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1.
Artigo em Inglês | MEDLINE | ID: mdl-31660779

RESUMO

Purpose: Adolescents (15-19 years) with soft tissue sarcomas (STS) have worse survival than children. One reason is the former's limited access to expert centers. We investigated where adolescents with STS are treated in Italy, analyzing hospital discharge records (HDRs) countrywide. Methods: We applied to the Health Ministry to obtain the HDRs of all adolescents hospitalized in 2002-2015. We excluded prevalent cases hospitalized with STS in 2002-2006 to obtain a cohort of incident cases 2007-2014. We defined main treatments observing 12 months from diagnosis. Thus, the cohorts end in 2014 rather than 2015. We computed "hospital volume" as the number of adolescents treated by a hospital in 8 years. Patient migration across geographical areas was investigated comparing patients' place of residence and of hospitalization. Results: We identified 381 adolescents with STS, 63% of them were treated at AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica [Italian Association of Pediatric Hematology and Oncology]) centers. These patients were treated at 44 different AIEOP centers, with 1 center treating 62 adolescents (26% of all those treated by AIEOP centers). The remaining 142 adolescents with STS were treated at 66 non-AIEOP centers, one of which managed 17 adolescents. Centers in the north of Italy were more likely to attract patients from other regions. Conclusion: Although HDRs have some limitations, they are the only tool for investigating access to care in countries without national cancer registries. Our findings support the use of HDRs for such purposes, confirm the efficacy of the Italian pediatric oncology network, and make the case for closer collaboration between pediatric and adult oncologists.

2.
J Hum Genet ; 64(11): 1083-1090, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31501477

RESUMO

Primary familial brain calcification (PFBC) is a rare disease characterized by brain calcifications that mainly affect the basal ganglia, thalamus, and cerebellum. Among the four autosomal-dominant genes known to be associated with the disease, SLC20A2 pathogenic variants are the most common, accounting for up to 40% of PFBC dominant cases; variants include both point mutations, small insertions/deletions and intragenic deletions. Over the last 7 years, we have collected a group of 50 clinically diagnosed PFBC patients, who were screened for single nucleotide changes and small insertions/deletions in SLC20A2 by Sanger sequencing. We found seven pathogenic/likely pathogenic variants: four were previously described by our group, and three are reported here (c.303delG, c.21delG, and c.1795-1G>A). We developed and validated a synthetic Multiplex Ligation-dependent Probe Amplification (MLPA) assay for SLC20A2 deletions, covering all ten coding exons and the 5' UTR (SLC20A2-MLPA). Using this method, we screened a group of 43 PFBC-patients negative for point mutations and small insertions/deletions, and identified two novel intragenic deletions encompassing exon 6 NC_000008.10:g.(42297172_42302163)_(423022281_42317413)del, and exons 7-11 including the 3'UTR NC_000008.10:g.(?_42275320)_(42297172_42302163)del. Overall, SLC20A2 deletions may be highly underestimated PFBC cases, and we suggest MLPA should be included in the routine molecular test for PFBC diagnosis.

7.
Transplantation ; 102(5): 823-828, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29377874

RESUMO

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is curative in patients with primary immunodeficiencies. However, pre-HSCT conditioning entails unacceptably high risks if the liver is compromised. The presence of a recurrent opportunistic infection affecting the biliary tree and determining liver cirrhosis with portal hypertension posed particular decisional difficulties in a 7-year-old child with X-linked CD40-ligand deficiency. We aim at adding to the scanty experience available on such rare cases, as successful management with sequential liver transplantation (LT) and HSCT has been reported in detail only in 1 young adult to date. METHODS: A closely sequential strategy, with a surgical complication-free LT, followed by reduced-intensity conditioning, allowed HSCT to be performed only one month after LT, preventing Cryptosporidium parvum recolonization of the liver graft. RESULTS: Combined sequential LT and HSCT resolved the cirrhotic evolution and corrected the immunodeficiency so that the infection responsible for the progressive sclerosing cholangitis did not recur. CONCLUSIONS: Hopefully, this report of the successful resolution of a potentially fatal combination of immunodeficiency and chronic opportunistic infection with end-stage organ damage in a child will encourage others to adapt a sequential transplant approach to this highly complex pathology. However, caution is to be exercised to carefully balance the risks intrinsic to transplant surgery and immunosuppression in primary immunodeficiencies.

