Publications by authors named "Silverio Perrotta"

146 Publications

Targeted Next Generation Sequencing and Diagnosis of Congenital Hemolytic Anemias: A Three Years Experience Monocentric Study.

Front Physiol 2021 21;12:684569. Epub 2021 May 21.

UOS Fisiopatologia delle Anemie, UOC Ematologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Congenital hemolytic anemias (CHAs) are heterogeneous and rare disorders caused by alterations in structure, membrane transport, metabolism, or red blood cell production. The pathophysiology of these diseases, in particular the rarest, is often poorly understood, and easy-to-apply tools for diagnosis, clinical management, and patient stratification are still lacking. We report the 3-years monocentric experience with a 43 genes targeted Next Generation Sequencing (t-NGS) panel in diagnosis of CHAs; 122 patients from 105 unrelated families were investigated and the results compared with conventional laboratory pathway. Patients were divided in two groups: 1) cases diagnosed with hematologic investigations to be confirmed at molecular level, and 2) patients with unexplained anemia after extensive hematologic investigation. The overall sensitivity of t-NGS was 74 and 35% for families of groups 1 and 2, respectively. Inside this cohort of patients we identified 26 new pathogenic variants confirmed by functional evidence. The implementation of laboratory work-up with t-NGS increased the number of diagnoses in cases with unexplained anemia; cytoskeleton defects are well detected by conventional tools, deserving t-NGS to atypical cases; the diagnosis of Gardos channelopathy, some enzyme deficiencies, familial siterosterolemia, X-linked defects in females and other rare and ultra-rare diseases definitely benefits of t-NGS approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2021.684569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176228PMC
May 2021

Response to Measles, Mumps and Rubella (MMR) Vaccine in Transfusion-Dependent Patients.

Vaccines (Basel) 2021 May 27;9(6). Epub 2021 May 27.

Department of Women, Child and General and Specialized Surgery, University "Luigi Vanvitelli", 80138 Naples, Italy.

Measles, mumps and rubella (MMR) still determine significant morbidity and mortality, although a highly effective vaccine is available. Postponing the MMR vaccination until 6 months after the last red blood cell (RBC) transfusion is recommended, but this delay is incompatible with chronic transfusions. The present study aimed at investigating the impact of blood transfusions on the immunogenicity of the MMR vaccine. In this observational study, a group of 45 transfusion- dependent (TD) patients was compared to 24 non-transfusion-dependent (NTD) patients. Immunity to measles was achieved in 35 (78%) TD and 21 (88%) NTD subjects (p = 0.7), to mumps in 36 (80%) TD and 21 (88%) NTD subjects (p = 0.99), and to rubella in 40 (89%) TD and 23 (96%) NTD subjects (p = 0.99). No significant difference was observed in the number of non-immune individuals or those with doubtful protection between the two groups ( > 0.05). The mean IgG value, assayed in 50 pre-storage leukoreduced RBC units, was 0.075 ± 0.064 mg/mL, ten times lower than the level assumed in blood units and considered detrimental to the immune response in TD patients. This work shows a favorable response to MMR vaccination in TD and NTDT patients and paves the way for further larger studies assessing the impact of chronic transfusions on vaccine response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/vaccines9060561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227230PMC
May 2021

Association of Immune Thrombocytopenia and Coeliac Disease in Children (Retrospective Case Control Study).

Turk J Haematol 2021 May 18. Epub 2021 May 18.

U.O.C. Oncoematologia Pediatrica - ARNAS Civico - Di Cristina - Benfratelli, Palermo.

Objective: The association between coeliac disease (CD) and immune thrombocytopenia (ITP) is still uncertain. The aim of this study was to characterize the coexistence of these two diseases in Italian children.

Materials And Methods: This is a multicenter retrospective study investigating the occurrence of CD in 28 children with ITP diagnosed from January 1th 2000 to December 31th 2019.

Results: The first diagnosis was ITP in 57.1% and CD in 32.1% of patients. In 3 patients (10.7%) the two diagnosis were simultaneous. All the potential and silent CDs in our cohort were diagnosed in the groups of and . In all children ITP was mild and in 2 out of 8 not recovered from ITP at the time of CD diagnosis a normalization of platelet counts (> 100,000/mmc) occurred after 3 and 5 months from starting gluten free diet.

Discussion: We think that screening for celiac disease should be considered in children with ITP, regardless the presence of gastrointestinal symptoms. Furthermore some patients could recover from ITP after starting gluten-free diet.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4274/tjh.galenos.2021.2021.0128DOI Listing
May 2021

Diagnostic issues faced by a rare disease healthcare network during Covid-19 outbreak: data from the Campania Rare Disease Registry.

J Public Health (Oxf) 2021 05 13. Epub 2021 May 13.

Centro di Coordinamento Malattie Rare, Regione Campania Naples 80131, Italy.

Background: The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period.

Methods: To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period.

Results: Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P < 0.001 and 37 versus 349, P < 0.001, respectively) and 2018 (117 versus 389, P < 0.001 and 37 versus 282, P < 0.001, respectively). Eighty-two among 98 rare disease experts completed the questionnaire. Diagnostic success (95%), access to diagnosis (80%) and follow-up (72%), lack of Personal Protective Equipment (60%), lack of Covid-19 guidelines (50%) and the need for home therapy (78%) were the most important issues raised during Covid-19 outbreak.

Conclusions: This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/pubmed/fdab137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194710PMC
May 2021

The interactome of the N-terminus of band 3 regulates red blood cell metabolism and storage quality.

Haematologica 2021 May 13. Epub 2021 May 13.

Department of Biochemistry and Molecular Genetics, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO.

