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This study evaluated sewage sludge production in real-scale and modeled sidestream enhanced biological phosphorus removal (S2EBPR) systems under various mixing, organic feeding, and solids retention time (SRT) conditions. The S2EBPR process involves diverting a portion of recycle activated sludge (RAS) to an anaerobic sidestream reactor (SSR) to stimulate biological phosphorus uptake. A portion of the full-scale wastewater treatment plant (WWTP) was modified to carry out a demonstration study. This study comprised two different biological systems operating in parallel: the S2EBPR system and a conventional activated sludge (CAS) system. Data collected during an 11-month experimental campaign were used to estimate and compare sludge production in terms of observed sludge yield (Yobs) between the two biological processes. In the S2EBPR system, Yobswas 47% lower compared to the reference CAS when complete mixing was provided to the SSR and no external carbon was added. When mixing was provided only at the inlet and outlet of the SSR a 23% reduction was observed. The addition of external carbon did not yield significant benefits in terms of reducing Yobs. Modeling the S2EBPR performances at higher SRT values (20–50 d) indicated a potential further reduction in sludge production, ranging from 12% to 24%, by maintaining the SRT between 30 and 50 days. Sludge settleability was not significantly affected by SSR addition and nor by different operating conditions tested.

Phosphorus (P) is an essential element to produce feed and fertilizers but also a nonrenewable resource. Both the predicted exhaustion of phosphatic rocks and the risk of eutrophication lead to an increasing necessity for P recovery methodologies to be applied in municipal wastewater treatment plants (WWTPs). One of the most promising solutions involves the precipitation of P‐based minerals reusable as slow‐release fertilizers. In this study, P recovery as struvite and hydroxyapatite from a municipal WWTP digestate liquid fraction (centrate) was investigated at varying pH (8–10), reagent typologies (MgCl2, NaOH, Ca(OH)2, and CaCl2), and concentrations under limiting magnesium doses through liquid‐ and solid‐phase analyses and thermodynamical modeling. A maximum P recovery of 87.3% was achieved at pH 9 by adding NaOH and MgCl2at a dose of 656 mg/L (the higher tested). According to these data, it was estimated that 92.0 tons/year of struvite and 33.2 tons/year of hydroxyapatite could be recovered from the WWTP centrate with a cost for reagent consumption being almost 50% of the mean P market value. An increase in P precipitation was observed while comparing experiments with the same pH values but with a higher Mg2+dose. Ca2+addition led to extensive P precipitation but mainly as amorphous phases that interfere with struvite formation. Precipitation tests to recover phosphorus (P) with low magnesium addition from a full‐scale plant were performed.Liquid‐phase analysis allowed to measure P removal at different pHs, reagent dose, and types of alkalizing agents.Solid‐phase analysis coupled with thermodynamical modeling allowed to assess precipitate formation and speciation.A preliminary evaluation was performed to assess the economic feasibility of the approach.

ABSTRACTBackgroundHydroxyurea (HU) has been widely used in clinical practice to manage patients with non-transfusion dependent thalassemia (NTDT). Few data are available about the effects of its administration in Italian patients. We assessed hematological and non-hematological outcomes following short- and long-term exposure to HU.Research design and methodsWe considered 71 NTDT patients (30 females) enrolled in the Myocardial Iron Overload in Thalassemia Network and treated for >12 months with HU.ResultsThe mean duration of HU treatment was 8.23±5.79 years, starting at a mean age of 37.02±12.06 years. A significant increase in hemoglobin and mean corpuscular volume values and a down-regulation of all erythropoietic and/or hemolysis indices were detected after at least 12 months of treatment. In 28 patients the hemoglobin increase was ≥1.0 g/dl, associated with a higher HU dose. The hematological response dropped in long-term treatment. A favorable impact of HU treatment in limiting the progression of several complications typical of NTDT syndrome was observed.ConclusionOur findings seemed to suggest that in several NTDT patients HU could be still a valid option to limit the advance in overall disease clinical burden without carrying significant adverse events and increase in mortality.

