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.

Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with ß-thalassemia.

ß-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with ß-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non-transfusion dependent (mean hemoglobin, <10.0 g/dL; <4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent (≥4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for ≥5 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 consecutive days (without RBC transfusions) for non-transfusion-dependent patients or RBC transfusion burden reduction ≥20% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non-transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase ≥1.5 g/dL over ≥14 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved ≥20% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cutoff, 33 patients remain on study. In this study, a high percentage of ß-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. These findings support a randomized clinical trial to assess efficacy and safety. This study was registered at www.clinicaltrials.gov as #NCT01749540 and #NCT02268409.

Pseudoxanthoma Elasticum-Like in ß-Thalassemia Major, a matter of α-Klotho and Parathyroid Hormone?

Pseudoxanthoma elasticum-like (PXL) condition is one of the complications faced by patients with ß-thalassemia major (ß-TM). Histopathological features include abnormal, mineralized and fragmented elastic fibers in skin, eyes and arterial blood vessels (elastorrhexia). The pathogenesis of PXL lesions in ß-TM is not yet completely understood. This study was aimed at analyzing a possible implication of α-Klotho in the clinical manifestation of PXL in patients with ß-TM (30 with and 78 without PXL). A significant correlation was observed between Klotho, parathyroid hormone (PTH) and serum calcium (Ca). Our analysis seems to indicate α-Klotho and PTH as factors that can affect the development of PXL.

Klotho, a new marker for osteoporosis and muscle strength in ß-thalassemia major.

Aim of this study was to compare plasma levels of the secreted protein Klotho in ß-thalassemia major patients and in healthy controls. Also, we examined the existence of correlations between the protein level and osteoporosis, poor muscle strength and fractures. A total of 106 patients with ß-thalassemia major and 95 healthy blood donors were enrolled. Klotho level in plasma was measured by mean of an ELISA test and the hand-grip strength using a dynamometer. Intact parathyroid hormone (PTH), 25-hydroxy vitamin D (Vitamin D), serum calcium (Ca), phosphate (P), total alkaline phosphatase (ALP), ferritin, creatinine were measured by standard clinical techniques. DXA was used to measure bone mineral density (BMD) at the lumbar spine (L2-L4), femoral neck and total hip. We found that the Klotho protein concentration was lower in the blood of patients with ß-thalassemia major than in healthy controls, and it was directly correlated to the hand-grip strength. In ß-thalassemia major patients, the secreted Klotho was lower than in healthy controls. The preliminary investigation into the correlation between markers of osteo- and sarcopenia and Klotho demonstrated a decreased Klotho concentration in ß-TM patients and a higher probability of having had fragility fractures.

Myocardial iron overload in thalassaemia major. How early to check?

The age at which it is necessary to start Cardiovascular Magnetic Resonance (CMR) T2* screening in thalassaemia major (TM) is still uncertain. To clarify this point, we evaluated the prevalence of myocardial iron overload (MIO), function and fibrosis by CMR in TM patients younger than 10 years. We retrospectively selected 35 TM patients enrolled in the Myocardial Iron Overload in Thalassaemia network. MIO was measured by T2* multislice multiecho technique. Biventricular function parameters were evaluated by cine images. To detect myocardial fibrosis, late gadolinium enhancement images were acquired. Patients' age ranged from 4·2 to 9·7 years. All scans were performed without sedation. Nine patients showed no MIO, 22 patients had heterogeneous MIO with a T2* global value ≥20 ms; two patients had heterogeneous MIO with a T2* global value <20 ms and two patients showed homogeneous MIO. No patient showed myocardial fibrosis. Among the patients with heart T2*<20 ms, the youngest was 6 years old, none showed heart dysfunction and the iron transfused was <35 g in all cases. Cardiac iron loading can occur much earlier than previously described. The first cardiac T2* assessment should be performed as early as feasible without sedation, especially if chelation is started late or if poor compliance is suspected.

Hepatocellular carcinoma in thalassaemia: an update of the Italian Registry.