Band 3 (anion exchanger 1 - AE1) is the most abundant membrane protein in red blood cells (RBCs), the most abundant cell in the human body. A compelling model posits that - at high oxygen saturation - the N-term cytosolic domain of AE1 binds to and inhibits glycolytic enzymes, thus diverting metabolic fluxes to the pentose phosphate pathway to generate reducing equivalents. Dysfunction of this mechanism occurs during RBC aging or storage under blood bank conditions, suggesting a role for AE1 in the regulation of blood storage quality and efficacy of transfusion - a life-saving intervention for millions of recipients worldwide. Here we leverage two murine models carrying genetic ablations of AE1 to provide mechanistic evidence of its role in the regulation of erythrocyte metabolism and storage quality. Metabolic observations in mice recapitulated those in a human subject lacking expression of AE11-11 (band 3 Neapolis), while common polymorphisms in the region coding for AE11-56 correlate with increased susceptibility to osmotic hemolysis in healthy blood donors. Through thermal proteome profiling and cross-linking proteomics, we provide a map of the RBC interactome, with a focus on AE11-56 and validate recombinant AE1 interactions with glyceraldehyde 3-phosphate dehydrogenase (GAPDH). As a proof-of-principle and further mechanistic evidence of the role of AE1 in the regulation of redox homeostasis of stored RBCs, we show that incubation with a cell-penetrating AE11-56 peptide can rescue the metabolic defect in glutathione recycling and boost post-transfusion recoveries of stored RBCs from healthy human donors and genetically ablated mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2020.278252DOI Listing
May 2021

A novel MEIS2 mutation explains the complex phenotype in a boy with a typical NF1 microdeletion syndrome.

Eur J Med Genet 2021 May 17;64(5):104190. Epub 2021 Mar 17.

Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy. Electronic address:

Concurrence of distinct genetic conditions in the same patient is not rare. Several cases involving neurofibromatosis type 1 (NF1) have recently been reported, indicating the need for more extensive molecular analysis when phenotypic features cannot be explained by a single gene mutation. Here, we describe the clinical presentation of a boy with a typical NF1 microdeletion syndrome complicated by cleft palate and other dysmorphic features, hypoplasia of corpus callosum, and partial bicoronal craniosynostosis caused by a novel 2bp deletion in exon 2 of Meis homeobox 2 gene (MEIS2) inherited from the mildly affected father. This is only the second case of an inherited MEIS2 intragenic mutation reported to date. MEIS2 is known to be associated with cleft palate, intellectual disability, heart defects, and dysmorphic features. Our clinical report suggests that this gene may also have a role in cranial morphogenesis in humans, as previously observed in animal models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2021.104190DOI Listing
May 2021

Evaluation of Browning Agents on the White Adipogenesis of Bone Marrow Mesenchymal Stromal Cells: A Contribution to Fighting Obesity.

Cells 2021 Feb 16;10(2). Epub 2021 Feb 16.

Department of Experimental Medicine, Biotechnology and Molecular Biology Section, School of Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy.

Brown-like adipocytes can be induced in white fat depots by a different environmental or drug stimuli, known as "browning" or "beiging". These brite adipocytes express thermogenin UCP1 protein and show different metabolic advantages, such as the ability to acquire a thermogenic phenotype corresponding to standard brown adipocytes that counteracts obesity. In this research, we evaluated the effects of several browning agents during white adipocyte differentiation of bone marrow-derived mesenchymal stromal cells (MSCs). Our in vitro findings identified two compounds that may warrant further in vivo investigation as possible anti-obesity drugs. We found that rosiglitazone and sildenafil are the most promising drug candidates for a browning treatment of obesity. These drugs are already available on the market for treating diabetes and erectile dysfunction, respectively. Thus, their off-label use may be contemplated, but it must be emphasized that some severe side effects are associated with use of these drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10020403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919793PMC
February 2021

Non-transfusion-dependent thalassemia in Italy: less blues, no role of reds.

Ann Hematol 2021 Feb 4. Epub 2021 Feb 4.

Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Università degli Studi della Campania "Luigi Vanvitelli", Via Luigi de Crecchio 4, 80138, Naples, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-021-04444-9DOI Listing
February 2021

Acute kidney injury in children hospitalized for acute gastroenteritis: prevalence and risk factors.

Pediatr Nephrol 2021 Jun 7;36(6):1627-1635. Epub 2021 Jan 7.

Department of Pediatrics, AORN Sant'Anna e San Sebastiano, via Ferdinando Palasciano, 81100, Caserta, Italy.

Background: We aimed to evaluate prevalence of acute kidney injury (AKI) and its risk factors in children hospitalized for acute gastroenteritis (AGE) to identify early predictors of AKI.

Methods: We retrospectively collected clinical and biochemical data of 114 children (57.9% male; mean age 2.9 ± 2.8 years) hospitalized for AGE. AKI was defined according to Kidney Disease/Improving Global Outcomes creatinine criteria. We considered basal serum creatinine as value of creatinine estimated with Hoste (age) equation assuming basal eGFRs were median age-based eGFR normative values for children ≤ 2 years of age, and eGFR 120 mL/min/1.73m for children > 2 years. Univariate and multivariate logistic regression models were used to explore associations with AKI. We included in multivariate analyses only variables with significant p after Bonferroni correction.

Results: AKI was found in 28/114 (24.6%) patients. No patients required hemodialysis, 2 (1.8%) reached AKI stage 3, 2 (1.8%) AKI stage 2, and 24 (21.0%) AKI stage 1. Mean length of stay was 3.6 ± 1.2, 5.0 ± 1.8, and 10.5 ± 5.8 days, for patients with no, mild, and severe AKI (p < 0.001), respectively. Duration of symptoms before hospitalization (OR = 2.5; 95% CI = 1.3-5.0; p = 0.006), dehydration > 5% (OR = 43.1; 95% CI = 5.4-344.1; p = < 0.001), and serum bicarbonate levels (OR = 1.6; 95% CI = 1.2-2.1; p = 0.001) were independent predictors of AKI.

