediate/high/very high-risk non-metastatic prostatic cancer (IHR-nmPca), there is still no consensus on the optimal treatment strategy in this setting. Remarkably, the role of elective nodal irradiation (ENI) is still highly controversial. The PROspective multicenter observational study on Elective Pelvic nodes Irradiation (PRO-EPI) was designed to provide "real life" data regarding the patterns of care for IHR-nmPca. Forty-three Italian Radiation Oncology centers participated in the PROspective multicenter observational study on Elective Pelvic nodes Irradiation (PRO-EPI) project, with 1029 patients enrolled. In this preliminary analysis, we longitudinally evaluated the impact of Elective Nodal Irradiation (ENI) and radiotherapy features on toxicity and quality of life (QoL). Six months follow-up data were available for 913 patients and 12 months data for 762 patients. Elective Nodal Irradiation was given to 506 patients (48.9%). Volumetric Intensity-Modulated Radiation Therapy (IMRT) was adopted in more than 77% of patients and Image-Guided Radiation Therapy (IGRT) in 84.4%. Androgen deprivation therapy (ADT) was administered to the majority of patients (68.3%), and it was associated to ENI in 408 cases (81.1%). Toxicity was mostly mild and reversible and IGRT resulted in a significant reduction of rectal toxicity, although a non-significant trend toward increased urinary toxicity was observed. No statistically significant differences in QoL and toxicity were seen in patients treated with or without ENI. The adoption of IGRT is widespread and increasing and could reduce treatment toxicity. ENI is not yet the standard treatment, but it is performed in a growing fraction of cases and not resulting into an increase in toxicity or in a deterioration of QoL. Further analyses are needed to clarify the long-term toxicity profile and the impact of ENI on survival.

Transfusional Approach in Multi-Ethnic Sickle Cell Patients: Real-World Practice Data From a Multicenter Survey in Italy.

Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder characterized by recurrent acute vaso-occlusive crises (VOCs and anemia). Gold standard treatments are hydroxycarbamide (HC) and/or different red blood cell (RBC) transfusion regimens to limit disease progression. Here, we report a retrospective study on 1,579 SCD patients (median age 23 years; 802 males/777 females), referring to 34 comprehensive Italian centers for hemoglobinopathies. Although we observed a similar proportion of Caucasian (47.9%) and African (48.7%) patients, Italian SCD patients clustered into two distinct overall groups: children of African descent and adults of Caucasian descent. We found a subset of SCD patients requiring more intensive therapy with a combination of HC plus chronic transfusion regimen, due to partial failure of HC treatment alone in preventing or reducing sickle cell-related acute manifestations. Notably, we observed a higher use of acute transfusion approaches for SCD patients of African descent when compared to Caucasian subjects. This might be related to (i) age of starting HC treatment; (ii) patients' low social status; (iii) patients' limited access to family practitioners; or (iv) discrimination. In our cohort, alloimmunization was documented in 135 patients (8.5%) and was more common in Caucasians (10.3%) than in Africans (6.6%). Alloimmunization was similar in male and female and more frequent in adults than in children. Our study reinforces the importance of donor-recipient exact matching for ABO, Rhesus, and Kell antigen systems for RBC compatibility as a winning strategy to avoid or limit alloimmunization events that negatively impact the clinical management of SCD-related severe complications. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT03397017.

Thalassaemia is paradoxically associated with a reduced risk of in-hospital complications and mortality in COVID-19: Data from an international registry.