8.
Br J Haematol ; 180(5): 680-693, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29359790

RESUMO

Relapse remains the leading cause of treatment failure in children with acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem cell transplantation (HSCT). We retrospectively investigated the prognostic role of minimal residual disease (MRD) before and after HSCT in 119 children transplanted in complete remission (CR). MRD was measured by polymerase chain reaction in bone marrow samples collected pre-HSCT and during the first and third trimesters after HSCT (post-HSCT1 and post-HSCT3). The overall event-free survival (EFS) was 50%. The cumulative incidence of relapse and non-relapse mortality was 41% and 9%. Any degree of detectable pre-HSCT MRD was associated with poor outcome: EFS was 39% and 18% in patients with MRD positivity <1 × 10-3 and ≥1 × 10-3 , respectively, versus 73% in MRD-negative patients (P < 0·001). This effect was maintained in different disease remissions, but low-level MRD had a very strong negative impact only in patients transplanted in second or further CR. Also, MRD after HSCT enabled patients to be stratified, with increasing MRD between post-HSCT1 and post-HSCT3 clearly defining cohorts with a different outcome. MRD is an important prognostic factor both before and after transplantation. Given that MRD persistence after HSCT is associated with dismal outcome, these patients could benefit from early discontinuation of immunosuppression, or pre-emptive immuno-therapy.

9.
Pediatr Blood Cancer ; 65(5): e26958, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29316150

RESUMO

Social media are powerful means of communication that can also have an important role in the healthcare sector. They are sometimes seen with diffidence in the healthcare setting, partly because they risk blurring professional boundaries. This issue is particularly relevant to relations between caregivers and adolescent patients. The Italian Pediatric Hematology and Oncology Association created a multidisciplinary working group to develop some shared recommendations on this issue. After reviewing the literature, the working group prepared a consensus statement in an effort to suggest an analytical approach rather than restrictive rules.

10.
Pediatr Blood Cancer ; 65(2)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29090525

RESUMO

Here, we report a patient with Niemann-Pick disease type B, with early severe onset of disease and pulmonary involvement, treated with hematopoietic stem cell transplant (HSCT) from a bone marrow matched unrelated donor. We confirm that HSCT is feasible and potentially beneficial for patients with severe phenotype. Noteworthy, we discussed the potential usefulness of the activity of peripheral chitotriosidase for the longitudinal evaluation of HSCT success and effectiveness.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Hexosaminidases/sangue , Doença de Niemann-Pick Tipo B/sangue , Doença de Niemann-Pick Tipo B/terapia , Doadores não Relacionados , Aloenxertos , Pré-Escolar , Feminino , Humanos
12.
Oncotarget ; 7(50): 82123-82138, 2016 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-27893415

RESUMO

Acute Graft-versus-Host Disease (GvHD) remains a major complication of allogeneic haematopoietic stem cell transplantation, with a significant proportion of patients failing to respond to first-line systemic corticosteroids. Reliable biomarkers predicting disease severity and response to treatment are warranted to improve its management. Thus, we sought to determine whether pentraxin 3 (PTX3), an acute-phase protein produced locally at the site of inflammation, could represent a novel acute GvHD biomarker. Using a murine model of the disease, we found increased PTX3 plasma levels after irradiation and at GvHD onset. Similarly, plasma PTX3 was enhanced in 115 pediatric patients on day of transplantation, likely due to conditioning, and at GvHD onset in patients experiencing clinical symptoms of the disease. PTX3 was also found increased in skin and colon biopsies from patients with active disease. Furthermore, PTX3 plasma levels at GvHD onset were predictive of disease outcome since they resulted significantly higher in both severe and therapy-unresponsive patients. Multiple injections of rhPTX3 in the murine model of GvHD did not influence the disease course. Taken together, our results indicate that PTX3 constitutes a biomarker of GvHD severity and therapy response useful to tailor treatment intensity according to early risk-stratification of GvHD patients.