Conclusions: About one quarter of patients hospitalized for AGE may suffer from AKI with a longer stay for patients with more severe AKI. Particular attention, however, should be paid to volemia and kidney health of patients with AGE especially in the presence of increased duration of symptoms before hospitalization, dehydration, and lower serum bicarbonate levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00467-020-04834-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084840PMC
June 2021

Risk factors for endocrine complications in transfusion-dependent thalassemia patients on chelation therapy with deferasirox: a risk assessment study from a multicentre nation-wide cohort.

Haematologica 2021 Jan 7. Epub 2021 Jan 7.

Department of Women, Child and General and Specialized Surgery, University " Luigi Vanvitelli", via Luigi De Crecchio n. 4, 80138, Naples.

Transfusion-dependent patients typically develop iron-induced cardiomyopathy, liver disease, and endocrine complications. We aimed to estimate the incidence of endocrine disorders in transfusion-dependent thalassemia (TDT) patients during long-term iron-chelation therapy with deferasirox (DFX).We developed a multicentre follow-up study of 426 TDT patients treated with once-daily DFX for a median duration of 8 years, up to 18.5 years. At baseline, 118, 121, and 187 patients had 0, 1, or ≥2 endocrine diseases respectively. 104 additional endocrine diseases were developed during the follow-up. The overall risk of developing a new endocrine complication within 5 years was 9.7% (95%CI=6.3-13.1). Multiple Cox regression analysis identified 3 key predictors: age showed a positive log-linear effect (adjusted HR for 50% increase=1.2, 95%CI=1.1-1.3, P=0.005), the serum concentration of thyrotropin (TSH) showed a positive linear effect (adjusted HR for 1 mIU/L increase=1.3, 95%CI=1.1-1.4, P.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2020.272419DOI Listing
January 2021

Age of first pain crisis and associated complications in the CASiRe international sickle cell disease cohort.

Blood Cells Mol Dis 2021 05 2;88:102531. Epub 2021 Jan 2.

Division of Pediatric Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA; Center for Cancer and Blood Disorders, Children's National Medical Center; George Washington University School of Medicine Health Sciences, Washington, DC, USA. Electronic address:

Pain is a hallmark of Sickle Cell Disease (SCD) affecting patients throughout their life; the first pain crisis may occur at any age and is often the first presentation of the disease. Universal newborn screening identifies children with SCD at birth, significantly improving morbidity and mortality. Without early screening, diagnosis is generally made after disease manifestations appear. The Consortium for the Advancement of Sickle Cell Research (CASiRe) is an international collaborative group evaluating the clinical severity of subjects with SCD using a validated questionnaire and medical chart review, standardized across 4 countries (United States, United Kingdom, Italy and Ghana). We investigated the age of first pain crisis in 555 sickle cell subjects, 344 adults and 211 children. Median age of the first crisis in the whole group was 4 years old, 5 years old among adults and 2 years old among children. Patients from the United States generally reported the first crisis earlier than Ghanaians. Experiencing the first pain crisis early in life correlated with the genotype and disease severity. Early recognition of the first pain crisis could be useful to guide counseling and management of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcmd.2020.102531DOI Listing
May 2021

Effects of Iron Chelation in Osteosarcoma.

Curr Cancer Drug Targets 2021 ;21(5):443-455

Department of Woman, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.

Background: Osteosarcoma is an aggressive bone tumor. It represents the principal cause of cancer-associated death in children. Considering the recent findings on the role of iron in cancer, iron chelation has been investigated for its antineoplastic properties in many tumors. Deferasirox is the most used iron chelator compound and in previous studies showed an anticancer effect in hematologic and solid malignancies. Eltrombopag is a Thrombopoietin receptor used in thrombocytopenia that also binds and mobilize iron. It demonstrated an effect on iron overload conditions and also in contrasting cancer cell proliferation.

Objective: We analyzed the effects of deferasirox and eltrombopag in human osteosarcoma cells in an attempt to identify other therapeutic approaches for this tumor.

Methods: We cultured and treated with deferasirox and Eltrombopag, alone and in combination, two human osteosarcoma cell lines, MG63 and 143B. After 72h exposure, we performed RTqPCR, Western Blotting, Iron Assay and cytofluorimetric assays to evaluate the effect on viability, apoptosis, cell cycle progression and ROS production.

Results: The iron-chelating properties of the two compounds are also confirmed in osteosarcoma, but we did not observe any direct effect on tumor progression.

Discussion: We tested deferasirox and eltrombopag, alone and in combination, in human osteosarcoma cells for the first time and demonstrated that their iron-chelating activity does not influence biochemical pathways related to cancer progression and maintenance.

Conclusion: Although further investigations on possible effects mediated by cells of the tumor microenvironment could be of great interest, in vitro iron chelation in osteosarcoma does not impair tumor progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1568009620666201230090531DOI Listing
January 2021

Effects of Eltrombopag on In Vitro Macrophage Polarization in Pediatric Immune Thrombocytopenia.

Int J Mol Sci 2020 Dec 24;22(1). Epub 2020 Dec 24.

Department of Woman, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.