The risk of developing hepatocellular carcinoma (HCC) in patients with thalassaemia is increased by transfusion-transmitted infections and haemosiderosis. All Italian Thalassaemia Centres use an ad hoc form to report all diagnoses of HCC to the Italian Registry. Since our last report, in 2002, up to December 2012, 62 new cases were identified, 52% of whom were affected by thalassaemia major (TM) and 45% by thalassaemia intermedia (TI). Two had sickle-thalassaemia (ST). The incidence of the tumour is increasing, possibly because of the longer survival of patients and consequent longer exposure to the noxious effects of the hepatotropic viruses and iron. Three patients were hepatitis B surface antigen-positive, 36 patients showed evidence of past infection with hepatitis B virus (HBV). Fifty-four patients had antibodies against hepatitis C virus (HCV), 43 of whom were HCV RNA positive. Only 4 had no evidence of exposure either to HCV or HBV. The mean liver iron concentration was 8 mg/g dry weight. Therapy included chemoembolization, thermoablation with radiofrequency and surgical excision. Three patients underwent liver transplant, 21 received palliative therapy. As of December 2012, 41 patients had died. The average survival time from HCC detection to death was 11·5 months (1·4-107·2 months). Ultrasonography is recommended every 6 months to enable early diagnosis of HCC, which is crucial to decrease mortality.

Characterization of Hb Calvino (HBB: c.406G > A): a new silent ß-globin gene variant found in coexistence with α-thalassemia in a family of African origin.

We report a new silent ß-globin gene variant found in a family from Angola living in the north eastern Italian city of Ferrara. The probands, two young sisters, presented with hematological parameters compatible with a ß-thalassemia (ß-thal) minor but with normal Hb A2 levels and normal hemoglobin (Hb) separation on high performance liquid chromatography (HPLC). Molecular analyses revealed a homozygosity for the common -α(3.7) (rightward) deletion and heterozygosity for a novel transition (GCT > ACT) at codon 135 of the ß-globin gene, leading to an Ala → Thr single amino acid substitution that was inherited from the healthy father.

Mosaic segmental uniparental isodisomy and progressive clonal selection: a common mechanism of late onset ß-thalassemia major.

Genomic DNA of 3 patients, born as healthy carriers and developing a late-onset severe transfusion-dependent beta-thalassemia major was studied by high-density genome wide SNP array analysis. A mosaic loss of heterozygosity for almost the entire 11p was found, not attributable to deletions but involving mosaicism for segmental paternal isodisomy of 11p. Mitotic recombination leading to mosaic segmental uniparental isodisomy on chromosome 11p in multiple tissues has been described as a molecular disease mechanism for a subset of sporadic Beckwith-Wiedemann syndrome cases. A similar mechanism also seems to be involved in causing late-onset disease in carriers of recessive mutations in other genes located in 11p, such as late-onset beta-thalassemia major and sickle cell disease. We suggest that the loss of maternally imprinted IGF-2 and H19 genes may account for the selective advantage of hematopoietic cells containing this segmental paternal isodisomy of 11p carrying the ß-thalassemia mutation.

Neridronate improves bone mineral density and reduces back pain in ß-thalassaemia patients with osteoporosis: results from a phase 2, randomized, parallel-arm, open-label study.

Neridronate is a third generation bisphosphonate with established efficacy in metabolic bone disease. In this randomized, open-label study, 118 adults with ß-thalassaemia and bone mineral density (BMD) Z scores ≤-2·0 were randomized 1:1-500 mg calcium with 400 international unis (iu) vitamin D daily or 500 mg calcium with 400 iu vitamin D daily plus neridronate 100 mg intravenously every 90 d. Significant increases in BMD at the lumbar spine and total hip were noted in the neridronate group at 6 and 12 months from baseline (P < 0·001), and values were significantly higher than the control group at both time intervals. Neridronate also significantly decreased serum bone alkaline phosphatase and C-telopeptide of collagen type 1 levels from as early as 3 months (P = 0·04 and P < 0·001, respectively), reaching significantly lower values at 12 months compared with the control group (P < 0·05). Reductions in back pain and analgesic use were also evident, starting 3 months from commencing treatment. Treatment was well tolerated by all patients. In this largest randomized trial in thalassaemia-induced osteoporosis to date, neridronate was safe and effective in reducing bone resorption and increasing BMD. The associated reduction in back pain and improved quality of life will encourage adherence to therapy. (Clinicaltrials.gov identifier NCT01140321.).

Management of chronic viral hepatitis in patients with thalassemia: recommendations from an international panel.

Chelation therapy with new drugs prevents cardiac damage and improves the survival of thalassemia patients. Liver diseases have emerged as a critical clinical issue. Chronic liver diseases play an important role in the prognosis of thalassemia patients because of the high frequency of viral infections and important role of the liver in regulating iron metabolism. Accurate assessment of liver iron overload is required to tailor iron chelation therapy. The diagnosis of hepatitis B virus- or hepatitis C virus-related chronic hepatitis is required to detect patients who have a high risk of developing liver complications and who may benefit by antiviral therapy. Moreover, clinical management of chronic liver disease in thalassemia patients is a team management issue requiring a multidisciplinary approach. The purposes of this paper are to summarize the knowledge on the epidemiology and the risks of transmission of viral infections, to analyze invasive and noninvasive methods for the diagnosis of chronic liver disease, to report the knowledge on clinical course of chronic viral hepatitis, and to suggest the management of antiviral therapy in thalassemia patients with chronic hepatitis B or C virus or cirrhosis.

