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1.
Artigo em Inglês | MEDLINE | ID: mdl-32169379

RESUMO

BACKGROUND: X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarse. OBJECTIVE: To describe the natural history of X-linked agammaglobulinemia. METHODS: A nationwide multicenter study based on the IPINet registry was established in 2000 in Italy. Affected patients were enrolled by documenting centers and patients' laboratory, clinical and imaging data were recorded on an annual base. RESULTS: Patients' data (N=168) derived from a cumulative follow-up of 1370 patient years with a mean follow-up of 8.35 years per patient. Mean age at diagnosis decreased upon the establishment of the IPINet registry (84 months before versus 23 months after). Respiratory, skin and gastrointestinal manifestations were the most frequent clinical symptoms at diagnosis and during long-term follow-up. Regular immunoglobulin replacement treatment reduced the incidence of invasive infections. Affected patients developed chronic lung disease over time (47% after 40 years of follow-up) in the presence of chronic sinusitis (84%). Malignancies were documented in a minority of cases (3.7%). Overall survival for affected patients was significantly reduced when compared to the healthy male Italian population, and further deteriorated in the presence of chronic lung disease. CONCLUSIONS: This is the first detailed long-term follow-up study for XLA patients revealing that while immunoglobulin replacement treatment reduces the incidence of invasive infections, it does not appear to influence the development of chronic lung disease. Overall survival of affected patients is reduced. Further studies are warranted in order to improve patients' clinical management and increase awareness among physicians.

4.
Eur Radiol ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32052169

RESUMO

OBJECTIVES: R2* cardiac magnetic resonance (CMR) allows the non-invasive measurement of myocardial iron. We calibrated cardiac R2* values against myocardial tissue-measured iron concentration by using a segmental approach and we assessed the iron distribution. METHODS: Five hearts of thalassemia patients were donated after death/transplantation to the CoreLab of the Myocardial Iron Overload in Thalassemia Network. A multislice multiecho R2* approach was adopted. After CMR, used as guidance, the heart was cut in three short-axis slices and each slice was cut into different equiangular segments according to AHA segmentation and differentiated into endocardial and epicardial layers. Tissue iron concentration was measured by atomic absorption spectrometer technique. RESULTS: Fifty-five samples were used since only for two hearts all the 16 samples were analyzed. Mean iron concentration was 4.71 ± 4.67 mg/g dw. Segmental iron levels ranged from 0.24 to 13.78 mg/g dw. The coefficient of variability of iron for myocardial segments ranged from 8.08 to 24.54% (mean 13.49 ± 6.93%). Iron concentration was significantly higher in the epicardial than in the endocardial layer (5.99 ± 6.01 vs 4.84 ± 4.87 mg/g dw; p = 0.042). Four different circumferential regions (anterior, septal, inferior, and lateral) were defined. A circumferential heterogeneity was noted, with more iron in the anterior region, followed by the inferior region. The direct nonlinear fitting of R2* and [Fe] data led to the calibration curve: [Fe] = 0.0022 ∙ (R2*-ROI)1.462 (R-square = 0.956). CONCLUSIONS: Our data further validate R2* CMR using a segmental approach as a sensitive and early technique for quantifying iron distribution in the current clinical practice. KEY POINTS: • Calibration in humans for cardiovascular magnetic resonance R2* against myocardial iron concentration was provided. • A circumferential heterogeneity in cardiac iron distribution was detected: more iron was observed in the anterior region, followed by the inferior region. This finding corroborates the use of a segmental T2* CMR approach in the clinical practice to detect a heterogeneous iron distribution. • The comparison between the cardiac T2* values obtained with the region-based and the pixel-wise approaches showed a significant correlation and no significant difference but, in presence of significant iron load, the region-based approach resulted in significantly higher T2* values.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31963108