Immune Thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibodies-mediated platelet destruction, a prevalence of M1 pro-inflammatory macrophage phenotype and an elevated T helper 1 and T helper 2 lymphocytes (Th1/Th2) ratio, resulting in impairment of inflammatory profile and immune response. Macrophages are immune cells, present as pro-inflammatory classically activated macrophages (M1) or as anti-inflammatory alternatively activated macrophages (M2). They have a key role in ITP, acting both as effector cells, phagocytizing platelets, and, as antigen presenting cells, stimulating auto-antibodies against platelets production. Eltrombopag (ELT) is a thrombopoietin receptor agonist licensed for chronic ITP to stimulate platelet production. Moreover, it improves T and B regulatory cells functions, suppresses T-cells activity, and inhibits monocytes activation. We analyzed the effect of ELT on macrophage phenotype polarization, proposing a new possible mechanism of action. We suggest it as a mediator of macrophage phenotype switch from the M1 pro-inflammatory type to the M2 anti-inflammatory one in paediatric patients with ITP, in order to reduce inflammatory state and restore the immune system function. Our results provide new insights into the therapy and the management of ITP, suggesting ELT also as immune-modulating drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22010097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796119PMC
December 2020

A cancer-associated CDKN1B mutation induces p27 phosphorylation on a novel residue: a new mechanism for tumor suppressor loss-of-function.

Mol Oncol 2021 Apr 6;15(4):915-941. Epub 2021 Feb 6.

Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

CDKN1B haploinsufficiency promotes the development of several human cancers. The gene encodes p27 , a protein playing pivotal roles in the control of growth, differentiation, cytoskeleton dynamics, and cytokinesis. CDKN1B haploinsufficiency has been associated with chromosomal or gene aberrations. However, very few data exist on the mechanisms by which CDKN1B missense mutations facilitate carcinogenesis. Here, we report a functional study on a cancer-associated germinal p27 variant, namely glycine9->arginine-p27 (G9R-p27 ) identified in a parathyroid adenoma. We unexpectedly found that G9R-p27 lacks the major tumor suppressor activities of p27 including its antiproliferative and pro-apoptotic functions. In addition, G9R-p27 transfection in cell lines induces the formation of more numerous and larger spheres when compared to wild-type p27 -transfected cells. We demonstrated that the mutation creates a consensus sequence for basophilic kinases causing a massive phosphorylation of G9R-p27 on S12, a residue normally never found modified in p27 . The novel S12 phosphorylation appears responsible for the loss of function of G9R-p27 since S12AG9R-p27 recovers most of the p27 tumor suppressor activities. In addition, the expression of the phosphomimetic S12D-p27 recapitulates G9R-p27 properties. Mechanistically, S12 phosphorylation enhances the nuclear localization of the mutant protein and also reduces its cyclin-dependent kinase (CDK)2/CDK1 inhibition activity. To our knowledge, this is the first reported case of quantitative phosphorylation of a p27 variant on a physiologically unmodified residue associated with the loss of several tumor suppressor activities. In addition, our findings demonstrate that haploinsufficiency might be due to unpredictable post-translational modifications due to generation of novel consensus sequences by cancer-associated missense mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/1878-0261.12881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024736PMC
April 2021

Juvenile erythrocytosis in children after liver transplantation: prevalence, risk factors and outcome.

Sci Rep 2020 06 16;10(1):9683. Epub 2020 Jun 16.

Pediatric Clinic, Department of Medicine, Surgery and Dentistry, University of Salerno, "Scuola Medica Salernitana", Baronissi (Salerno), Italy.

Most reports of post-transplant erythrocytosis have involved kidney recipients and, so far, there have been no large studies of onset of erythrocytosis after orthotopic liver transplantation (OLT) in children. We present a long-term survey of pediatric liver recipients, evaluating prevalence, outcome and the main potential causes of erythrocytosis, including a comprehensive mutational analysis of commonly related genes (mutations of HBB and HBA, JAK2, EPOR, VHL, EPAS1 and EGLN1). Between 2000 and 2015, 90 pediatric OLT recipients were observed for a median period of 8.7 years (range 1-20.4 [IQR 4.9-13.6] years). Five percent of the study population (4 males and 1 female) developed erythrocytosis at 8.5 years post OLT (range 4.1-14.9 [IQR 4.7-14.7]) at a median age of 16.6 years (range 8.2-18.8 [IQR 11.7-17.7]). Erythrocytosis-free survival after OLT was 98.6% at 5 years, 95% at 10 years, and 85% at 15 years, with an incidence rate of 6/1000 person-years. No cardiovascular events or thrombosis were reported. No germinal mutation could be clearly related to the development of erythrocytosis. One patient, with high erythropoietin levels and acquired multiple bilateral renal cysts, developed clinical hyper-viscosity symptoms, and was treated with serial phlebotomies. In conclusion, this prospective longitudinal study showed that erythrocytosis is a rare complication occurring several years after OLT, typically during adolescence. Erythrocytosis was non-progressive and manageable. Its pathogenesis is still not completely understood, although male gender, pubertal age, and renal cysts probably play a role.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-66586-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298026PMC
June 2020

Retrospective Multicentric Study on Non-Optic CNS Tumors in Children and Adolescents with Neurofibromatosis Type 1.

Cancers (Basel) 2020 May 31;12(6). Epub 2020 May 31.

Department of Pediatric Neurosurgery, Santobono-Pausilipon Children's Hospital, Via Mario Fiore 6, 80129 Naples, Italy.

s: The natural history of non-optic central nervous system (CNS) tumors in neurofibromatosis type 1 (NF1) is largely unknown. Here, we describe prevalence, clinical presentation, treatment, and outcome of 49 non-optic CNS tumors observed in 35 pediatric patients (0-18 years). Patient- and tumor-related data were recorded. Overall survival (OS) and progression-free survival (PFS) were evaluated. Eighteen patients (51%) harbored an optic pathway glioma (OPG) and eight (23%) had multiple non-optic CNS lesions. The majority of lesions (37/49) were managed with a wait-and-see strategy, with one regression and five reductions observed. Twenty-one lesions (42.9%) required surgical treatment. Five-year OS was 85.3%. Twenty-four patients progressed with a 5-year PFS of 41.4%. Patients with multiple low-grade gliomas progressed earlier and had a lower 5-year PFS than those with one lesion only (14.3% vs. 57.9%), irrespective of OPG co-presence. Non-optic CNS tumors are common in young patients with NF1. Neither age and symptoms at diagnosis nor tumor location influenced time to progression in our series. Patients with multiple lesions tended to have a lower age at onset and to progress earlier, but with a good OS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12061426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353051PMC
May 2020

An Analysis of Racial and Ethnic Backgrounds Within the CASiRe International Cohort of Sickle Cell Disease Patients: Implications for Disease Phenotype and Clinical Research.

