Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with β-thalassemia major

Background

Prospective data on cardiac iron removal are limited beyond one year and longer-term studies are, therefore, important.

Design and Methods

Seventy-one patients in the EPIC cardiac substudy elected to continue into the 3^rd year, allowing cardiac iron removal to be analyzed over three years.

Results

Mean deferasirox dose during year 3 was 33.6±9.8 mg/kg per day. Myocardial T2*, assessed by cardiovascular magnetic resonance, significantly increased from 12.0 ms ±39.1% at baseline to 17.1 ms ±62.0% at end of study (P<0.001), corresponding to a decrease in cardiac iron concentration (based on ad hoc analysis of T2*) from 2.43±1.2 mg Fe/g dry weight (dw) at baseline to 1.80 ±1.4 mg Fe/g dw at end of study (P<0.001). After three years, 68.1% of patients with baseline T2* 10 to <20 ms normalized (≥20 ms) and 50.0% of patients with baseline T2* >5 to <10 ms improved to 10 to <20 ms. There was no significant variation in left ventricular ejection fraction over the three years. No deaths occurred and the most common investigator-assessed drug-related adverse event in year 3 was increased serum creatinine (n=9, 12.7%).

Conclusions

Three years of deferasirox treatment along with a clinically manageable safety profile significantly reduced cardiac iron overload versus baseline and normalized T2* in 68.1% (32 of 47) of patients with T2* 10 to <20 ms.     

Fetal iron levels are regulated by maternal and fetal Hfe genotype and dietary iron

Background

Iron metabolism during pregnancy maintains fetal iron levels at the expense of the mother. The mechanism behind this regulation is still not clear despite recent advances. Here we examine the role of maternal and fetal Hfe, its downstream signaling molecule, hepcidin and dietary iron in the regulation of placental iron transfer.

Design and Methods

Hfe wild-type, knockout and heterozygote dams were fed iron deficient (12.5 ppm), adequate (50 ppm) and replete (150 ppm) iron diets and mated with heterozygote males to produce pups of all genotypes. Dams and pups were sacrificed at Day 18 of gestation; serum, placenta, body and liver iron parameters were measured. Protein and mRNA levels of various iron transporter genes were determined in duodenum, liver and placenta by Western blotting and real time PCR.

Results

Maternal liver iron levels were dependent on both dietary iron intake and Hfe genotype. Increasing iron levels in the maternal diet resulted in increased total iron in the fetus, primarily in the liver. However, fetuses of Hfe-knockout mothers showed further elevation of liver iron levels, concomitant with elevated expression of Tfr1, Dmt1 and Fpn in the placenta. Hfe-knockout fetuses that express low levels of liver hepcidin accumulated more iron in their liver than wild-type fetuses due to increased ferroportin levels in the placenta.

Conclusions

Maternal and fetal status, as well as dietary iron, is important in regulating iron transfer across placenta. Maternal Hfe regulates iron transfer by altering gene expression in the placenta. Fetal Hfe is important in regulating placental iron transfer by modulating fetal liver hepcidin expression.     

Younger donor's age and upfront tandem are two independent prognostic factors for survival in multiple myeloma patients treated by tandem autologous-allogeneic stem cell transplantation: a retrospective study from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)

Background

How tandem autologous-allogeneic stem cell transplantation should be integrated in the treatment of multiple myeloma remains controversial. We examined the long-term outcome of patients with multiple myeloma managed with tandem autologous-allogeneic stem cell transplantation and present a prognostic factor analysis based on the experience of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Design and Methods

This French, retrospective, registry-based study included 146 patients who had undergone tandem autologous-allogeneic transplantation for multiple myeloma at 20 SFGM-TC centers between 1998 and 2010. The patients included in the study had fully completed the two steps of a planned tandem autologous-allogeneic transplantation. No treatment had to be administered between the autologous and allogeneic parts of the tandem procedure.

Results

Seventy-seven patients (53%) underwent tandem autologous-allogeneic transplantation as part of upfront treatment, i.e. after a single line of treatment not including autologous transplantation. The median follow-up from the allogeneic transplant was 47.5 months (range, 1.2–132 months). At 4 years, the overall survival and event-free survival rates were 48% (95% CI 39–57 %) and 27% (95% CI 19–36), respectively. Eighteen patients (12%) experienced grade III–IV acute graft-versus-host disease and 43 patients (30%) had chronic graft-versus-host disease. The transplant-related mortality rate at 1 year was 15% (95% CI 10–22). Patients receiving tandem transplantation as upfront treatment had significantly improved event-free survival (36% versus 11%; P=0.005) and overall survival (56% versus 34%; P=0.02). Donor’s age ≤50 years was associated with improved event-free survival (35% versus 16%; P=0.005) and overall survival (54% versus 41%; P=0.02). In the multivariable analysis, upfront tandem transplantation, donor’s age ≤50 years and full chimerism were independent prognostic factors for better outcome.