AbstractIn the present research, an environmentally sustainable material as wheat straw deriving from Apulia region, Southern Italy, was added to cement mortars and characterized by thermal, acoustic, mechanical, and microstructural measurements. The straw and the matrix composition were not modified and the mixture preparation did not require complex manufacturing or expensive procedures. The aim was to obtain a lightweight product for indoor applications using a renewable material from the agro-food industry and adopting a safe and cheap process. The samples with high straw content showed very low thermal conductivities exceeding 0.16 W/mK and good acoustic absorptions in the 500–1000 Hz range. The results were strongly dependent on the porosity of the composites, ascribed to the straw features and to the voids at the cellulose fibers/cement matrix interface. Moreover, preliminary observations of the material stability (microstructural analysis) demonstrated that the conglomerate components did not show detectable effects of degradation.

Hematopoietic cell transplant (HCT) recipients have a substantial risk of developing secondary solid cancers (SSCs). The aim of this retrospective study was to compare the incidence of SSC in a monocentric cohort of thalassemia major (TM) patients (n=122) who received HCT versus an hematopoietic cell donor monocentric cohort (n=122) and versus a large multicenter cohort of age- and sex-matched TM patients (n=244) who received conventional therapy. With a median follow-up of 24 years, 8 transplanted patients were diagnosed with SSC at a median of 18 years after HCT and at a median age of 33 years. Three patients died of cancer progression and 5 are living after a follow-up ranging from 10 months to 16 years after SSC diagnosis. The 30-year cumulative incidence of developing SSC was 13.24%. The occurrence of solid cancers in the hematopoietic cell donor cohort was limited to only one case for a significantly lower cumulative incidence (3.23%, P=0.02) and to 3 cases in the cohort of nontransplant patients for a significantly lower cumulative incidence (1.32%, P=0.005). This study shows that the magnitude of increased risk of SST is fourfold to sixfold for patients treated with HCT as compared with hematopoietic cell donors and nontransplant patients.

Objective:Although IFN therapy is known to cause neutropenia, data on the risk of deferiprone (DFP)-induced haematological complications in patients receiving IFN are lacking.Research design and methods:This was a retrospective single-centre study to assess the association between exposure to IFN for hepatitis C virus treatment and haematological side effects of DFP therapy in patients with thalassemia major and intermedia using a large database spanning 2001 – 2008. During observation time, a total of 66 patients, including 63 affected by thalassemia major and 3 by thalassemia intermedia, were treated with chelation DFP-based regimens. A subset of 25 patients was treated at least for 3 months also with IFN (6 were cotreated and 19 were pretreated).Results:Overall, the incidence of neutropenia and agranulocytosis was 9.83 and 1.14/100 patient/year, respectively. Receipt of IFN was significantly associated with increased risk of haematological complications of DFP therapy: among patients receiving IFN, 48 and 12% experienced at least one episode of neutropenia and agranulocytosis, respectively.Conclusions:These results suggest that IFN therapy may increase the risk of complications of DFP-based iron chelation therapy in patients with thalassemia. Further research is needed to assess whether the association observed in this retrospective single-centre observational study is due to IFN or other factors.

A retrospective report was conducted on clinical and instrumental data of 3 patients treated for esophageal perforation after anterior cervical spine surgery.

Abstract: A rapid detection method based on PCR amplification of Pseudomonas syringae pv. tomato chromosomal sequences was developed. Primer design was based on the P. syringae DC3000 hrpZPst gene, which maps on a pathogenicity-associated operon of the hrp/hrc pathogenicity island.A 532 bp product corresponding to an internal fragment of hrpZPst was amplified from 50 isolates of P. syringae pv. tomato belonging to a geographically representative collection. The amplification product was also obtained from three coronatine-deficient strains of P. syringae pv. tomato.On the other hand, PCR did not produce any such products from 100 pathogenic and symbiotic bacterial strains of the genera Pseudomonas, Xanthomonas, Erwinia, and Rhizobium and 75 unidentified bacterial saprophytes isolated from tomato plants. The method was tested using leaf and fruit spots from naturally-infected tomato plants and asymptomatic nursery plants and artificially contaminated tomato seeds. The results confirmed the high specificity observed using pure cultures.