J Racial Ethn Health Disparities 2021 02 16;8(1):99-106. Epub 2020 May 16.

Department of Physiology, University of Ghana Medical School, Accra, Ghana.

Millions are affected by sickle cell disease (SCD) worldwide with the greatest burden in sub-Saharan Africa. While its origin lies historically within the malaria belt, ongoing changes in migration patterns have shifted the burden of disease resulting in a global public health concern. We created the Consortium for the Advancement of Sickle Cell Research (CASiRe) to understand the different phenotypes of SCD across 4 countries (USA, UK, Italy, and Ghana). Here, we report the multi-generational ethnic and racial background of 877 SCD patients recruited in Ghana (n = 365, 41.6%), the USA (n = 254, 29%), Italy (n = 81, 9.2%), and the UK (n = 177, 20.2%). West Africa (including Benin Gulf) (N = 556, 63.4%) was the most common geographic region of origin, followed by North America (N = 184, 21%), Caribbean (N = 51, 5.8%), Europe (N = 27, 3.1%), Central Africa (N = 24, 2.7%), and West Africa (excluding Benin Gulf) (N = 21, 2.4%). SCD patients in Europe were primarily West African (73%), European (10%), Caribbean (8%), and Central African (8%). In the USA, patients were largely African American (71%), Caribbean (13%), or West African (10%). Most subjects identified themselves as Black or African American; the European cohort had the largest group of Caucasian SCD patients (8%), including 21% of the Italian patients. This is the first report of a comprehensive analysis of ethnicity within an international, transcontinental group of SCD patients. The diverse ethnic backgrounds observed in our cohort raises the possibility that genetic and environmental heterogeneity within each SCD population subgroup can affect the clinical phenotype and research outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40615-020-00762-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669607PMC
February 2021

A study of the geographic distribution and associated risk factors of leg ulcers within an international cohort of sickle cell disease patients: the CASiRe group analysis.

Ann Hematol 2020 Sep 6;99(9):2073-2079. Epub 2020 May 6.

Division of Pediatric Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA.

Vasculopathy is a hallmark of sickle cell disease ultimately resulting in chronic end organ damage. Leg ulcer is one of its sequelae, occurring in ~ 5-10% of adult sickle cell patients. The majority of leg ulcer publications to date have emanated from single center cohort studies. As such, there are limited studies on the geographic distribution of leg ulcers and associated risk factors worldwide. The Consortium for the Advancement of Sickle Cell Research (CASiRe) was formed to improve the understanding of the different phenotypes of sickle cell disease patients living in different geographic locations around the world (USA, UK, Italy, Ghana). This cross-sectional cohort sub-study of 659 sickle cell patients aimed to determine the geographic distribution and risk factors associated with leg ulcers. The prevalence of leg ulcers was 10.3% and was associated with older age, SS genotype, male gender, and Ghanaian origin. In fact, the highest prevalence (18.6%) was observed in Ghana. Albuminuria, proteinuria, increased markers of hemolysis (lower hemoglobin, higher total bilirubin), lower oxygen saturation, and lower body mass index were also associated with leg ulceration. Overall, our study identified a predominance of leg ulcers within male hemoglobin SS patients living in sub-Saharan Africa with renal dysfunction and increased hemolysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-020-04057-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430152PMC
September 2020

Pretreatment Endocrine Disorders Due to Optic Pathway Gliomas in Pediatric Neurofibromatosis Type 1: Multicenter Study.

J Clin Endocrinol Metab 2020 06;105(6)

Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Università degli studi della Campania "Luigi Vanvitelli", Naples, Italy.

Context: Up to 20% of children with neurofibromatosis type 1 (NF1) develop low-grade optic pathway gliomas (OPGs) that can result in endocrine dysfunction. Data on prevalence and type of endocrine disorders in NF1-related OPGs are scarce.

Objectives: The aim of the study was to determine the prevalence of endocrine dysfunctions in patients with NF1 and OPGs and to investigate predictive factors before oncological treatment.

Design: Multicenter retrospective study.

Settings And Patients: Records were reviewed for 116 children (64 females, 52 males) with NF1 and OPGs followed at 4 Italian centers.

Main Outcome Measures: We evaluated endocrine function and reviewed brain imaging at the time of OPG diagnosis before radio- and chemotherapy and/or surgery. OPGs were classified according to the modified Dodge classification.

Results: Thirty-two children (27.6%) with a median age of 7.8 years had endocrine dysfunctions including central precocious puberty in 23 (71.9%), growth hormone deficiency in 3 (9.4%), diencephalic syndrome in 4 (12.5%), and growth hormone hypersecretion in 2 (6.2%). In a multivariate cox regression analysis, hypothalamic involvement was the only independent predictor of endocrine dysfunctions (hazard ratio 5.02 [1.802-13.983]; P = .002).

Conclusions: Endocrine disorders were found in approximately one-third of patients with Neurofibromatosis type 1 and OPGs before any oncological treatment, central precocious puberty being the most prevalent. Sign of diencephalic syndrome and growth hormone hypersecretion, although rare, could be predictive of optic pathway gliomas in NF1. Tumor location was the most important predictor of endocrine disorders, particularly hypothalamic involvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa138DOI Listing
June 2020

A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia.

