La maggior parte dei contributi che riguardano la relazione tra operatore sanitario e paziente ha... more La maggior parte dei contributi che riguardano la relazione tra operatore sanitario e paziente ha reso evidente la necessitŕ di approfondire un aspetto importante della formazione dell'operatore, quello che riguarda l'acquisizione di abilitŕ a prestare attenzione alla "risonanza emotiva" suscitata dalla relazione con l'altro. A questo proposito č in corso una ricerca presso il reparto di Oncologia pediatrica dell'ospedale Sant'Orsola di Bologna che ha tra gli obiettivi quello di verificare il grado di coerenza, nel colloquio clinico tra medico e genitore del giovane paziente, della risposta emozionale non verbale del medico, con i segnali espressivo-emozionali prodotti dal genitore. I risultati confermano che la maggior parte dei segnali non verbali e delle espressioni prodotte dal medico hanno, soprattutto, funzione comunicativo- relazionale e non esprimono emozioni in sintonia con quelle espresse dal genitore. Tale aspetto si puň considerare indicativ...
Many studies have reported a more favorable outcome in younger patients with Hodgkin lymphoma (HL... more Many studies have reported a more favorable outcome in younger patients with Hodgkin lymphoma (HL). The aims of this study were to find an appropriate age cutoff able to identify low-risk children and to describe the natural history of 135 very young patients affected by classic HL (cHL). The best age cutoff was identified at 7 years of age. EFS (p = .0451) and PFS (p = .00921) were significantly better in the group of younger patients. The OS rate at 10 years was 97.0% in the younger group and 92.5% in the older one (p = .0448). However, age was not found to be an independent prognostic factor in multivariate analysis and the better prognosis in younger patients seems to be related to more favorable disease characteristics at presentation.
A wait and see approach for desmoid tumors (DT) has become part of the routine treatment strategy... more A wait and see approach for desmoid tumors (DT) has become part of the routine treatment strategy. However, predictive factors to select the risk of progressive disease are still lacking. A translational project was run in order to identify genomic signatures in patients enrolled within an Italian prospective observational study. Among 12 DT patients (10 CTNNB1-mutated and 2 wild type) enrolled from our institution only two patients (17%) showed a progressive disease. Tumor biopsies were collected for whole exome sequencing. Overall, DT exhibited low somatic sequence mutation rate and no additional recurrent mutation was found. In the two wild type (WT) cases, two novel alterations were detected: a complex deletion of APC and a pathogenic mutation of LAMTOR2. Focusing on WT DT subtype, deep sequencing of CTNNB1, APC and LAMTOR2 was conducted on a retrospective series of 11 WT DT using a targeted approach. No other mutation of LAMTOR2 was detected, while APC was mutated in two cases....
Bronchiectasis in pediatric age is a heterogeneous disease associated with significant morbidity.... more Bronchiectasis in pediatric age is a heterogeneous disease associated with significant morbidity.The most common medical conditions leading to bronchial damage are previous pneumonia and recurrent lower airway infections followed by underlying diseases such as immune-deficiencies, congenital airway defects, recurrent aspirations and mucociliary clearance disorders.The most frequent symptom is chronic wet cough. The introduction of high-resolution computed tomography (HRCT) has improved the time of diagnosis allowing earlier treatment.However, the term "bronchiectasis" in pediatric age should be used with caution, since some lesions highlighted with HRCT may improve or regress. The use of chest magnetic resonance imaging (MRI) as a radiation-free technique for the assessment and follow-up of lung abnormalities in non-Cystic Fibrosis chronic lung disease is promising.Non-Cystic Fibrosis Bronchiectasis management needs a multi-disciplinary team. Antibiotics and airway clearan...
The inflammatory myofibroblastic tumor (IMT) is a rare lesion of unclear etiology and variable cl... more The inflammatory myofibroblastic tumor (IMT) is a rare lesion of unclear etiology and variable clinical course, consisting of a proliferation of fibroblasts and myofibroblasts, mixed with inflammatory cells. Synonyms of IMT are inflammatory pseudotumor and plasma cell granuloma reflecting the alleged inflammatory nature attributed to this lesion, even though this heterogeneity in the disease denomination is probably involved in a dispersion of the literature data. Among primary pulmonary neoplasms, it represents the most frequent endobronchial tumor of childhood and beyond the lung it has been described mainly in the bladder, mediastinum and mesentery. Despite having a tendency for local recurrence, the risk of distant metastasis is low. Clinical presentation depends on localization therefore lung peripheral lesions are often asymptomatic resulting in a delayed diagnosis. Radiological findings can suggest the diagnosis that must be confirmed by histopathology assessment. The tumor h...