Rigid-chain metallomesogenic polymers containing Cu(II) or VO(II) were prepared and characterized. All the polymers were soluble and melted without decomposition. They showed a thermotropic liquid–crystal (LC) behavior, and the mesophases were invariably preserved for a long time at room temperature in a metastable condition, with respect to the semicrystalline state. The nature of the mesophases of the Cu(II)-containing polymers was similar to that observed in analogous organic rigid-chain polymers having long lateral alkyl chains packed as extended ribbons. The VO(II)-containing polymers showed an LC polymorphism involving a smectic A and a nematic phase. For all the polymers in a smectic or smecticlike state at room temperature, X-ray diffraction data suggested short mean distances among the metal ions arranged in layers. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 2342–2349, 2001

Longo: Bristol Myers Squibb: Honoraria; BlueBird Bio: Honoraria. Bardón-Cancho: Novartis Oncology Spain: Research Funding. Flevari: PROTAGONIST COMPANY: Research Funding; ADDMEDICA: Consultancy, Research Funding; BMS: Research Funding; IMARA COMPANY: Research Funding; NOVARTIS COMPANY: Research Funding. Voskaridou: BMS: Consultancy, Research Funding; IMARA: Research Funding; NOVARTIS: Research Funding; ADDMEDICA: Consultancy, Research Funding; GENESIS: Consultancy, Research Funding; PROTAGONIST: Research Funding. Biemond: GBT: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Honoraria; Celgene: Honoraria; Sanquin: Research Funding. Nur: Celgene: Speakers Bureau; Roche: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Beneitez-Pastor: Agios: Honoraria; Alexion: Honoraria; Novartis: Honoraria; Forma Therapeutics: Honoraria. Pepe: Chiesi Farmaceutici S.p.A: Other: no profit support; Bayer S.p.A.: Other: no profit support. de Montalembert: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Addmedica: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Membership on an entity's Board of Directors or advisory committees; Vertex: Membership on an entity's Board of Directors or advisory committees. Glenthøj: Agios: Consultancy; Novo Nordisk: Honoraria; Novartis: Consultancy; Alexion: Research Funding; Bluebird Bio: Consultancy; Bristol Myers Squibb: Consultancy; Saniona: Research Funding; Sanofi: Research Funding. Benghiat: Novartis: Consultancy; BMS: Consultancy. Labarque: Novartis: Consultancy; Bayer: Consultancy; Sobi: Consultancy; NovoNordisk: Consultancy; Octapharma: Consultancy. Diamantidis: Genesis Pharma: Honoraria; Uni-Pharma: Honoraria; Bristol Myers Squibb: Consultancy; IONIS Pharmaceuticals: Research Funding; NOVARTIS, Genesis Pharma SA: Research Funding. Kerkhoffs: Sanofi: Research Funding; Terumo BCT: Research Funding. Iolascon: Celgene: Other: Advisory Board; Bluebird Bio: Other: Advisory Board. Taher: Vifor Pharma: Consultancy, Research Funding; Agios Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Colombatti: Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novonordisk: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Addmedica: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding. Mañú Pereira: Novartis: Research Funding; Agios Pharmaceuticals: Research Funding.

Abstract:  Vincristine (1.4 mg/m2 on day 1, followed by 1 mg on days 4 and 7) was given to eight patients with thrombotic thrombocytopenic purpura (TTP) who were refractory to plasma exchange (n=4) or plasma infusion (n=4). Seven of eight patients (87%) achieved a complete response; one was refractory to treatment and died within a few weeks. After a median follow-up of 50 months, all responding patients are alive and well. Two patients relapsed and were successfully retreated with vincristine. Toxicity was mild, consisting of two episodes of leukopenia and one of autonomic neuropathy leading to paralytic ileus in a patient aged 70 years. We conclude that vincristine is highly effective in the treatment of patients suffering from refractory TTP, with negligible toxicity.

In this paper we present an Italian initiative, involving relevant research institutions and national libraries, aimed at implementing an NBN Persistent Identifiers (PI) infrastructure based on a novel hardware/software architecture. We describe a distributed and hierarchical approach for the management of an NBN namespace and illustrate assignment policies and identifier resolution strategies based on request forwarding mechanisms. Starting from the core motivations for the assignment of "persistent identifiers" to digital objects, we draw a state of art in PI technologies, standards and initiatives, and illustrate other NBN implementations. We then describe structure and goals of our initiative and illustrate the features already implemented in our system and the results of our testing activities. Finally, we draw some conclusions and point out the future directions of our work. [ABSTRACT FROM AUTHOR]