N Engl J Med 2020 03;382(13):1219-1231

From the Department of Clinical Sciences and Community, University of Milan, IRCCS Ca' Granda Foundation Maggiore Policlinico Hospital, Milan (M.D.C.), Centro della Microcitemia e Anemie Congenite e del Dismetabolismo del Ferro, E.O. Ospedali Galliera, Genoa (G.L.F.), Ospedale Pediatrico Microcitemico A. Cao, Azienda Ospedaliera G. Brotzu, Cagliari (R.O.), Ematologia e Oncologia Pediatrica, Università della Campania L. Vanvitelli, Caserta (S.P.), and the Department of Clinical and Biological Sciences, University of Turin, Turin (A.P.) - all in Italy; Siriraj Hospital, Mahidol University, Bangkok (V.V.), and the Division of Hematology, Department of Internal Medicine, Chiang Mai University, Chiang Mai (A. Tantiworawit) - both in Thailand; the Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (A.T.T.); St. George University Hospital for Active Treatment and Medical University of Plovdiv, Plovdiv (P. Georgiev), University Specialized Hospital for Active Treatment in Oncology, Sofia (P. Ganeva), and University Hospital St. Marina, Varna (L.G.) - all in Bulgaria; the Division of Medical Oncology and Hematology, Department of Medicine, University Health Network and Division of Hematology, Department of Medicine, University of Toronto, Toronto (K.H.M.K.); the Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, and Keck School of Medicine of the University of Southern California, Los Angeles (T.C.), and the University of California San Francisco Benioff Children's Hospital, Oakland (A. Lal) - all in California; the Thalassemia and Sickle Cell Center, Laiko General Hospital (E. Voskaridou), and the First Department of Pediatrics, National and Kapodistrian University of Athens (A. Kattamis), Athens, and the Adult Thalassemia Unit, Hippokration Hospital, Thessaloniki (E. Vlachaki) - all in Greece; Hospital Sultanah Bahiyah, Alor Setar (H.K.L.), Hospital Umum, Sarawak, Kuching (L.P.C.), the University of Malaya Medical Center, Kuala Lumpur (P.C.B.), and Hospital Sultanah Aminah, Johor Bahru (S.M.L.) - all in Malaysia; the Comprehensive Center of Thalassemia, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel (I.P.-K.); Farhat Hached University Hospital, Sousse (A. Khelif), and the National Bone Marrow Transplant Center and Faculty of Medicine, University of Tunis El Manar, Tunis (M.B.) - both in Tunisia; the Department of Pediatric Hematology and Oncology, Ege University Hospital, Izmir, Turkey (Y.A.); Royal Prince Alfred Hospital and the University of Sydney, Sydney (P.J.H.); National Taiwan University, Taipei, Taiwan (M.-Y. L.); the Department of Haematology, Whittington Health NHS Trust (F.S.), and the Department of Haematology, University College London and University College London Hospitals NHS Foundation Trust (J.P.) - all in London; St. Jude Children's Research Hospital, Memphis, TN (E.J.N.); Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago (A. Thompson); Celgene, Summit, NJ (A. Laadem, J. Zou, J. Zhang); Celgene, Boudry, Switzerland (J.K.S., D.M., T.Z.); Acceleron Pharma, Cambridge, MA (P.G.L., M.L.S.); and the Department of Hematology, Necker Hospital, Assistance Publique-Hôpitaux de Paris (O.H.), and Imagine Institute, INSERM Unité 1163, University of Paris (O.H.) - both in Paris.

Background: Patients with transfusion-dependent β-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients.

Methods: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent β-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies.

Results: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 μg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo.

Conclusions: The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1910182DOI Listing
March 2020

Effects of Germline VHL Deficiency on Growth, Metabolism, and Mitochondria.

N Engl J Med 2020 02;382(9):835-844

From the Departments of Woman, Child, and General and Specialized Surgery (S.P., D.R., M. Caiazza, S.S., I.T., M. Casale), Precision Medicine (D.B., E.S., A.B., F.D.R.), and Advanced Medical and Surgical Sciences (A.A.S.), University of Campania Luigi Vanvitelli, Naples, and the Departments of Pharmacology and Biomolecular Science, University of Milan, Milan (P.C., A.M.R.) - both in Italy; the Departments of Physiology, Development, and Neuroscience (K.A.O., A.J.M.) and Biochemistry (J.A.W., J.L.G.), University of Cambridge, Cambridge, the Centre for Ultrastructural Imaging (L.A., R.A.F.) and the Centre for Human and Applied Physiological Sciences, Faculty of Life Sciences and Medicine (F.F.), King's College London, London, and the Department of Physiology, Anatomy, and Genetics (P.A.R., F.F.) and Nuffield Division of Anaesthetics (F.F.), University of Oxford, Oxford - all in the United Kingdom; and the Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia (C.F.-A.).

Mutations in , which encodes von Hippel-Lindau tumor suppressor (VHL), are associated with divergent diseases. We describe a patient with marked erythrocytosis and prominent mitochondrial alterations associated with a severe germline VHL deficiency due to homozygosity for a novel synonymous mutation (c.222C→A, p.V74V). The condition is characterized by early systemic onset and differs from Chuvash polycythemia (c.598C→T) in that it is associated with a strongly reduced growth rate, persistent hypoglycemia, and limited exercise capacity. We report changes in gene expression that reprogram carbohydrate and lipid metabolism, impair muscle mitochondrial respiratory function, and uncouple oxygen consumption from ATP production. Moreover, we identified unusual intermitochondrial connecting ducts. Our findings add unexpected information on the importance of the VHL-hypoxia-inducible factor (HIF) axis to human phenotypes. (Funded by Associazione Italiana Ricerca sul Cancro and others.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1907362DOI Listing
February 2020

Changing the diagnostic approach to diabetes insipidus: role of copeptin.