Factors affecting yawning frequencies in preterm neonates.

Yawning is a long neglected behavioral pattern, but it has recently gained an increasing interdisciplinary attention for its theoretical implications as well as for its potential use as a clinical marker, with particular regard to perinatal neurobehavioral assessment. The present study investigated the factors affecting yawning frequencies in hospitalized preterm neonates (N = 58), in order to distinguish the effects of hunger and sleep-related modulations and to examine the possible impact of demographic and clinical variables on yawning frequencies. Results showed that preterm neonates yawned more often before than after feeding, and this modulation was not explained by the amount of time spent in quiet sleep in the two conditions. Moreover, second born twins, known to be more prone to neonatal mortality and morbidity, showed increased yawning rates compared to first born twins. Overall, our results are consistent with the hypothesis that yawning frequencies in preterm neonates are modulated by separate mechanisms, related e.g. to hunger, vigilance and stress. These findings, although preliminary and based only on behavioral data, might indicate that several distinct neuropharmacological pathways that have been found to be involved in yawn modulation in adults are already observable in preterm neonates.

Cardiac iron and cardiac disease in males and females with transfusion-dependent thalassemia major: a T2* magnetic resonance imaging study.

BACKGROUND: It has been repeatedly reported that female patients with thalassemia major survive longer than males and that the difference is due to a lower rate of cardiac disease in females. DESIGN AND METHODS: We compared the cardiac iron load as measured by T2* magnetic resonance imaging in 776 patients (370 males) examined at the National Research Council as part of an Italian cooperative study. We also established normal left ventricular ejection fraction values for our population. RESULTS: The prevalence of cardiac disease was higher in males than in females (105 males versus 69 females; P < 0.0001). Cardiac T2* was significantly lower in patients with heart dysfunction (P < 0.0001), but no difference was observed according to sex. Twenty males and five females had a history of cardiac arrhythmias. Their cardiac T2* was not significantly lower than that of patients without arrhythmias (24 ms versus 26 ms; P = 0.381), nor was there a difference between sexes. Liver T2* was significantly lower in males and females with heart dysfunction compared to those without. Ferritin levels were higher in patients of both sexes with heart dysfunction without significant differences between males and females. Conclusions Males and females are at the same risk of accumulating iron in their hearts, but females tolerate iron toxicity better, possibly as an effect of reduced sensitivity to chronic oxidative stress.

Thiamine-responsive megaloblastic anemia syndrome: long term follow-up.

Thiamine-responsive megaloblastic anemia is a rare autosomal recessive disorder whose main symptoms are anemia, diabetes mellitus, and sensorineural deafness. We describe a 20-year follow-up of 2 previously reported patients and of 1 patient diagnosed before onset of symptoms and treated with thiamine since the first sign of disease.

Epidemiology of rotavirus-associated hospital admissions in the province of Ferrara, Italy.

OVERVIEW: Hospital discharge forms with specific codes for rotavirus gastroenteritis in children 0 to 14 years of age were reviewed in the period 2003-2005 in the province of Ferrara. RESULTS: A total of 4,238 children were admitted to the pediatric departments; 151 patients were diagnosed with rotavirus gastroenteritis. The average annual rate of hospitalization for rotavirus gastroenteritis was 1.54/1,000 children <14 years of age and 2.9/1,000 children <5 years of age. Most hospitalizations (72%) involved children aged <60 months. The average length of hospital stay was about 5 days. Considering the Emilia Romagna regional reimbursement codes referable to rotavirus disease, the estimated costs of our 151 cases range from 214,033 euros to 341,832 euros. CONCLUSIONS: The results of this study contribute to the awareness of rotavirus epidemiology in Italy and underline the potential impact of rotavirus vaccination in our province.

Pseudoxanthoma-elasticum-like syndrome and thalassemia: an update.

