Laura Zanaboni

Growth hormone deficiency (GHD) in adult thalassaemic patients

Background and objectiveu2002 Short stature and growth hormone deficiency (GHD) are frequent occurrences in thalassaemic children, while data on the prevalence of GHD in adult patients are lacking. Therefore, we elected to study the growth hormone and insulin‐like growth factor‐I (GH–IGF‐I) axis in a large group of adult thalassaemic subjects.

Cardiac iron removal and functional cardiac improvement by different iron chelation regimens in thalassemia major patients

Heart failure due to myocardial iron overload remains the leading cause of morbidity and mortality in adult thalassemia major (TM) patients. We evaluated the removal of cardiac iron and the changes of cardiac function by different iron chelation in TM patients by T2* cardiac magnetic resonance (CMR). Sixty-seven TM patients (27 males/40 females; mean age, 35u2009±u20096xa0years) on different chelation regimens underwent T2* CMR at baseline (t0), after 6–14xa0months (t1) and after 32u2009±u20097xa0months (t2). Patients were divided in four groups according to chelation treatment: group A (deferasirox), group B (deferoxamine), group C (combined treatment, deferoxamine plus deferiprone) and group D (deferiprone alone). Myocardial T2* at t0 was <10xa0ms in 8 patients, between 10 and 20xa0ms in 22 patients and ≥20xa0ms in 37 patients. Progressive changes in T2* were observed at t1 and t2. Ten patients (10/36, 27.8xa0%) in group A, three patients (3/15, 20xa0%) in group B and three patients (3/12, 25xa0%) in group C moved from an abnormal T2* to normal values. We observed an improvement of left ventricular ejection fraction and a reduction of end-systolic and end-diastolic left ventricular volumes only in patients in group A with baseline cardiac T2* between 10 and 20xa0ms. Rigorous compliance to any chelation therapy at proper doses significantly improve myocardial T2*. Treatment with deferasirox significantly improves left ventricular function. Combination therapy seems to ameliorate cardiac T2* in a shorter period of time in severe siderosis.

Combination of deferasirox and deferoxamine in clinical practice: An alternative scheme of chelation in thalassemia major patients

The availability of three iron chelators improved the scenario of chelation therapy for transfusion-dependent thalassemia (TDT) patients, allowing tailoring of drugs according to the goals expected for each patient. The use of Deferiprone/Deferoxamine (DFP/DFO) combined in different schemes has been reported since many years. Only recently data from combination of Deferasirox/Deferoxamine (DFX/DFO) have been reported showing that it can be safe and efficacious to remove iron overload, particularly in patients who do not respond adequately to a single chelating agent. We investigated the efficacy, tolerability and safety of combined DFX/DFO in thalassemia major patients. Ten TDT patients have started DFX/DFO for different reasons: 1) lack of efficacy in removing liver/cardiac iron with monotherapy; 2) agranulocytosis on DFP; and 3) adverse events with elevated doses of monotherapies. The study design included: cardiac and hepatic T2* magnetic resonance (CMR), transient elastography evaluation (Fibroscan), biochemical evaluation, and audiometric and ocular examinations. The drugs starting doses were: DFO 32 ± 4 mg/kg/day for 3-4 days a week and DFX 20 ± 2 mg/kg/day. Seven patients completed the one-year follow-up period. At baseline the mean pre-transfusional Hb level was 9.4 ± 0.4 g/dl, the mean iron intake was 0.40 ± 0.10mg/kg/day, the median ferritin level was 2254 ng/ml (range 644-17,681 ng/ml). Data available at 1 year showed no alteration of renal/hepatic function and no adverse events. A marked reduction in LIC (6.54 vs 11.44 mg/g dw at baseline) and in median ferritin (1346 vs 2254 ng/ml at baseline) was achieved. A concomitant reduction of non-transferrin-bound iron (NTBI) at six months was observed (2.1 ± 1.0 vs 1.7 ± 1.2 μM). An improvement in cardiac T2* values was detected (26.34 ± 15.85 vs 19.85 ± 12.06 at baseline). At 1 year an increased dose of DFX was administered (27 ± 6 mg/kg/day vs 20 ± 2 mg/kg/day at baseline, p=0.01) with a stable dose of DFO (32 ± 4 mg/kg/day). Combined or alternated DFX/DFO can be considered when monotherapy is not able to remove the iron overload or in the presence of adverse events.