Ann Transl Med 2019 Dec;7(Suppl 8):S285

Department of Pediatrics, IRCCS Istituto Giannina Gaslini, University of Genova, Genova, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm.2019.11.80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976509PMC
December 2019

Asymptomatic intracranial aneurysms in beta-thalassemia: a three-year follow-up report.

Orphanet J Rare Dis 2020 01 20;15(1):21. Epub 2020 Jan 20.

Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Università degli studi della Campania "Luigi Vanvitelli", Via L. De Crecchio 4, Naples, Italy.

Background: No information is currently available regarding the natural history of asymptomatic intracranial aneurysms in beta-thalassemia, raising several concerns about their proper management.

Methods: We performed a prospective longitudinal three-year-long MR-angiography study on nine beta-thalassemia patients (mean-age 40.3 ± 7.5, six females, 8 transfusion dependent) harboring ten asymptomatic intracranial aneurysms. In addition, we analyzed the clinical files of all adult beta-thalassemia patients (160 patients including those followed with MR-angiography, 121 transfusion dependent) referring to our Centers between 2014 and 2019 searching for history of subarachnoid hemorrhage or history of symptomatic intracranial aneurysms.

Results: At the end of the three-year-long follow-up, no patient showed any change in the size and shape of the aneurysms, none presented new intracranial aneurysms or artery stenoses, none showed new brain vascular-like parenchymal lesions or enlargement of the preexisting ones. Besides, in our database of all adult beta-thalassemia patients, no one had history of subarachnoid hemorrhage or history of symptomatic intracranial aneurysms.

Conclusions: Incidental asymptomatic intracranial aneurysms do not seem to be associated, in beta-thalassemia, with an increased risk of complications (enlargement or rupture) at least in the short term period, helping to optimize human and economic resources and patient compliance during their complex long-lasting management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-020-1302-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971974PMC
January 2020

Headache in beta-thalassemia: An Italian multicenter clinical, conventional MRI and MR-angiography case-control study.

Blood Cells Mol Dis 2020 03 31;81:102403. Epub 2019 Dec 31.

Dipartimento di Medicina e Chirurgia, Scuola Medica Salernitana, Sezione di Neuroscienze, Università di Salerno, Salerno, Italy.

Objectives: A strikingly increased headache prevalence was recently noted in Sri Lankan beta-thalassemia patients, raising several concerns regarding long-term neurological involvement in this condition.

Methods: We interviewed on headache occurrence and characteristics 102 Italian beta-thalassemia patients and 129 healthy controls. 3T-MRI, MR-angiography, MR-venography, cognitive and psychiatric findings were considered.

Results: Headache was diagnosed in 39/102 (38.2%) beta-thalassemia patients without significant phenotype-related differences and in 51/129 (39.5%) controls. Patients and controls did not differ significantly regarding episode number (5.9 ± 6.2 vs 5.4 ± 4.4 days/month), subjective severity-score (6.8 ± 1.4 vs 7.1 ± 1.3), age-at-onset (24.3 ± 13.0 vs 19.5 ± 9.6 years) and headache-subtype rate. No main demographic, clinical or laboratory data was associated with headache but female gender. Headache was not associated with white matter lesions (number or maximal diameter), intracranial aneurysms, intracranial artery stenoses or venous sinus thrombosis. Cognitive and psychiatric evaluations were worse in beta-thalassemia, however, headache did not correlate with full-scale Intelligence Quotient (75.4 ± 18.0 vs 76.7 ± 15.3, with and without headache, respectively) or Brief Psychiatric Rating Scale scores (29.1 ± 2.7 vs 28.5 ± 3.4).

Conclusions: Among Italian beta-thalassemia patients, headache does not seem to be more common or severe than in the general population. In addition, patients with headache do not seem to present increased conventional MRI, MR-angiography and cognitive/psychiatric changes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcmd.2019.102403DOI Listing
March 2020

An Educational Study Promoting the Delivery of Transcranial Doppler Ultrasound Screening in Paediatric Sickle Cell Disease: A European Multi-Centre Perspective.

J Clin Med 2019 Dec 24;9(1). Epub 2019 Dec 24.

Ultrasonic Angiology Department, Guy's & St Thomas' NHS Foundation Trust, London SE1 9RT, UK.

Background: Effective stroke prevention in sickle cell disease (SCD) is recommended for children with sickle cell anaemia. Effective implementation relies on the correct stratification of stroke risk using Transcranial Doppler Ultrasound (TCD), prior to committing children to long-term treatment with transfusion. Nevertheless, less than 50% of children with SCD in Europe receive annual TCD-one of the reasons being a lack of trained personnel. The present European multi-centre study was designed to promote the standardisation and delivery of effective screening.

Methods: Fifty-five practitioners from differing professional backgrounds were recruited to the TCD training program. The impact of the training programme was evaluated in three European haematology clinics by comparing stroke risk classification and middle cerebral artery time-averaged maximum velocity (TAMMV) obtained from a cohort of 555 patients, before and after training.

Results: 42% (23/55) of trainees successfully completed the program. The TAMMV, used to predict stroke risk at each Centre, demonstrated the highest values in Centre 3 ( < 0.0001) before training. The imaging-TCD TAMMV was also higher in Centre 3 ( < 0.001). Following training, the TAMMV showed closer agreement between centres for both imaging-TCD and non-imaging TCD. The stroke risk distribution of children at each centre varied significantly before training ( < 0.001), but improved after training (Fisher's Exact: no treatment = 5.6, = 0.41, treatment = 13.8, < 0.01). The same consistency in stroke risk distribution following training was demonstrated with both non-imaging and imaging-TCD data.