Conclusions

We confirmed the feasibility of tandem autologour-allogeneic transplantation in heavily treated patients with multiple myeloma. We identified younger donor’s age and upfront tandem transplantation as two independent prognostic factors for survival which could be further explored in prospective studies.     

Trace element status and fatty acids metabolism during healthy ageing: an example of a population from the Tunisian eastern coast

Micronutrients as well as essential fatty acids are indispensable for the correct functioning of the organism. The risk of disturbance in the associated nutrition and metabolism is expected to increase during ageing. In addition, it seems that trace elements are involved in the fatty acids metabolism. The aim of the present study was then to assess age-related changes in trace elements status and in plasma essential fatty acids composition with an emphasis on the desaturase activity estimation. Two hundred healthy Tunisian subjects (30-85 years old) were recruited and separated into two subgroups: elderly (65-85 years old) and middle-aged (30-60 years old). The findings revealed that plasma zinc and calcium concentrations significantly decreased according to age. The prevalence of zinc deficiency was therefore shown to increase in old age (over 60% of elderly subjects were deficient or at risk of deficiency). No age-related changes were obtained for copper or magnesium status. The Δ6 desaturase, involved in the EFAs conversion, was shown to decrease according to age and to be associated with the plasma zinc level. Since elderly subjects were at risk of nutritional imbalance, it would be interesting to set optimal dietary proportion. This will help to prevent age-associated alterations and diseases for a better and healthy ageing.     

Incremental value of live/real time three-dimensional transesophageal echocardiography over the two-dimensional technique in the assessment of aortic aneurysm and dissection

We compared findings from intraoperative live/real time three-dimensional transesophageal echocardiography (3DTEE) and two-dimensional transesophageal echocardiography (2DTEE) with surgery in 67 patients having aortic aneurysm and/or aortic dissection. Of these, 20 patients had aortic aneurysm without dissection, 21 aortic aneurysm and dissection, and 26 aortic dissection without aneurysm. 3DTEE diagnosed the type and location of aneurysm correctly in all patients unlike 2DTEE, which missed an aneurysm in one case. There were four cases of aortic aneurysm rupture. Three of them were diagnosed by 3DTEE but only one by 2DTEE, and one missed by both techniques. The mouth of saccular aneurysm, site of aortic aneurysm rupture, and communication sites between perfusing and nonperfusing lumens of aortic dissection could be viewed en face only with 3DTEE, enabling comprehensive measurements of their area and dimensions as well as increasing the confidence level of their diagnosis. In all patients with aortic dissection, 3DTEE enabled a more confident diagnosis of dissection because the dissection flap when viewed en face presented as a sheet of tissue rather than a linear echo seen on 2DTEE which can be confused with an artifact. 2DTEE missed dissection in one patient. In six cases the dissection flap involved the right coronary artery orifice by 3DTEE and surgery. These were missed by 2DTEE. Aortic regurgitation severity was more comprehensively assessed by 3DTEE than 2DTEE. Aneurysm size by 3DTEE correlated well with 2DTEE and surgery/computed tomography scan. In conclusion, 3DTEE provides incremental information over 2DTEE in patients with aortic aneurysm and dissection.     

Melatonin attenuates hypochlorous acid-mediated heme destruction, free iron release, and protein aggregation in hemoglobin

Abstract: In inflammatory diseases, where hypochlorous acid (HOCl) is elevated, iron homeostasis is disturbed, resulting in accumulation of free iron. Free iron is toxic by virtue of its ability to generate free radicals through the Fenton reaction. HOCl is generated by myeloperoxidase, (MPO) using chloride and hydrogen peroxide as substrates. Recent studies demonstrate that HOCl binds to the heme moiety of hemoglobin (Hb), which generates a transient ferric species whose formation and decay kinetics indicate it participates in protein aggregation, heme destruction, and free iron release. Here, we show that melatonin prevents HOCl‐mediated Hb heme destruction and protein aggregation, using a combination of UV‐vis spectrophotometry, ferrozine colorimetric assay, and in‐gel heme staining. We also show that melatonin treatment prevents HOCl‐mediated loss of red blood cell (RBC) viability, indicating biologic relevance of this finding. The mechanism by which melatonin prevents HOCl‐mediated Hb heme destruction is by direct scavenging of HOCl and/or through the destabilization of the higher Hb oxidative states intermediates, ferryl porphyrin radical cation Hb‐Fe(IV)=O^+π? and Hb‐Fe(IV)=O, which are formed through the reaction of HOCl with Hb. Our work establishes a direct mechanistic link between melatonin and its protective effect in chronic inflammatory diseases. Collectively, in addition to acting as an antioxidant and as a MPO inhibitor, melatonin can also exert its protective effect by inhibiting HOCl‐mediated heme destruction of hemoproteins and subsequent free iron release.