Assuntos
Corticosteroides/uso terapêutico , Proteína C-Reativa/análise , Doença Enxerto-Hospedeiro/sangue , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Componente Amiloide P Sérico/análise , Adolescente , Fatores Etários , Animais , Biomarcadores/sangue , Criança , Pré-Escolar , Modelos Animais de Doenças , Resistência a Medicamentos , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Itália , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Valor Preditivo dos Testes , Estudos Prospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Transplante Homólogo , Resultado do Tratamento , Regulação para Cima , Adulto Jovem
13.
J Pediatr Hematol Oncol ; 38(7): e260-2, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27258031

RESUMO

Diamond Blackfan anemia (DBA) is an inherited syndrome usually presenting with severe macrocytic anemia in infancy, paucity of erythroid precursors in the bone marrow, and congenital anomalies. We describe a child with mild, transfusion independent normocytic anemia whose diagnosis of DBA was established by identification of a novel de novo mutation disrupting normal splicing of the ribosomal protein RPL5. The diagnosis of DBA was confirmed by elevated erythrocyte adenosine deaminase levels and an abnormal ribosomal RNA profile. This case demonstrates the usefulness of genomic analysis in establishing the diagnosis of DBA in patients with a nonclassical presentation of the disease.


Assuntos
Anemia de Diamond-Blackfan/diagnóstico , Mutação , Proteínas Ribossômicas/genética , Adenosina Desaminase/sangue , Anemia de Diamond-Blackfan/genética , Feminino , Humanos , Lactente
14.
Br J Haematol ; 172(5): 782-5, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26763766

RESUMO

Diamond-Blackfan anaemia (DBA) is an inherited disease characterized by pure erythroid aplasia that has been tagged as a 'ribosomopathy'. We report a multi-centre study focused on the analysis of rRNA processing of 53 Italian DBA patients using capillary electrophoresis analysis of rRNA maturation of the 40S and 60S ribosomal subunits. The ratio of 28S/18S rRNA was higher in patients with mutated ribosomal proteins (RPs) of the small ribosomal subunit. In contrast, patients with mutated RPs of the large ribosomal subunit (RPLs) had a lower 28S/18S ratio. The assay reported here would be amenable for development as a diagnostic tool.


Assuntos
Anemia de Diamond-Blackfan/diagnóstico , RNA Ribossômico/genética , Anemia de Diamond-Blackfan/genética , Estudos de Casos e Controles , Eletroforese Capilar/métodos , Deleção de Genes , Humanos , Mutação
15.
PLoS One ; 10(9): e0138200, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26394034

RESUMO

Diamond-Blackfan Anaemia (DBA) is a rare inherited anaemia caused by heterozygous mutations in one of 13 ribosomal protein genes. Erythroid progenitors (BFU-E and CFU-E) in bone marrow (BM) show a proapoptotic phenotype. Suspicion of DBA is reached after exclusion of other forms of BM failure syndromes. To improve DBA diagnosis, which is confirmed by mutation analysis, we tested a new approach based on the study of extracellular vesicles (EVs) isolated from plasma by differential centrifugations and analysed by flow cytometry. We chose CD34, CD71 and CD235a markers to study erythroid EVs. We characterised the EVs immunophentoypic profiles of 13 DBA patients, 22 healthy controls and 16 patients with other haematological diseases. Among the three EVs clusters we found, only the CD34+/CD71low population showed statistically significant differences between DBA patients and controls (p< 0.05). The absence of this cluster is in agreement with the low levels of BFU-E found in DBA patients. The assessment of ROC curves demonstrated the potential diagnostic value of this population. We suggest that this assay may be useful to improve DBA diagnosis as a quicker and less invasive alternative to BM BFU-E culture analysis.