Objectives: Myocardial fibrosis in noninfarcted myocardium is emerging as a principal phenotype of vulnerability to adverse events such as mortality and hospitalization for heart failure (HHF), but its optimal noninvasive measurement remains uncertain despite consistently robust histologic validation data for extracellular volume fraction (ECV). We therefore compared ECV, native T1, post contrast T1, the gadolinium contrast partition coefficient (lambda), and the presence of nonischemic scar in their associations with mortality and HHF outcomes. Method: To quantify of myocardial fibrosis, we performed T1 mapping (MOLLI) in basal and mid short axis slices with cardiovascular magnetic resonance (CMR) before contrast and 12-30 minutes post contrast bolus in 1185 consecutive patients without amyloidosis, hypertrophic or stress cardiomyopathy. We assessed associations with outcomes using Kaplan-Meier plots and chi square values from univariable Cox regression models. All standard T1 mapping parameters were obtained: native and post contrast myocardial T1, the partition coefficient lambda, and ECV. ECV = (1-hematocrit) · [ΔR1myocardium]/[ΔR1bloodpool], where R1 = 1/T1 Late gadolinium enhancement imaging with phase sensitive reconstruction identified nonischemic scar. Results: Over a median of 1.7 years, 111 individuals experienced events after CMR: 55 HHF events and 74 deaths. ECV yielded better separation of Kaplan-Meier curves in a dose dependent fashion (Figure) and also stronger associations with the combined endpoint of death or HHF. The ECV chi square (77.3, p < 0.001) was at least twice as large as the Native T1 chi square (37.5, p < 0.001), the lambda chi square (34.8, p < 0.001) and nonischemic scar (chi square = 20.5, p<0.001). Post-contrast T1 was not associated with outcomes, even when adjusting further for time after contrast bolus, renal function, and patient weight (chi square <3, p >0.10). Conclusion: Analogous to histologic previously published validation data, quantitative ECV myocardial fibrosis measures associated with outcomes far stronger than other surrogate measures outcome measures such as native T1, post contrast T1 and nonischemic scar on LGE images. These data suggest that ECV is the noninvasive metric of choice to measure myocardial fibrosis. Figure. Kaplan-Meier Plots for T1 mapping parameters.

Gadolinium based contrast agents (GBCA) are used in magnetic resonance imaging (MRI) in order to improve the detection and the characterization of pathophysiologic processes. Many studies have reported an association between increased signal intensities (SI) on unenhanced T1-weighted MRI images in different brain regions and the history of repeated intravenous administrations of GBCAs in patients with normal renal function. We conducted a prospective study aimed to evaluate signal changes in the dentate nucleus (DN), globus pallidus (GP), pons, and thalamus (normalized to the deep cerebellum white matter) in T1-MRI images after serial injections of Gadobutrol for the study of the heart in patients with thalassemia.

Hematopoietic cell transplant (HCT) recipients have a substantial risk of developing secondary solid cancers (SSC). There is limited information about the incidence of SSC following HCT for patients with thalassemia major (TM).

De Franceschi: F. Hoffmann-La Roche Ltd, Basel, Switzerland: Research Funding. Pepe:Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc.

Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) technique is the only validated non-invasive approach used for detecting macroscopic myocardial fibrosis. Galectin-3 has been shown to participate in tissue fibrogenesis and was already associated with LGE-assessed myocardial replacement fibrosis in a cohort of patients with non-ischemic dilated cardiomyopathy (NICM).

Pepe: ApoPharma Inc: Speakers Bureau; Novartis: Speakers Bureau; Chiesi: Speakers Bureau.

Background:In thalassemia major (TM) three iron chelators are available to treat chronic iron overload due to blood transfusions: subcutaneous desferrioxamine (DFO), oral deferiprone (DFP) and oral deferasirox (DFX).

No relevant conflicts of interest to declare.

Epidemiologic as well as clinical studies confirm a close link between diabetes mellitus (DM) and heart failure (HF) in the general population. In a retrospective historical thalassemia major (TM) cohort, DM was demonstrated to lead to an higher frequency of cardiac complications also independently of cardiac iron status, but not prospective data are available. So, we determined prospectively the predictive value of DM for HF, arrhythmias and cardiac complications (HF, arrhythmias and pulmonary hypertension) in TM.