RESUMO

There is still little research on psychological wellbeing, life satisfaction and reported problems in preadolescents and adolescents under therapy for leukaemia, and also little research comparing them with their healthy peers. The present study aimed to analyse the life satisfaction, hope, psychological wellbeing and reported problems' intensity in 60 patients aged 8-18 during the first year of therapy, to identify those more at risk and to compare their reports with matched healthy peers. A battery of self-reported questionnaires was administered during hospitalisation or day hospital admissions post 6 months and post 12 months from the diagnosis. Younger patients (aged 8-13 years) were more at risk than older ones in their problems' intensity and psychological symptoms; females and Acute Myeloid Leukaemia patients reported lower current life satisfaction perceptions; hope was associated with lower depression symptoms and mood problems. Healthy peers have a better perception of current life, but reported a lower hope score, more anxiety symptoms and more cognitive problems than patients. The first 6 months were more critical for patients' psychological health. Basing on these empirical data, the inclusion of mental health care professionals or supportive psychotherapy into the treatment is recognized as extremely useful.

6.
Pediatr Hematol Oncol ; 37(2): 164-169, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31847684

RESUMO

Among fungal infection, mucormycosis is a rare but severe etiology in immunocompromised patients. Lung and sinus are the usual sites; the involvement of blood vessels is also described. The diagnosis is a real challenge, because blood tests (galactomannan, beta-D-glucan) are negative and the only diagnostic tool is usually the biopsy of the affected zone. Aortitis is rare and usually caused by bacterial infection, fungal etiology is unusual and only episodic cases are reported in literature. Medical therapy alone is usually not sufficient and debilitating surgical intervention is required. We report the case of a child affected by B precursor acute lymphoblastic leukemia, presenting a systemic fungal infection complicated by aortitis, probably due to Mucor. The patient developed fever and pneumonia during the Induction phase of chemotherapy. At the beginning, the infection was treated as bacterial and the diagnosis of Mucor infection was possible only after surgical intervention with histological analysis. Medical therapy (antifungal) was not sufficient alone to cure the infection and an urgent surgical intervention was required. This case underlines the challenge in the diagnosis of mucomycosis, that should be suspected in case of prolonged fever during aplasia, not responding to standard antibiotic and antifungal therapies. Mucor infection often require a combined intervention, both medical and surgical to cure the infection.

8.
Eur J Cancer ; 122: 61-71, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31629941

RESUMO

BACKGROUND: Adolescents (aged 10-17 years) with acute lymphoblastic leukaemia (ALL) have unfavourable disease features and an inferior outcome when compared with younger children, but it is still unclear if differences in disease biology and prognosis exist between adolescents older or younger than 15 years. METHODS: We retrospectively analysed outcomes of 1094 adolescents with ALL, aged 10-17 years, treated within the AIEOP-BFM ALL 2000 trial, overall and by the age groups 10-14 and 15-17 years. FINDINGS: Compared with younger children (aged 1-9 years, n = 3647), adolescents had a statistically inferior 5-year event-free survival (EFS) [74.6% (1.3) vs. 84.4% (0.6)] and overall survival (OS) [83.4% (1.1) vs. 92.7% (0.4); p < 0.001]. Clinical and biological disease characteristics did not differ between the two subgroups of adolescents, including minimal residual disease (MRD) results during initial therapy, except for ETV6-RUNX1 frequency and gender. With a median follow-up of 8.8 years, the 5-year EFS and OS were 76.2% (1.5) and 84.9% (1.3), respectively, for those aged 10-14 years and 70.0% (2.8) and 78.8% (2.5) for those aged 15-17 years (p = 0.06; 0.05). There was no significant difference in the cumulative incidence of relapses [17.8% (1.4) and 18.3% (2.4); p = 0.98], while the incidence of treatment-related deaths as a first event was 2.6% (0.6) versus 7.4% (1.6) (p < 0.001) with, in particular, a higher incidence in the high-risk arm. INTERPRETATION: Further prospective studies and biological investigations are required to define optimal treatment for adolescents, in particular for those aged 15-17 years. Newer agents (immunotherapy, targeted therapy) in early treatment phases of patients at higher risk of treatment failure could replace most toxic treatment elements, with the aim of reducing both toxicity and the risk of relapses.