A 5-year follow-up in deferasirox treatment: improvement of cardiac and hepatic iron overload and amelioration in cardiac function in thalassemia major patients

Deferasirox (DFX) is an oral iron chelator with established efficacy and safety. We evaluated by T2* cardiovascular magnetic resonance (CMR) the efficacy of DFX in preventing and removing cardiac and liver iron load and cardiac volume changes, along 5xa0years in adult thalassemia major (TM) patients. Twenty-three TM patients (9 males/14 women, mean age 36u2009±u20094xa0years) were included in this study. Repeated CMR was performed to assess myocardial and liver iron loadxa0(baseline t0, after 2.5 years t1, after 5 years t2). Myocardial T2* values changed progressively and increased significantly between t0 and t2 (t0: 27.15u2009±u20099.58 vs t2: 36.64u2009±u20096.68, pu2009=u20090.0001). At baseline evaluation, a cardiac T2* value <20xa0ms was detected in six patients (26xa0%): they showed an improvement of cardiac T2* values between t0 and t1, with normal T2* levels reached in all patients at t2. In the overall population, a significant reduction of both end-diastolic and end-systolic left ventricular volumes (EDV, ESV) were detected between t0 and t2 (EDV, t0: 132u2009±u200931xa0ml vs t2: 124u2009±u200922xa0ml, pu2009=u20090.033; ESV, t0: 48u2009±u200914xa0ml vs t2: 41u2009±u200910xa0ml, pu2009=u20090.0007). A significant reduction in liver iron concentration (LIC) was detected at t1 (5.36u2009±u20093.58xa0mg/g dw at baseline vs 3.35u2009±u20092.68xa0mg/g dw at t1, pu2009=u20090.004). In patients with cardiac iron overload at baseline (n.6), mean cardiac T2* values doubled at t2, and mean LIC value is reduced of 29xa0%. After 5xa0years of treatment, DFX continually and significantly reduced myocardial and liver iron overload, and it prevented further iron deposition.

Plerixafor and G-CSF combination mobilizes hematopoietic stem and progenitors cells with a distinct transcriptional profile and a reduced in vivo homing capacity compared to plerixafor alone

For decades, bone marrow (BM) has been the preferred source of hematopoietic stem and progenitor cells (HSPCs) for transplants following myeloablative conditioning. At present, mobilized peripheral blood stem cells are commonly used for transplantation, particularly in the autologous setting.[1][1

Increase in lipolysis and decrease in plasma-heparin lipoprotein lipase activity and alpha1lipoprotein level after aminophylline in man

SummaryIntravenous aminophylline 0.48 g produced a sharp increase in plasma free fatty acids. After three days of treatment with aminophylline 0.96 g/day i. v., plasma post-heparin lipoprotein lipase was significantly reduced, and post-heparin hepatic triglyceridase remained unchanged. Alpha1lipoprotein was reduced by treatment, in parallel with lipoprotein lipase, while other lipoprotein fractions, serum cholesterol and triglycerides were unaffected.

Serum lipoproteins in diabetes: Relation of alpha-lipoprotein level to therapy

SummaryThree hundred and sixty diabetic patients (125 on insulin, 109 on sulfonylureas and 126 on diet alone) were selected to investigate the effect of the type of treatment and of the degree of metabolic control on serum lipoproteins. Prebeta-lipoprotein concentration was higher than normal in all treatment groups. Beta-lipoproteins were significantly higher in diabetic women than in controls. No difference in beta- and prebeta-lipoprotein concentration existed between the 3 treatment groups. Alpha-lipoproteins were significantly higher in insulin-treated than in diet-treated patients irrespective of the degree of metabolic control. The daily dose of insulin and, in patients on diet or sulfonylureas, serum IRI were positively correlated to alpha-lipoprotein concentration while this lipoprotein fraction was not significantly correlated to fasting blood sugar. Alpha-lipoprotein concentration, then, appears to be markedly influenced by exogenous and endogenous insulin, independently of the degree of metabolic control.