Although numerous patient-specific co-factors have been shown to be associated with worse outcomes in COVID-19, the prognostic value of thalassaemic syndromes in COVID-19 patients remains poorly understood. We studied the outcomes of 137 COVID-19 patients with a history of transfusion-dependent thalassaemia (TDT) and transfusion independent thalassaemia (TIT) extracted from a large international cohort and compared them with the outcomes from a matched cohort of COVID-19 patients with no history of thalassaemia. The mean age of thalassaemia patients included in our study was 41 ± 16 years (48.9% male). Almost 81% of these patients suffered from TDT requiring blood transfusions on a regular basis. 38.7% of patients were blood group O. Cardiac iron overload was documented in 6.8% of study patients, whereas liver iron overload was documented in 35% of study patients. 40% of thalassaemia patients had a history of splenectomy. 27.7% of study patients required hospitalization due to COVID-19 infection. Amongst the hospitalized patients, one patient died (0.7%) and one patient required intubation. Continuous positive airway pressure (CPAP) was required in almost 5% of study patients. After adjustment for age-, sex- and other known risk factors (cardiac disease, kidney disease and pulmonary disease), the rate of in-hospital complications (supplemental oxygen use, admission to an intensive care unit for CPAP therapy or intubation) and all-cause mortality was significantly lower in the thalassaemia group compared to the matched cohort with no history of thalassaemia. Amongst thalassaemia patients in general, the TIT group exhibited a higher rate of hospitalization compared to the TDT group (p = 0.001). In addition, the rate of complications such as acute kidney injury and need for supplemental oxygen was significantly higher in the TIT group compared to the TDT group. In the multivariable logistic regression analysis, age and history of heart or kidney disease were all found to be independent risk factors for increased in-hospital, all-cause mortality, whereas the presence of thalassaemia (either TDT or TIT) was found to be independently associated with reduced all-cause mortality. The presence of thalassaemia in COVID-19 patients was independently associated with lower in-hospital, all-cause mortality and few in-hospital complications in our study. The pathophysiology of this is unclear and needs to be studied in vitro and in animal models.

National networking in rare diseases and reduction of cardiac burden in thalassemia major.

AIMS: A tailored chelation therapy guided by magnetic resonance imaging (MRI) is a strategy to improve the prognosis in iron-loaded patients, in many cases still hampered by limited MRI availability. In order to address this issue, the Myocardial Iron Overload in Thalassemia (MIOT) network was established in Italy and we aimed to describe the impact of 10-year activity of this network on cardiac burden in thalassemia major (TM). METHODS AND RESULTS: Within the MIOT network, 1746 TM patients (911 females; mean age 31.2 ± 9.1 years) were consecutively enrolled and prospectively followed by 70 thalassemia and 10 MRI centres. Patients were scanned using a multiparametric approach for assessing myocardial iron overload (MIO), biventricular function, and myocardial fibrosis. At the last MRI scan, a significant increase in global heart T2* values and a significantly higher frequency of patients with no MIO (all segmental T2* ≥20 ms) were detected, with a concordant improvement in biventricular function, particularly in patients with baseline global heart T2* <20 ms. Forty-seven percentage of patients changed the chelation regimen based on MRI. The frequency of heart failure (HF) significantly decreased after baseline MRI from 3.5 to 0.8% (P < 0.0001). Forty-six patients died during the study, and HF accounted for 34.8% of deaths. CONCLUSION: Over 10 years, continuous monitoring of cardiac iron and a tailored chelation therapy allowed MIO reduction, with consequent improvement of cardiac function and reduction of cardiac complications and mortality from MIO-related HF. A national networking for rare diseases therefore proved effective in improving the care and reducing cardiac outcomes of TM patients.

Biventricular Reference Values by Body Surface Area, Age, and Gender in a Large Cohort of Well-Treated Thalassemia Major Patients Without Heart Damage Using a Multiparametric CMR Approach.