9.
Front Immunol ; 10: 1908, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456805

RESUMO

Severe combined immunodeficiencies (SCIDs) are a group of inborn errors of the immune system, usually associated with severe or life-threatening infections. Due to the variability of clinical phenotypes, the diagnostic complexity and the heterogeneity of the genetic basis, they are often difficult to recognize, leading to a significant diagnostic delay (DD). Aim of this study is to define presenting signs and natural history of SCID in a large cohort of patients, prior to hematopoietic stem cell or gene therapies. To this purpose, we conducted a 30-year retro-prospective multicenter study within the Italian Primary Immunodeficiency Network. One hundred eleven patients, diagnosed as typical or atypical SCID according to the European Society for Immune Deficiencies criteria, were included. Patients were subsequently classified based on the genetic alteration, pathogenic mechanism and immunological classification. A positive relationship between the age at onset and the DD was found. SCID patients with later onset were identified only in the last decade of observation. Syndromic SCIDs represented 28% of the cohort. Eight percent of the subjects were diagnosed in Intensive Care Units. Fifty-three percent had an atypical phenotype and most of them exhibited a discordant genotype-immunophenotype. Pre-treatment mortality was higher in atypical and syndromic patients. Our study broadens the knowledge of clinical and laboratory manifestations and genotype/phenotype correlation in patients with SCID and may facilitate the diagnosis of both typical and atypical forms of the disease in countries where newborn screening programs have not yet been implemented.

10.
Anticancer Res ; 39(3): 1259-1266, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30842156

RESUMO

BACKGROUND/AIM: In the last few decades, treatment strategies for acute lymphoblastic leukemia (ALL) have been associated not only with improvement of prognosis, but also with an increasing rate of late complication as osteonecrosis (ON). Herein, the cumulative incidence, risk factors, new conservative therapeutic strategies as hyperbaric oxygen therapy (HBO), and outcome of symptomatic ON were studied in pediatric patients with ALL. PATIENTS AND METHODS: Between 2000 and 2017, 495 children and young adolescents with a diagnosis of ALL were evaluated. All the symptomatic patients underwent magnetic resonance imaging (MRI) to detect bone vascularization and structure. RESULTS: Twenty-three out of 495 patients presented ON (4.6%). ON was associated with an older age (p<0.0001) and a higher steroid dose (p=0.0013). All the patients underwent standard therapies and HBO was performed in 8 of 23 patients. During the follow-up, 15 patients were stable: 6 were totally asymptomatic, 5 complained of pain during activity, and 4 presented mild function limitation. CONCLUSION: Our data highlight the importance of early diagnosis of ON by screening MRI in asymptomatic patients, in order to start conservative treatment strategies. Moreover, HBO could have beneficial effects on ON patients.


Assuntos
Osteonecrose/diagnóstico por imagem , Osteonecrose/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico por imagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Osso e Ossos/diagnóstico por imagem , Criança , Pré-Escolar , Diagnóstico Precoce , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Adulto Jovem
11.
J Allergy Clin Immunol Pract ; 7(7): 2369-2376, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30922987

RESUMO

BACKGROUND: Patients with 22q11.2 deletion syndrome (22q11.2DS) may develop severe thrombocytopenic purpura and hemolytic anemia. There are no reliable predictors for the development of hematologic autoimmunity (HA) in these patients. OBJECTIVE: To describe the peculiar B and T subpopulation defects in patients with 22q11DS who have developed HA and test if these defects precede the development of HA. METHODS: We performed a case-control multicenter study. Patients with HA were compared with a control population of 22q11.2DS without HA (non-HA). A complete immunological evaluation was performed at diagnosis and at the last follow-up including extensive T and B phenotypes. RESULTS: Immunophenotype at the last follow-up was available in 23 HA and 45 non-HA patients. HA patients had significantly decreased percentage of naïve CD4+ cells (26.8% vs 43.2%, P = .003) and recent thymic emigrants (48.6% vs 80.5%, P = .046); decreased class-switched B cells (2.0% vs 5.9%, P = .04) and increased naive B cells (83.5% vs 71.4%, P = .02); increased CD16+/56+ both in absolute number (312 vs 199, P = .009) and percentage (20.0% vs 13.0%, P = .03). Immunophenotype was performed in 36 patients (11 HA and 25 non-HA) at diagnosis. Odds ratio (OR) of immune cytopenia were estimated for both CD4 naïve ≤30% (OR 14.0, P = .002) and switched memory B cells ≤2% (OR 44.0, P = .01). The estimated survival curves reached statistical significance, respectively, P = .0001 and P = .002. CONCLUSIONS: Among patients with 22q11.2DS, those with HA have characteristic lymphocyte anomalies that appear considerably before HA onset. Systematic immunophenotyping of patients with 22q11.2DS at diagnosis is advisable for early identification of patients at risk for this severe complication.