Abstract:  We describe a case of stable complete remission in a patient with refractory anemia complicated by severe autoimmune hemolytic anemia, achieved with a single high dose (4 g/m2) of cyclophosphamide (cyclo). Concomitantly, an effective mobilization of CD34-positive cells was induced. Other immunosuppressive approaches including high-dose methylprednisolone, high-dose immunoglobulin, and cyclosporine had been ineffective. This finding suggests that, in selected cases, an immunologic mechanism may mediate cytopenia in myelodysplastic syndromes (MDS). In addition, it demonstrates that successful mobilization of peripheral blood stem cells can be induced with high-dose cyclo in MDS.

Magnetic Resonance (MR) is the unique non invasive suitable technique to evaluate quantitatively the changes in cardiac and hepatic iron and in cardiac function in thalassemia major (TM) patients under different chelation regimens. This study aimed to prospectively assess the efficacy of the sequential deferiprone–deferrioxamine (DFP-DFO) versus deferiprone (DFP) and deferrioxamine (DFO) in monotherapy in a large cohort of TM patients by quantitative MR.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. We evaluated prospectively the 35 patients treated with DFP-DFO versus the 39 patients treated with DFP and the 74 patients treated with DFO between the 2 MR scans. Iron concentrations were measured by T2* multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images.Excellent/good levels of compliance were similar in the DFP-DFO (97.1%) versus DFP (94.9%) and DFO (95.9%) groups. No significant differences were found in the frequency of side effects in DFP-DFO (15.6%) versus DFP group (9.4%). The percentage of patients who maintained a normal global heart T2* value (≥20 ms) was comparable between DFP-DFO (96%) versus DFP (100%) and DFO (98.1%) groups.Among the patients with myocardial iron overload (MIO) at baseline (global heart T2*<20 ms), in all three groups there was a significant improvement in the global heart T2* value (DFO-DFP: P=0.004, DFP: P=0.015 and DFO: ms P=0.007) and a significant reduction in the number of pathological segments (DFO-DFP: P=0.026, DFP: P=0.012 and DFO: P=0.002). In DFO-DFP and DFP groups there was a significant increment in the left ventricular (LV) ejection fraction (EF) (P=0.035 and P=0.045, respectively) as well as in the right ventricular (RV) EF (P=0.017 and P=0.001, respectively). The improvement in the global heart T2* and in biventricular function were not significantly different in DFO-DFP compared to the other groups (Table 1).Among the patients with hepatic iron at baseline (T2*<9.2 ms), only in DFO group there was a significant improvement in the liver T2* value (2.0±3.5 ms P=0.010). Liver T2*changes were not significantly different in DFO-DFP versus the other groups.Prospectively we did not find significant differences on cardiac and hepatic iron or in cardiac function in TM patients treated with sequential DFP–DFO therapy versus the TM patients treated with DFO or DFP in monotherapy.Pepe: Novartis: Speakers Bureau; Apotex: Speakers Bureau; Chiesi: Speakers Bureau. Off Label Use: Association of two chelators commercially available in order to obtain a higher efficacy. Lai:Novartis: Honoraria, Research Funding.

T2* Magnetic Resonance Imaging (MRI) technique allows noninvasive quantification of organ-specific iron burden, playing a key role in the management of thalassemia major (TM) patients. There are few data on the incidence of heart failure and arrhythmias in TM patients according to baseline T2* values. The aim of this study was to establish prospectively the risk of cardiac complications in a large cohort of well-treated TM patients.We considered 527 TM patients (252 males, mean age 30±9) for who clinical data relative to a period of 5 years after the first MRI were collected in a central data base. At time of the first scan mean ferritin levels were1653±1559 ng/l, global heart was 27±13 ms, and excellent/good level of compliance were present in the 96% of the study population.At 5 years of follow-up, we recorded 24 cardiac events: 4 episodes of cardiac failure, 15 of arrhythmia, 1 of pulmonary hypertension and 4 of other cardiac complications. The majority of these events (21/24) happened within the first 24 months subsequent to the MRI, so we considered this follow-up period. At the first MRI scan, in patients with cardiac complications the global heart T2* was 22.5 ±12.4 ms. In comparison with global heart T2* values ≥20 ms, there was not a significantly increased risk of cardiac complications associated with global heart T2* values <20 ms (HR= 2.028 P=0.09) (see figure). In the heart failure patients the global heart T2* was 19±12 ms. In comparison with global heart T2* values ≥20 ms, there was not a significantly increased risk of heart failure associated with global heart T2* values <20 ms (HR=1.9 P=0.524) or <10 ms (HR=2.6 P=0.443).In the arrhythmic patients the global heart T2* was 25±13 ms. In comparison with global heart T2* values ≥20 ms, there was not a significantly increased risk of arrhythmia associated with global heart T2* values <20 ms (HR=2.1 P=0.179) or <10 ms (HR=0.8 P=0.824). During the follow up changes in the chelation therapy (type and/or dose-frequencies) were found in > 25% of the study population.We detected very few cardiac events, almost all concentrated in the first 24 months. In a large cohort of well-treated TM patients heart T2* lost its power in predicting cardiac events probably due to a patient-specific adjustment of the chelation therapy MRI-guided.No relevant conflicts of interest to declare.