Bone turnover and mineral density in adult thalassemic patients: relationships with growth hormone secretory status and circulating somatomedins

Abstract Previous evidence supports a role for growth hormone (GH)–insulin-like growth factor (IGF)-I deficiency in the pathophysiology of osteopenia/osteoporosis in adult thalassemia. Moreover, serum IGF-II has never been studied in this clinical condition. Thus, we elected to study the GH secretory status and the levels of circulating somatomedins, correlating these parameters with bone mineral density (BMD) and biochemical markers of bone turnover. A hundred and thirty-nine normal weight adult thalassemic patients (72 men and 67 women) were studied. Lumbar and femoral neck BMD were measured in 106/139 patients. Sixty-eight patients underwent growth hormone releasing hormone plus arginine testing. Measurement of baseline IGF-I and IGF-II was performed in all patients, while osteocalcin, C-terminal telopeptide of type I collagen (CTx), and urinary cross-linked N-telopeptides of type I collagen (NTx) were assayed in 95 of them. Femoral and lumbar osteoporosis/Z score below the expected range for age were documented in 61.3 and in 56.6xa0% of patients, respectively. Severe GH deficiency (GHD) was demonstrated in 27.9xa0% of cases, whereas IGF-I SDS was low in 86.3xa0%. No thalassemic patients displayed circulating levels of IGF-II below the reference range. GH peaks were positively correlated with femoral, but not lumbar, Z score. No correlations were found between GH peaks and osteocalcin, CTx and NTx. GH peaks were positively correlated with IGF-I values, which in their turn displayed a positive correlation with osteocalcin, CTx, and NTx. No correlations emerged between IGF-I values and either femoral or lumbar Z scores. No correlations were found between IGF-II and any of the following parameters: GH peaks, osteocalcin, CTx, NTx, femoral Z score, and lumbar Z score. Our study, besides providing for the first time evidence of a normal IGF-II production in thalassemia, contributes to a better understanding of the involvement of the somatotropin-somatomedin axis in the pathophysiology of bone demineralization in this disease. In particular, the contribution of GHD to femoral osteoporosis appears to be likely mediated by locally produced rather than circulating IGF-I.

Thyroid cancer in β-thalassemia

Dear Editor, Poggi et al. (1) described two cases of thyroid cancer diagnosed in a population of more than 100 patients affected by β-thalassemia major (β-TM). The longer life expectancy produced by the modern treatment of this congenital anemia also had the effect of increasing the period of time for long-term complications to evolve. By analogy with liver disease, where an increased risk of hepatocellular carcinoma has emerged in recent years, the suspicion is now emerging of a possible carcinogenic role of the unavoidable iron overload in other tissues (2–4). Poggi et al. (1) focused on thyroid cancer, a malignancy with unknown prevalence in this population; the literature on this topic is sparse, except for the recent description of five cases of papillary carcinoma in the thalassemic patients followed at the Day Hospital for Thalassaemia and Haemoglobinopathies in Ferrara, Italy (5). In this scenario, we think that everyone’s experience warrants consideration, and we would like to present our own experience in a tertiary outpatient clinic in Milan, Italy, where about 170 patients with β-TM have been followed. We prescribed thyroid scans, once or repeatedly, for 88 of the patients on the basis of one or more of the following indications: family history of thyroid disease, detection of thyroid or lymph-node enlargement at physical examination of the neck, functional alteration (generally hypothyroidism). Nodules were found in 31 patients; 25 lesions were smaller than 1 cm in diameter at discovery, and free of features suspicious for malignancy. These

Influence of two non-steroidal anti-inflammatory drugs on lipolysis and on plasma post-heparin lipoprotein lipase activity in normal man.

SummaryIndomethacin 50 mg i.v. or p.o. and diclofenac sodium 50 mg p.o produced a prompt and significant increase in plasma free fatty acid concentration. In 10 subjects who took indomethacin 150 mg/d p.o. for 3 days, plasma post-heparin lipoprotein lipase activity was also significantly increased. The same effect occurred in 9 subjects treated for 3 days with diclofenac sodium 50 mg t.d.s. Since both indomethacin and diclofenac sodium are potent inhibitors of prostaglandin synthetase, these findings are consistent with the hypothesis that prostaglandins are involved in the feed-back regulation of lipolysis, and mediate the inhibitory effect of lipolysis on lipoprotein lipase activity.