BACKGROUND: Cardiac MRI plays a critical role in the management of thalassemic patients. No accurate biventricular reference values are available. PURPOSE: To establish the ranges for normal left ventricular (LV) and right ventricular (RV) volumes and ejection fraction (EF) and LV mass normalized to body surface area (BSA), age, and gender in a large cohort of well-treated beta-thalassemia major (ß-TM) patients without heart damage using a multiparametric MRI. STUDY TYPE: Retrospective/cohort study. POPULATION: In all, 251 ß-TM patients with no known risk factors or cardiac disease, normal electrocardiogram, no macroscopic myocardial fibrosis, and all cardiac segments with T2 * ≥20 msec, and 246 healthy subjects. FIELD STRENGTH/SEQUENCE: 1.5T/cine steady-state free precession (SSFP), gradient-echo T2 *, late gadolinium enhancement (LGE) images. ASSESSMENT: Biventricular end-diastolic volume, end-systolic volume, stroke volume, and LV mass were normalized to BSA (EDVI, ESVI, SVI). STATISTICAL TESTS: Comparisons between the two groups was performed with two-samples t-test or Wilcoxon's signed rank test. For more than two groups, one-way analysis of variance (ANOVA) or a Kruskal-Wallis test were applied. RESULTS: Compared to controls, males with ß-TM showed significantlt higher LVEDVI in all the age groups, while for the other volumes the difference was significant only within one or more age groups. In females the volumes were comparable between ß-TM patients and healthy subjects in all the age groups. In the male ß-TM population we found a significant effect of age on LVEDVI (P = 0.017), LVESVI (P = 0.001), RVESVI (P = 0.029), and RVEF (P = 0.031), while for females none of the biventricular parameters were significantly different among the age groups (LVEDVI: P = 0.614; LVESVI: P = 0.449; LVSVI: P = 0.186; LV mass index: P = 0.071; LVEF: P = 0.059; RVEDVI: P = 0.374; RVESVI: P = 0.180; RVSVI: P = 0.206; RVEF: P = 0.057). In ß-TM patients all biventricular volume indexes as well as the LV mass index were significantly larger in males than in females (P < 0.0001 in all cases). The LV and the RV EF were comparable between the sexes (P = 0.568 and P = 0.268, respectively). DATA CONCLUSION: Appropriate "normal" reference ranges normalized to BSA, sex, and age are recommended to avoid misdiagnosis of cardiomyopathy in ß-TM patients. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

Genotypic groups as risk factors for cardiac magnetic resonance abnormalities and complications in thalassemia major: a large, multicentre study.

BACKGROUND: The causes and effects of genotypic heterogeneity in beta-thalassemia major (ß-TM) have not been fully investigated. The aim of this multicentre study was to determine whether different genotype groups could predict the development of cardiovascular magnetic resonance abnormalities and cardiac complications. MATERIALS AND METHODS: We considered 708 ß-TM patients (373 females, age 30.05±9.47 years) consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network. Data were collected from birth to the first cardiac magnetic resonance scan. Myocardial iron overload was assessed using a T2* technique. Biventricular function was quantified by cine images. Macroscopic myocardial fibrosis was evaluated by a late gadolinium enhancement technique. RESULTS: Three groups of patients were identified: ß+ homozygotes (n=158), ß+/ß° heterozygotes (n=298) and ß° homozygotes (n=252). Compared to ß+ homozygotes, the other two groups showed a significantly higher risk of myocardial iron overload and left ventricular dysfunction. We recorded 90 (13.0%) cardiac events: 46 episodes of heart failures, 38 arrhythmias (33 supraventricular, 3 ventricular and 2 hypokinetic) and 6 cases of pulmonary hypertensions. ß° homozygotes showed a significantly higher risk than ß+ homozygotes of arrhythmias and cardiac complications considered globally. DISCUSSION: Different genotype groups predicted the development of myocardial iron overload, left ventricular dysfunction, arrhythmias and cardiac complications in ß-TM patients. These data support the importance of genotype knowledge in the management of ß-TM patients.

Changing patterns of thalassaemia in Italy: a WebThal perspective.