Assuntos
Anemia de Diamond-Blackfan/diagnóstico , Células Precursoras Eritroides/metabolismo , Vesículas Extracelulares/metabolismo , Imunofenotipagem/métodos , Adolescente , Adulto , Anemia de Diamond-Blackfan/sangue , Anemia de Diamond-Blackfan/genética , Antígenos CD/sangue , Antígenos CD34/sangue , Biomarcadores/sangue , Criança , Pré-Escolar , Ensaio de Unidades Formadoras de Colônias , Feminino , Citometria de Fluxo , Glicoforina/análise , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Curva ROC , Receptores da Transferrina/sangue , Adulto Jovem
16.
Br J Haematol ; 171(4): 566-73, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26223157

RESUMO

Paediatric patients with acute myeloid leukaemia (AML) who fail induction due to primary resistance to chemotherapy account for a significant proportion of cases and have a particularly dismal prognosis. We report the clinical and biological data, and final outcome of 48 paediatric patients with primary-resistant AML enrolled in the Associazione Italiana di Ematologia e Oncologia Pediatrica AML 2002/01 clinical trial. These patients had a significantly higher white blood cell count at diagnosis compared to other AML patients. Cytogenetic and molecular features did not differ between patients with primary induction failure and patients allocated to the high-risk group. For the whole patient population, the probability of overall survival, event-free survival (EFS) and disease-free survival (DFS) was 21·8% ± 6·2, 20·4% ± 5·9, and 49·5% ± 11·3, respectively. Twenty-eight (58%) patients received haematopoietic stem cell transplantation (HSCT); 3 were autologous and 25 were allogeneic. Patients who underwent HSCT had improved EFS (31·2% vs. 5%, P < 0·0001). Only one of the 20 patients who did not receive HSCT is alive and disease free. The 19 patients in complete remission at time of HSCT showed significantly better DFS than the 9 with active disease (46% vs. 0%, P = 0·02). This study represents one of the largest series with long-term follow up of paediatric AML patients with primary refractory disease. Children who underwent transplantation had an encouraging long-term outcome. Disease recurrence remains the major cause of treatment failure; a better understanding of the disease biology is desirable to develop more effective treatment strategies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Aloenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Incidência , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Prognóstico , Recidiva , Indução de Remissão , Condicionamento Pré-Transplante , Transplante Autólogo , Falha de Tratamento
17.
Biol Blood Marrow Transplant ; 21(6): 1099-105, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25708218

RESUMO

Robust T cell function recovery has been shown to be crucial in determining allogeneic hematopoietic stem cell transplantation (HSCT) outcome, and there is growing evidence that the thymus plays a central role in regulating this process. We performed a long-term analysis of the role of thymic activity recovery in a population of pediatric patients undergoing allogeneic HSCT by signal joint T cell receptor excision circle (sjTREC) quantification. In this study, characterized by a long-term follow-up (median, 72 months), we found patients with higher levels of sjTRECs before transplantation had a statistically significant reduced risk of death compared with patients with lower values (relative risk, .31; 95% confidence interval, .30 to .32; P = .02), showing this different outcome was mainly related to a reduction of relapse incidence (14% versus 43%, P = .02). Unlike previous reports, we observed no correlation between sjTREC levels and lymphocyte recovery. Moreover, we confirmed that only graft-versus-host disease influenced thymic activity after transplantation. In conclusion, our results suggest an association between pretransplantation thymic activity and the long-term outcome of pediatric patients undergoing HSCT, mainly through a reduction of relapse opportunities.


Assuntos
Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Timo/patologia , Condicionamento Pré-Transplante , Adolescente , Criança , Pré-Escolar , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Humanos , Imunossupressores/uso terapêutico , Lactente , Recém-Nascido , Masculino , Agonistas Mieloablativos/uso terapêutico , Prognóstico , Estudos Prospectivos , Receptores de Antígenos de Linfócitos T alfa-beta/análise , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Recidiva , Irmãos , Análise de Sobrevida , Linfócitos T/imunologia , Linfócitos T/patologia , Timo/imunologia , Transplante Homólogo , Doadores não Relacionados , Adulto Jovem
18.
Am J Hematol ; 89(10): 985-91, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25042156