Abstract 5298

Abstract 1089This icon denotes a clinically relevant abstract

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.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.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).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.No relevant conflicts of interest to declare.

T2* multiecho cardiovascular magnetic resonance (CMR) is largely used to assess iron overload in heart because of the established inverse relationship between the T2* value and the iron concentration in tissues (Wood JC et al, Hemoglobin 2008). The decay of CMR signal is sampled at several echo times (TEs) and the T2* is inferred by fitting the decay curve to an appropriate model (Positano V et al, NMR in Biomed 2007). Our aim was to quantify the reliance on TEs of the expected error in T2* value determination.The Cramer-Rao lower bounds theory (CRLB) was used. CRLB provide a fundamental limit to the accuracy in determination of the T2* value from experimental data in dependence of SNR at signal samples. CRLB were evaluated for a commonly used multi-echo sequence with the first TE equal to the minimum achievable (1.4-2 ms), ΔTE of about 2.3 ms to minimize the fat-water interface artifacts, 10 echoes to assure acquisition in a single breath-hold.Percent error in T2* values assessment was lower than 10% in the range of clinical interest, with the exception of very low T2* values. Precision in measurement of low T2* values is strongly dependent on the value of the first TE, that is limited by the used scanner. T2* values greater than 1.8 ms and 1.5 ms can be assessed with an error below 20% using a first TE of 2 ms and 1.5 ms, respectively (see Figure).T2* multiecho sequences used in clinical practice assure an acceptable precision for T2* values ≥ 2 ms, depending from the used hardware. This limit includes almost all patients with hemochromatosis or hemosiderosis in country where the patients can be well managed. For patients with very high myocardial iron overload sequences with lower minimum echo time and/or lower echoes interval may be useful.No relevant conflicts of interest to declare.

Abstract 5169

Abstract 4267

Cardiovascular Magnetic Resonance (CMR) by delayed enhancement (DE) has proven to visualize myocardial scarring, but no dedicated studies are available in thalassemia major. Aim of our study was to investigate the prevalence, extent, clinical and instrumental correlates of myocardial fibrosis or necrosis by DE CMR in thalassemia major patients. CMR-DE was performed in 115 thalassemia major patients. Myocardial iron overload was determined by multislice multiecho T2*. Cine images were obtained to evaluate biventricular function. All patients gave written informed consent to the protocol. The project was approved by the institutional ethics committee. DE areas were present in 28 patients (24%). Extent of DE was 3.9±2.4 %. In 26 patients the location of fibrosis was not specific and patchy distribution was prevalent. Two patients showed transmural DE following coronary distribution. The DE group was significantly older (P=0.004). DE correlated with cardiac risk factors (P=0.01), history of cardiac complications (P=0.001), anti-HCV antibodies (P = 0.04) and ECG-changes (P=0.002). We did not find significant relation of DE with heart T2* values and biventricular function. Figure shows a thalassemia major patient with no myocardial iron overload (all 16 segments T2* values > 20 ms) (A) and transmural DE (black arrows) following coronary distribution in the apical region (B,C). In conclusion, in thalassemia major patients the significant presence of myocardial fibrosis/necrosis seems to be a time dependent process correlating with cardiovascular risk factors and cardiac complications. HCV infection could be a causal agent in the pathogenesis of myocardial scarring. ECG-changes showed a good accuracy in predicting myocardial scarring. Figure Figure