BACKGROUND: Migration has impacted the spread of thalassaemia which is gradually becoming a global health problem. Italy, with an approximate estimation of 7,000 patients, does not have an accurate national record for haemoglobinopathies. This cross-sectional evaluation includes data for approximately 50% of beta-thalassaemia patients in Italy to provide an overview of the burden of thalassaemia syndromes. MATERIALS AND METHODS: The analysis included data on epidemiology, transfusions and clinical parameters from 3,986 thalassaemia patients treated at 36 centres in Italy who were alive on 31st December 2017. The study used WebThal, a computerised clinical record that is completely free-of-charge and that does not have any mandatory fields to be filled. RESULTS: For patients with thalassaemia major, 68% were aged ≥35 years and 11% were aged ≤18 years. Patients with thalassaemia intermedia were slightly older. Transfusion data, reported in a subgroup of 1,162 patients, showed 9% had pre-transfusion haemoglobin <9 g/dL, 63% had levels between ≥9 and <10 g/dL, and 28% had levels ≥10 g/dL. These 1,162 patients underwent 22,272 transfusion days during 2017, with a mean of 19 transfusion days/year/patient (range 1-54 days). Severity of iron overload was reported in 756 patients; many had moderate or mild liver iron load (74% had liver iron <7.5 mg/g dry weight). In the same cohort, 85% of patients had no signs of cardiac iron load (MRT2* >20 ms), and only 3% showed signs of high-risk heart condition (T2* <10 ms). Most patients had normal alanine amino transferase levels due to treatment with the new anti-hepatitis C virus (HCV) drugs. DISCUSSION: This study provides an overview of the current health status of patients with thalassaemia in Italy. Moreover, these data support the need for a national comprehensive thalassaemia registry.

Successful role of adjuvant radiotherapy in a rare case of tracheal inflammatory myofibroblastic tumor: a case report.

BACKGROUND: Inflammatory myofibroblastic tumor (IMT) is a rare benign cancer that can express a more aggressive phenotype related to the genetic mutation of the anaplastic lymphoma kinase receptor (ALK). Involvement of trachea is extremely rare and due to the clinical and radiologic nonspecificity, the definitive diagnosis is based on the histologic evaluation of tissue specimens. Total surgical excision is curative and chemotherapy or radiotherapy has been employed in the treatment of unresectable tumors or as adjuvant therapies. CASE PRESENTATION: The case described here is being reported because of the rare tracheal location and the atypical treatment approach used for an ALK-positive IMT. A 7-week pregnant woman voluntary interrupted pregnancy and underwent total surgical excision that resulted to have close margins. Although ALK-positive expression indicated the use of ALK inhibitors, she refused any type of adjuvant therapy that could affect ovarian function. Thus, 3D conformational external beam radiotherapy was performed with a daily dose of 180 cGy, 5 times per week, up to 45 Gy at the level of trachea. A total of 62 months of follow-up showed and no signs of disease recurrence or late radiation therapy-related toxicity. CONCLUSIONS: This report describes an extremely rare case of a tracheal IMT, underlying the key role of radiotherapy as adjuvant treatment able to definitively cure IMT, limiting systemic chemotherapy-related toxicity.

Prevalence of extramedullary hematopoiesis, renal cysts, splenic and hepatic lesions, and vertebral hemangiomas among thalassemic patients: a retrospective study from the Myocardial Iron Overload in Thalassemia (MIOT) network.

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.

Cardiac involvement by CMR in different genotypic groups of thalassemia major patients.

Beta thalassemia major (ß-TM) displays a great deal of phenotypic heterogeneity, not fully investigated in terms of cause-effect. We aimed to detect if different genotypic groups could be related to different levels of cardiac impairment, evaluated by cardiovascular magnetic resonance (CMR). We considered 671 ß-TM patients (age 30.1 years, 52.9% females) consecutively enrolled in the Myocardial Iron Overload (MIO) in Thalassemia network. MIO was assessed by T2* technique. Biventricular function was quantified by cine images. Myocardial fibrosis was evaluated by late gadolinium enhancement (LGE) technique. Three groups of patients were identified: heterozygotes ß+/ß° (N = 279), homozygotes ß + (N = 154), homozygotes ß° (N = 238). Transfusional needs resulted significantly lower in homozygous ß + TM patients when compared to the other groups. The homozygous ß + group versus the heterozygous and homozygous ß° groups showed higher global heart T2* values (P < 0.0001) and a lower number of patients with a global heart T2* value<20 ms (P < 0.001). The homozygotes ß + showed a lower number of patients with a pathological left ventricular ejection fraction (LVEF) than the other two groups (P < 0.05). The ß+/ß + TM patients showed less MIO and a concordant better systolic heart function. These data support the knowledge of different genotypic groups in the management of ß-TM patients.