Pseudoxanthoma Elasticum (PXE) is an autosomal recessive, multisystem disorder affecting connective tissues. We describe three cases of the acquired PXE-like syndrome that often occurs in association with hemolytic anemias, in particular the hemoglobinopathies, and review the literature on the subject. The pathogenesis of the acquired PXE-like lesions is not yet completely understood. None of the mutations observed in the inherited form has been detected in the syndrome accompanying thalassemia. The cardiovascular complications could be life-threatening. Therefore, an close surveillance of these patients is mandatory.

Extreme thrombocytosis in systemic juvenile idiopathic arthritis. A case report.

BACKGROUND: Systemic onset juvenile idiopathic arthritis (SoJIA) is a rare inflammatory disorder characterized by remitting fevers, evanescent rash, generalized lymphadenopathy, hepatomegaly/splenomegaly, and/or serositis. CASE PRESENTATION: Here we report the case of a 5 years-old girl with SoJIA complicated by severe thrombocytosis. Treatment with the Interleukin-1ß (IL-1ß) receptor antagonist Anakinra caused a fast reduction of blood platelets and of the associated systemic inflammatory response. Measurement of IL-1ß, IL-6 and Tpo plasma levels at different time points confirmed the etiopathogenetic role of IL-1ß in causing the thrombocytosis, while Tpo did not appear to be involved and this explains the excellent response to treatment with Anakinra. CONCLUSION: The excellent response to treatment with the IL-1ß receptor antagonist, suggests a key pathogenic role of IL-1ß in thrombocytosis as well as in the associated systemic symptoms of inflammation.

Multifocal Skin Tuberculosis: Report of A Case.

Tuberculosis (TB) is a severe problem in underdeveloped countries. Cutaneous TB is rare and often goes unrecognized. We report a Pakistani child with multifocal cutaneous and pulmonary TB. Microbiologic diagnosis was obtained when the abscesses were biopsied. Four-drug therapy produced rapid improvement of the lesions. A high level of suspicion must be maintained when evaluating children from countries at risk.

Assessment of Lactose-Free Diet on the Phalangeal Bone Mineral Status in Italian Adolescents Affected by Adult-Type Hypolactasia.

Adult-type hypolactasia (ATH) is a clinical syndrome of primary lactase deficiency. A lactose-free diet is advisable to avoid the symptoms linked to the condition, but this potentially creates problems for optimal bone mineralization due to reduced calcium intake. To evaluate the effect of the lactose-free diet on the bone mineral status (BMS), we compared the phalangeal BMS of adolescents with ATH to that of peers on a normal diet. Also, we analyzed the correlations between BMS and dietary behavior, physical exercise, and calcium and vitamin D intake. A total of 102 cases and 102 healthy controls filled out a diet record and underwent phalangeal Quantitative Ultrasound (QUS). No difference in BMS was observed. The time spent on lactose-free diet (4.8 ± 3.1 years) was inversely correlated to the BMS. More than 98% of cases consumed lactose-free milk, but calcium and vitamin D intake were significantly lower. Calcium intake was correlated to physical exercise but not to BMS. Our results suggest that a lactose-free diet does not affect the phalangeal BMS of adolescents with primary lactase deficiency when their diet includes lactose-free cow’s milk. However, there is still a significantly lower calcium intake than in the population reference. The inverse correlation observed between the BMS and the time spent on a lactose-free diet suggests that a long-term follow-up is advisable.

Burden of hospitalizations due to Rotavirus infection in Emilia Romagna, Italy.

The aim of this study was to collect data on hospitalizations due to gastrointestinal diseases, in particular Rotavirus gastroenteritis (RVGE), in the Region of Emilia Romagna, Italy. The national hospital discharge database was used to evaluate the epidemiology of RV infections in the 2000-2003 period, analyzing only the principal diagnosis. The available age groups were 0-14 years, 15-64 years and, >64 years. Hospitalization related costs were estimated through Diagnosis Related Group (DRG) rates even though a specific DRG for RVGE does not exist. In the 0-14yr. old subjects, RV were responsible for an average of 310 GE-related hospitalizations per year and globally represented 17% of admissions for enteritis and 84% of hospitalized viral GE. Fifty-six percent of the enteritis was of undefined origin. Considering the three possible DRG codes to which the disease can be referred (184, 298, 422) and the classification of hospitals in two categories, the cost of each admission for RVGE ranged between 1,293.83 Euro and 2,263.79 Euro. RV seems to play an important role as a cause of severe viral gastroenteritis, although RV infections are certainly underestimated for several reasons, one of them being the low sensitivity of hospital discharge forms. Today we have safe and effective vaccines that can be used in order to protect from moderate/severe forms of RV-related diarrhea. The extensive use of these vaccines could reduce hospitalizations and related costs in industrialized countries.