Segmental distribution of T2* values can be assessed in heart iron overloaded patients by multislice, multiecho cardiovascular MRI. A significant heterogeneity in T2* segmental distribution was demonstrated in previous studies in thalassemia major (TM) patients [1] and may represent true heterogeneous iron density or could be generated by geometric and susceptibility artefacts. In this study we investigate the relationship between T2* heterogeneity and iron overload progression in a large patient population in order to understand if susceptibility artefact may account for inhomogeneous T2* values segmental distribution. 230 TM patients consecutively affered to our laboratory were studied. Informed consent was obtained for all of them. MRI was performed using a 1.5 T MR scanner (GE Signa, CV/i). For the measurements of myocardial T2*, a fast gradient echo-multiecho sequence (FA=25°, matrix=256×192, FOV=35×35 cm, thickness=8.0 mm, NEX=0.75) was used with ECG triggering. Each slice was acquired at nine echo times (2.2–20.3 ms, with echo spacing of 2.26 ms) in a single end-expiratory breath-hold. Three short axis views (basal, medium, and apical) of the left ventricle were obtained and analyzed using a custom-written, previous validated software (HIPPO MIOT®) The myocardium was automatically segmented into a 16-segments standardized heart model and the T2* value on each segment was calculated as well as the global T2* value. The level of heterogeneity of the T2* segmental distribution on each patient was evaluated by computing the coefficient of variation (CoV) as the standard deviation of the absolute value of differences between the segmental T2* values and the global T2* value divided by their means, and expressed as the percentage. A surrogate data sets was obtained stating that the inhomogeneous segmental distribution of T2* would be generated only by susceptibility artefacts that are additive in the R2* (1/T2*) domain. These artefacts were characterized in a previous study by the analysis of the segmental T2* distribution in normal subject [2]. In 45 (20%) TM patients, segmental T2* values were all below the lower limit of normal (20 ms). In 104 (45%) patients, T2* values were heterogeneous with respect to the normal threshold. Of these patients, 74% showed a normal T2* global value. Eighty-one (35%) patients had all normal segments. Figure 1 shows the distribution of heterogeneous T2* among the patients population. Figure 2 shows the CoV in myocardial T2* distribution vs. the global T2* values in patients and surrogate data. Patients were sorted using the global T2* values and averaged on a 20-point window to smooth the resulting graph. Mean and normal global T2* value for healthy subjects were assessed in a previous study. Montecarlo simulation was performed on 10,000 surrogate data sets. For surrogate data, the mean CoV values together with the mean⊠2SD limits are shown. T2* heterogeneity for patients without iron overload was compatible with the hypothesis that the heterogeneity was generated by additive susceptibility artefacts. Below the normal limit of global T2* the heterogeneity abruptly increased of about 10%. Starting from this level, the heterogeneity decreased linearly returning to 25% in patients with high iron overload levels. Figure 2 shows In conclusion, a large percentage of thalassemia major patients shows a significant heterogeneity of segmental distribution of T2* values in myocardium, measured by multislice multiecho T2* cardiac magnetic resonance. T2* segmental heterogeneity in TM patients cannot be explained by the effect of susceptibility artefacts, that are additive and should vanish at high iron overload levels. A possible interpretation is that a true heterogeneity in iron overload distribution is present in TM patients. This heterogeneity seems more important in the early development of iron overload and reduces when the iron overload level increases. Figure 1 Figure 1. Figure 2 Figure 2.

Little is known about cardiac involvement in Thalassemia Intermedia (TI) using magnetic resonance imaging (MRI). Thus, we investigated myocardial and liver iron overload, myocardial fibrosis, biventricular function parameters and their inter-relationship in 60 TI using MRI. Then, we compared the data of 35 selected TI with age < 39 years with that of 60 Thalassemia Major (TM) patients matched for age. Myocardial Iron Overload (MIO) was assessed using a multislice multiecho T2* approach. Biventricular function parameters were measured quantitatively by cine images. Myocardial fibrosis was evaluated by late gadolinium-enhanced. MIO was present in the 22% of TI patients, more frequently (92%) with an heterogeneous distribution. TI patients with myocardial fibrosis (32%) showed significantly reduced left ventricular ejection fraction (LVEF) (P=0.01). No significant correlation was found between myocardial fibrosis and MIO. Figure shows a TI patient with no myocardial iron overload (all 16 segments and the mid-ventricular septum with T2* values > 20 ms) (A) and late enhancement (white arrows) in the antero-septal junction, in the infero-septal junction and in the mid-ventricular septum (B). In TI patients MIO was significantly lower respect to TM patients; conversely volumes, cardiac indexes, LVEF, bi-atrial areas, and liver iron overload were significantly higher. Myocardial fibrosis was comparable between the 2 groups. TI patients showed lower myocardial iron burden and more pronounced high cardiac output findings with myocardial fibrosis significantly associated to impaired heart function. These data seem to suggest using MRI also for TI patients and could place the basis to reconsider the current cardiological and haematological management in this population. Figure Figure