RESUMO

Diamond Blackfan anemia (DBA), a syndrome primarily characterized by anemia and physical abnormalities, is one among a group of related inherited bone marrow failure syndromes (IBMFS) which share overlapping clinical features. Heterozygous mutations or single-copy deletions have been identified in 12 ribosomal protein genes in approximately 60% of DBA cases, with the genetic etiology unexplained in most remaining patients. Unlike many IBMFS, for which functional screening assays complement clinical and genetic findings, suspected DBA in the absence of typical alterations of the known genes must frequently be diagnosed after exclusion of other IBMFS. We report here a novel deletion in a child that presented such a diagnostic challenge and prompted development of a novel functional assay that can assist in the diagnosis of a significant fraction of patients with DBA. The ribosomal proteins affected in DBA are required for pre-rRNA processing, a process which can be interrogated to monitor steps in the maturation of 40S and 60S ribosomal subunits. In contrast to prior methods used to assess pre-rRNA processing, the assay reported here, based on capillary electrophoresis measurement of the maturation of rRNA in pre-60S ribosomal subunits, would be readily amenable to use in diagnostic laboratories. In addition to utility as a diagnostic tool, we applied this technique to gene discovery in DBA, resulting in the identification of RPL31 as a novel DBA gene.


Assuntos
Precursores de RNA , Processamento Pós-Transcricional do RNA/genética , RNA Ribossômico , Proteínas Ribossômicas , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/metabolismo , Feminino , Humanos , Lactente , Células K562 , Precursores de RNA/genética , Precursores de RNA/metabolismo , RNA Ribossômico/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Subunidades Ribossômicas Maiores de Eucariotos/genética , Subunidades Ribossômicas Maiores de Eucariotos/metabolismo , Subunidades Ribossômicas Menores de Eucariotos/genética , Subunidades Ribossômicas Menores de Eucariotos/metabolismo
19.
Br J Haematol ; 165(5): 673-81, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24611452

RESUMO

Allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative option for patients with Diamond Blackfan anaemia (DBA). We report the transplantation outcome of 30 Italian DBA patients referred to the Italian Association of Paediatric Haematology and Oncology Registry between 1990 and 2012. This is one of the largest national registry cohorts of transplanted DBA patients. Most patients (83%) were allografted after 2000. A matched sibling donor was employed in 16 patients (53%), the remaining 14 patients (47%) were transplanted from matched unrelated donors. Twenty-eight of the 30 patients engrafted. One patient died at day +6 due to veno-occlusive disease without achieving neutrophil recovery and another patient remained transfusion-dependent despite the presence of a full donor chimerism. The 5-year overall survival and transplant-related mortality was 74·4% and 25·6%, respectively. Patients younger than 10 years as well as those transplanted after 2000 showed a significantly higher overall survival and a significantly lower risk of transplant-related mortality. No difference between donor type was observed. Our data suggest that allogeneic HSCT from a related or unrelated donor was a reasonable alternative to transfusion therapy in young and well chelated DBA patients.


Assuntos
Anemia de Diamond-Blackfan/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Adolescente , Fatores Etários , Anemia de Diamond-Blackfan/mortalidade , Causas de Morte , Criança , Pré-Escolar , Feminino , Seguimentos , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Lactente , Itália/epidemiologia , Masculino , Sistema de Registros , Fatores de Risco , Análise de Sobrevida
20.
Pediatr Blood Cancer ; 61(7): 1319-21, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24453067

RESUMO

Mutations in the hematopoietic transcription factor GATA-1 alter the proliferation/differentiation of hemopoietic progenitors. Mutations in exon 2 interfere with the synthesis of the full-length isoform of GATA-1 and lead to the production of a shortened isoform, GATA-1s. These mutations have been found in patients with Diamond-Blackfan anemia (DBA), a congenital erythroid aplasia typically caused by mutations in genes encoding ribosomal proteins. We sequenced GATA-1 in 23 patients that were negative for mutations in the most frequently mutated DBA genes. One patient showed a c.2T > C mutation in the initiation codon leading to the loss of the full-length GATA-1 isoform.


Assuntos
Anemia de Diamond-Blackfan/genética , Códon de Iniciação/genética , Fator de Transcrição GATA1/genética , Mutação Puntual , Feminino , Humanos , Masculino , Isoformas de Proteínas/genética
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