Conclusion: The attainment of competency in stroke screening using transcranial Doppler scanning (TCD) in sickle cell disease is more feasible for professionals with an ultrasound imaging background. A quality assurance (QA) system is required to ensure that standards are maintained. Further work is in progress to develop an achievable and reproducible QA program.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9010044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019609PMC
December 2019

Blood transfusions and adverse acute events: a retrospective study from 214 transfusion-dependent pediatric patients comparing transfused blood components by apheresis or by whole blood.

Ann Ist Super Sanita 2019 Oct-Dec;55(4):351-356

Dipartimento di Scienze Cliniche e Chirurgiche Avanzate, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.

Introduction: Blood transfusion is a lifesaving procedure for patients affected by hematological diseases or hemorrhage risk.

Aim: This retrospective study was aimed to evaluate clinical safety of pediatric transfusions by comparing the frequency of adverse events caused by apheretic blood components vs whole blood.

Methods: From 2011 to 2015, 214 patients (blood malignancy patients, n = 144 and thalassemic patients, n = 70) received 12 531 units of blood components. The adverse acute reactions occurred during patient hospitalization were reported to the Hemovigilance system and assessed by fitting a logistic mixed-effect model.

Results: A total of 33 (0.3%) adverse acute events occurred. Odds ratio (OR) of adverse events from apheresis vs whole blood transfusion adjusted by patient classification was not statistically significant (OR [95% CI], 0.75 [0.23-2.47]).

Conclusion: Our findings showed no significant differences in the prevalence of adverse acute events between blood component collected by apheresis vs whole blood in our study center.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4415/ANN_19_04_08DOI Listing
May 2020

HbS/β+ thalassemia: Really a mild disease? A National survey from the AIEOP Sickle Cell Disease Study Group with genotype-phenotype correlation.

Eur J Haematol 2020 Mar 12;104(3):214-222. Epub 2019 Dec 12.

Unit of Pediatric Hematology and Oncology, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.

Objectives: HbS/β+ patients' presence in Italy increased due to immigration; these patients are clinically heterogeneous, and specific guidelines are lacking. Our aim is to describe a cohort of HbS/β+ patients, with genotype-phenotype correlation, in order to offer guidance for clinical management of such patients.

Methods: Retrospective cohort study of HbS/β+ patients among 15 AIEOP Centres.

Results: A total of 41 molecularly confirmed S/β+ patients were enrolled (1-55 years, median 10.9) and classified on β+ mutation: IVS-I-110, IVS-I-6, promoter, and "others." Prediagnostic events included VOC 16/41 (39%), ACS 6/41 (14.6%), sepsis 3/41 (3.7%), and avascular necrosis 3/41 (7,3%). Postdiagnostic events were VOC 22/41 (53.6% %), sepsis 4/41 (9.7%), ACS 4/41 (9.7%), avascular necrosis 3/41 (7.3%), aplastic crisis 2/41 (4.8%), stroke 1/41 (2.4%), ACS 1/41 (2.4%), and skin ulcerations 1/41 (2.4%). The IVS-I-110 group presented the lowest median age at first SCD-related event (P = .02 vs promoter group) and the higher median number of severe events/year (0.26 events/patient/year) (P = .01 vs IVS-I-6 and promoter groups). Promoter group presented a specific skeletal phenotype. Treatment regimen applied was variable among the centers.

Conclusions: HbS/β+ is not always a mild disease. Patients with IVS-I-110 mutation could benefit from a standard of care like SS and S/β° patients. Standardization of treatment is needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejh.13362DOI Listing
March 2020

Brain iron content in systemic iron overload: A beta-thalassemia quantitative MRI study.

Neuroimage Clin 2019 25;24:102058. Epub 2019 Oct 25.

Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, Baronissi, Salerno 84081, Italy; Department of Diagnostic Imaging, University Hospital "San Giovanni di Dio e Ruggi d'Aragona", Scuola Medica Salernitana, Salerno 84131, Italy.

Objective: Multisystem iron poisoning is a major concern for long-term beta-thalassemia management. Quantitative MRI-based techniques routinely show iron overload in heart, liver, endocrine glands and kidneys. However, data on the brain are conflicting and monitoring of brain iron content is still matter of debate.

Methods: This 3T-MRI study applied a well validated high-resolution whole-brain quantitative MRI assessment of iron content on 47 transfusion-dependent (mean-age: 36.9 ± 10.3 years, 63% females), 23 non-transfusion dependent (mean-age: 29.2 ± 11.7 years, 56% females) and 57 healthy controls (mean-age: 33.9 ± 10.8 years, 65% females). Clinical data, Wechsler Adult Intelligence Scale scores and treatment regimens were recorded. Beside whole-brain R2* analyses, regional R2*-values were extracted in putamen, globus pallidum, caudate nucleus, thalamus and red nucleus; hippocampal volumes were also determined.

Results: Regional analyses yielded no significant differences between patients and controls, except in those treated with deferiprone that showed lower R2*-values (p<0.05). Whole-brain analyses of R2*-maps revealed strong age-R2* correlations (r=0.51) in both groups and clusters of significantly increased R2*-values in beta-thalassemia patients in the hippocampal formations and around the Luschka foramina; transfusion treatment was associated with additional R2* increase in dorsal thalami. Hippocampal formation R2*-values did not correlate with hippocampal volume; hippocampal volume did not differ between patients and controls. All regions with increased R2*-values shared a strict anatomical contiguity with choroid plexuses suggesting a blooming effect as the likely cause of R2* increase, in agreement with the available histopathologic literature evidence.

Conclusion: According to our MRI findings and the available histopathologic literature evidence, concerns about neural tissue iron overload in beta-thalassemia appear to be unjustified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nicl.2019.102058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849415PMC
September 2020
-->