Segmental distribution of T2* values can be assessed in heart iron overloaded patients by multislice, multiecho cardiovascular MRI. A significant heterogeneity in T2* segmental distribution was demonstrated in previous studies in thalassemia major (TM) patients [1] and may represent true heterogeneous iron density or could be generated by geometric and susceptibility artefacts. In this study we investigate the relationship between T2* heterogeneity and iron overload progression in a large patient population in order to understand if susceptibility artefact may account for inhomogeneous T2* values segmental distribution.

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).

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

Cardiovascular Magnetic Resonance (CMR) by delayed enhancement (DE) has proven to visualize myocardial scarring, but no dedicated studies are available in thalassemia major. Aim of our study was to investigate the prevalence, extent, clinical and instrumental correlates of myocardial fibrosis or necrosis by DE CMR in thalassemia major patients. CMR-DE was performed in 115 thalassemia major patients. Myocardial iron overload was determined by multislice multiecho T2*. Cine images were obtained to evaluate biventricular function. All patients gave written informed consent to the protocol. The project was approved by the institutional ethics committee. DE areas were present in 28 patients (24%). Extent of DE was 3.9±2.4 %. In 26 patients the location of fibrosis was not specific and patchy distribution was prevalent. Two patients showed transmural DE following coronary distribution. The DE group was significantly older (P=0.004). DE correlated with cardiac risk factors (P=0.01), history of cardiac complications (P=0.001), anti-HCV antibodies (P= 0.04) and ECG-changes (P=0.002). We did not find significant relation of DE with heart T2* values and biventricular function. Figure shows a thalassemia major patient with no myocardial iron overload (all 16 segments T2* values > 20 ms) (A) and transmural DE (black arrows) following coronary distribution in the apical region (B,C). In conclusion, in thalassemia major patients the significant presence of myocardial fibrosis/necrosis seems to be a time dependent process correlating with cardiovascular risk factors and cardiac complications. HCV infection could be a causal agent in the pathogenesis of myocardial scarring. ECG-changes showed a good accuracy in predicting myocardial scarring.

Little is known about cardiac involvement in Thalassemia Intermedia (TI) using magnetic resonance imaging (MRI). Thus, we investigated myocardial and liver iron overload, myocardial fibrosis, biventricular function parameters and their inter-relationship in 60 TI using MRI. Then, we compared the data of 35 selected TI with age < 39 years with that of 60 Thalassemia Major (TM) patients matched for age. Myocardial Iron Overload (MIO) was assessed using a multislice multiecho T2* approach. Biventricular function parameters were measured quantitatively by cine images. Myocardial fibrosis was evaluated by late gadolinium-enhanced. MIO was present in the 22% of TI patients, more frequently (92%) with an heterogeneous distribution. TI patients with myocardial fibrosis (32%) showed significantly reduced left ventricular ejection fraction (LVEF) (P=0.01). No significant correlation was found between myocardial fibrosis and MIO. Figure shows a TI patient with no myocardial iron overload (all 16 segments and the mid-ventricular septum with T2* values > 20 ms) (A) and late enhancement (white arrows) in the antero-septal junction, in the infero-septal junction and in the mid-ventricular septum (B). In TI patients MIO was significantly lower respect to TM patients; conversely volumes, cardiac indexes, LVEF, bi-atrial areas, and liver iron overload were significantly higher. Myocardial fibrosis was comparable between the 2 groups. TI patients showed lower myocardial iron burden and more pronounced high cardiac output findings with myocardial fibrosis significantly associated to impaired heart function. These data seem to suggest using MRI also for TI patients and could place the basis to reconsider the current cardiological and haematological management in this population.