12.
Expert Rev Hematol ; 12(5): 367-373, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30925843

RESUMO

INTRODUCTION: Essential thrombocythemia (ET) is a disease which is extremely rare in children. Only recently, data on pediatric ET have become available. Areas covered: In children with sustained platelet count over 450 x 109/L, secondary thrombocytosis must be ruled out. ET workup comprehends research of JAK2V617F, CALR and MPL mutations and bone marrow biopsy (BM). In asymptomatic children wait and watch is the best option. Aspirin controls headache and other microvascular disturbances. Patients with venous thrombosis need anticoagulation. Cytoreductive drugs in children with ET should be prescribed as a last choice. Hydroxyurea and IFN-a are first-line therapy at any age including children; Anagrelide is not licensed as first-line therapy for ET in Europe. New JAK2-inhibitors are not clearly useful in ET and hence not approved for ET. Expert opinion: The most challenging problem is to understand if a child with prolonged not secondary thrombocytosis really has ET. Diagnostic workup requires molecular and histological studies. The rare children with clonal ET have features like those of adults. Patients with ET have long expected survival and the treatment in children must be long-term efficacious and well tolerated.

14.
Acta Haematol ; 140(2): 105-111, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30227398

RESUMO

BACKGROUND: To date, no data on the adherence to specific guidelines for children with chronic myeloid leukemia (CML) in chronic phase (CP) have been reported. METHODS: Since 2001, guidelines for treatment with imatinib mesylate (IM) and monitoring in patients younger than 18 years with CP-CML have been shared with 9 pediatric referral centers (P centers) and 4 reference centers for adults and children/adolescents (AP centers) in Italy. In this study, the adherence to these guidelines was analyzed. RESULTS: Thirty-four patients with a median age of 11.4 years and 23 patients with a median age of 11.0 years were managed at 9 P and at 4 AP centers, respectively. Evaluations of bone marrow (BM) and/or peripheral blood (PB) were available for more than 90% of evaluable patients. Cytogenetics and molecular monitoring of PB were more consistently performed in AP centers, whereas molecular analysis of BM was carried out more frequently in P centers. Before 2009, some patients who responded to IM underwent a transplantation, contrary to the guidelines' recommendations. CONCLUSIONS: Our experience shows that having specific guidelines is an important tool for an optimal management of childhood CP-CML, together with exchange of knowledge and proactive discussions within the network.


Assuntos
Leucemia Mieloide de Fase Crônica/patologia , Adolescente , Medula Óssea/metabolismo , Medula Óssea/patologia , Criança , Pré-Escolar , Feminino , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Mesilato de Imatinib/uso terapêutico , Itália , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/terapia , Masculino , Inibidores de Proteínas Quinases/uso terapêutico
15.
Blood ; 132(5): 469-483, 2018 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-29891534

RESUMO

Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau (VHL) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with VHL disease, which is characterized by the development of highly vascularized tumors. Here, we identify a new VHL cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E1' in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E1' in addition to a mutation in VHL coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, we show that the mutations induced a dysregulation of VHL splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. In addition, we demonstrate a pathogenic role for synonymous mutations in VHL exon 2 that altered splicing through E2-skipping in 5 families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially affected splicing, correlating with phenotype severity. This study demonstrates that cryptic exon retention and exon skipping are new VHL alterations and reveals a novel complex splicing regulation of the VHL gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway.


Assuntos
Éxons , Predisposição Genética para Doença , Mutação , Policitemia/genética , Processamento de RNA , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/genética , Adolescente , Adulto , Criança , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Policitemia/classificação , Policitemia/patologia , Adulto Jovem , Doença de von Hippel-Lindau/patologia
16.
Pediatr Blood Cancer ; 65(10): e27272, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29873876

RESUMO

The relationship between myocardial iron load and eccentric myocardial remodeling remains an under-investigated area; it was thought that remodeling is rather linked to fibrosis. This study aims to determine whether or not measures of remodeling can be used as predictors of myocardial iron. For this purpose, 60 patients with thalassemia were studied with 3D echocardiography and myocardial relaxometry (T2*) by Cardiac MRI. 3D derived sphericity index was significantly higher in patients with myocardial iron load. It was correlated with T2* with a 100% sensitivity and specificity (cut-off value of 0.34) to discriminate between patients with and without myocardial iron overload.


Assuntos
Cardiomiopatias/diagnóstico por imagem , Sobrecarga de Ferro/diagnóstico por imagem , Talassemia beta , Adolescente , Criança , Estudos Transversais , Ecocardiografia Tridimensional/métodos , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Miocárdio/patologia , Sensibilidade e Especificidade , Remodelação Ventricular
17.
Orphanet J Rare Dis ; 13(1): 69, 2018 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-29716638

RESUMO

Vitamin A intoxication is a rare cause of liver disease, but the risk increases in patients with underlying liver dysfunction. We present a patient with Shwachman-Diamond Syndrome who developed liver fibrosis, portal hypertension and very severe hepatopulmonary syndrome as a consequence of chronic vitamin A intoxication. She underwent successful liver transplantation with complete resolution of the pulmonary shunting.


Assuntos
Doenças da Medula Óssea/cirurgia , Insuficiência Pancreática Exócrina/cirurgia , Síndrome Hepatopulmonar/etiologia , Síndrome Hepatopulmonar/cirurgia , Lipomatose/cirurgia , Hepatopatias/complicações , Transplante de Fígado/métodos , Vitamina A/toxicidade , Criança , Pré-Escolar , Feminino , Humanos , Hepatopatias/etiologia
20.
Eur J Haematol ; 100(3): 315-322, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29240266

RESUMO

BACKGROUND: Posaconazole is a triazole with limited pharmacokinetic information in children. This study assessed the correlation between posaconazole oral solution daily dosage/kg/body weight and trough plasma level. METHODS: A total of 97 hematology-oncology pediatric patients with ≥1 posaconazole plasma concentration level (PPC) assessment in the first 6 weeks after the start of posaconazole treatment were included. RESULTS: Posaconazole was used as prophylaxis in 84 of 97 (87%) patients and as therapy in 13 of 97 (13%). The median daily dose/kg/bw ranged from 10 to 12 mg in the prophylaxis group and 12.5 to 16.5 mg in the therapy group. The median value of PPC for the prophylaxis group was 0.9 and 0.8 µg/mL at the first and second/third determinations, respectively. Posaconazole prophylaxis failed in 4 of 84 patients (5%). The median value of PPC for the therapy group was 1.5 and 1.4 µg/mL at the first/second and the third determination, respectively. Posaconazole-related side effects were reported in 6 patients and all regressed with the suspension of the drug. In the prophylaxis group, the use of proton-pump inhibitors was significantly associated with a lower PPC, P = 0.04. CONCLUSIONS: Posaconazole may be a valuable antifungal agent in children despite the incomplete knowledge of its pharmacokinetic characteristics.


Assuntos
Anemia Aplástica/terapia , Antifúngicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Hematológicas/terapia , Síndromes de Imunodeficiência/terapia , Linfo-Histiocitose Hemofagocítica/terapia , Micoses/prevenção & controle , Triazóis/farmacocinética , Administração Oral , Adolescente , Anemia Aplástica/microbiologia , Anemia Aplástica/mortalidade , Anemia Aplástica/patologia , Antifúngicos/sangue , Criança , Pré-Escolar , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Feminino , Neoplasias Hematológicas/microbiologia , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Síndromes de Imunodeficiência/microbiologia , Síndromes de Imunodeficiência/mortalidade , Síndromes de Imunodeficiência/patologia , Lactente , Linfo-Histiocitose Hemofagocítica/microbiologia , Linfo-Histiocitose Hemofagocítica/mortalidade , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , Micoses/mortalidade , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Transplante Homólogo , Triazóis/sangue
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