A three-miRNA-based expression signature at diagnosis can predict occurrence of relapse in childr... more A three-miRNA-based expression signature at diagnosis can predict occurrence of relapse in children with t(8;21) RUNX1-RUNX1T1 acute myeloid leukaemia Children with acute myeloid leukaemia (AML) harbouring CBF anomalies notoriously have a more favourable prognosis than other AML cytogenetic subgroups. In the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP)-AML 2002/01 protocol, these patients were allocated to the standard-risk (SR) group and all achieved morphological complete remission (CR) after induction therapy (Pession et al, 2013; Manara et al, 2014). However, approximately one-third of themin particular those harbouring t(8;21)RUNX1/ RUNX1T1relapsed (Pession et al, 2013). These results prompted us to refine the definition of SR, trying to identify those t(8;21) AML patients who could be pre-emptively directed to an increased chemotherapy treatment or to allogeneic haematopoietic stem cell transplantation to properly tackle their higher risk to relapse. To this purpose, we performed, for the first time, a retrospective analysis to identify a prognostic model, based on micro RNA (miRNA) expression, capable of enhancing the prediction of recurrence in paediatric t(8;21) AML patients. We determined the miRNA expression profile of 33 patients enrolled in AIEOP AML 2002/01. In our cohort, 14 out of 33 (42Á4%) patients suffered relapse after a median time of 280 days and 6 of them Fig 1. miRNAs expression in t(8;21)RUNX1/RUNX1T1 patients. (A) Supervised hierarchical clustering analysis (Spearman Rank correlation distance) using the 115 differentially expressed miRNAs (Kruskal-Wallis test, P < 0Á05) identified among t(8;21)RUNX1/RUNX1T1 de novo acute myeloid leukaemia (AML) patients who did (red bar) or did not (green bar) experience leukaemia relapse. (B) Cumulative incidence of relapse (CIR) in t(8;21) AML patients stratified according to miRNA expression in the Training (N = 17) and Validation (N = 16) sets. Significant differences between groups were assessed by the Gray test with P-value < 0Á05.
A 3-year-old girl with Spinal Muscular Atrophy type I presented with a right pneumonia. On physic... more A 3-year-old girl with Spinal Muscular Atrophy type I presented with a right pneumonia. On physical examination pulmonary auscultation revealed an asymmetry of breath sounds between the 2 hemithoraces, owing to decreased breath sounds in the right hemithorax. Blood tests were normal. The initial working diagnosis was a suspected area of mucus accumulation. A treatment with Free Aspire was started. Within a few days, the girl was discharged with a normal physical examination and X-ray study result. Spinal Muscular Atrophy is a rare neuromuscular disorder characterized by loss of motor neurons and progressive muscle wasting. Cough in these patients result ineffective. Free-Aspire is an electromedical machine for removing bronchoalveolar secretions. The case show that Free Aspire in patients with ineffective cough and impaired removal of secretions is a safe and effective device for the removal of bronchial secretions and could be an another help in the management of airway clearance.
Background: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory arthritis of unknown or... more Background: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory arthritis of unknown origin which can be considered an autoimmune disease (AD). The aim of this study is to analyse the presence of two or more autoimmune diseases (polyautoimmunity) in patients suffering from JIA and to evaluate the occurrence of ADs in their families. Methods: Seventy-nine patients diagnosed with JIA aged 0-21 years, admitted to the Paediatric Rheumatology Unit, Sant'Orsola-Malpighi Hospital, Bologna were screened for ADs. Parents were asked about the presence of ADs in the living relatives of first and second degree. Results: Twelve of 79 patients (15.2%) had at least 1 AD associated with JIA. Eight patients (10.1%) suffered from autoimmune thyroid disease (AITD), three patients had celiac disease, three patients suffered from psoriasis, one from alopecia and 1 from insulin-dependent diabetes mellitus. The average age at diagnosis was 13.2 years and the cumulative incidence of AITD was 36%. Seventy-six families were studied for a total of 438 relatives. The prevalence of ADs was 13%, greater in first-degree relatives (16.7%) than in second-degree ones (11.1%). The most common AD was AITD; there was no difference in JIA's age of presentation between patients with positive and negative familiarity with ADs (p > 0.05). Conclusion: Children and adolescents with JIA present a high autoimmunity burden, most commonly represented by AITD. Familial autoimmunity is not negligible in patients suffering from JIA (almost 50% of patients have at least one relative with an AD) and it should always be carefully examined.
Although rabbit anti-T-lymphocyte globulin (ATLG) is largely used for the prevention of immune-me... more Although rabbit anti-T-lymphocyte globulin (ATLG) is largely used for the prevention of immune-mediated complications in patients given allogeneic haemopoietic stem-cell transplantation (HSCT) from an unrelated donor, the optimum dose of this drug in children is still undefined. We aimed to test whether a higher dose of ATLG was superior to a lower dose for prevention of grade II-IV acute graft-versus-host disease (GVHD). We conducted a multicentre, randomised, open-label, phase 3 trial in seven Italian centres comparing two different doses of ATLG (30 mg/kg vs 15 mg/kg, given intravenously over 3 days, from day -4 to -2) in children (aged 0-18 years) with haematological malignancies transplanted from an unrelated donor, selected using high-resolution typing for HLA-class I/II loci. All patients received a myeloablative regimen and cyclosporine-A plus short-term methotrexate as post-transplantation GVHD prophylaxis. Patients were randomly assigned (1:1) to either of the two groups and were stratified by the degree of HLA-compatibility with their donor, the source of haemopoietic stem cells used (bone marrow vs peripheral blood stem cells), and the disease risk category. The randomisation was open label; all investigators were aware of the treatment allocation. The primary endpoint of the study was 100-day cumulative incidence of grade II-IV acute GVHD. Statistical analyses were done according to the per-protocol principle. Other outcomes included cumulative incidence of chronic GVHD, non-relapse mortality, disease recurrence, and probability of overall survival and event-free survival. This study was registered with ClinicalTrials.gov, number NCT00934557. Between Jan 15, 2008, and Sept 25, 2012, 89 patients were randomly assigned to the 30 mg/kg ATLG group and 91 to the 15 mg/kg ATLG group; 84 patients in the 30 mg/kg ATLG group and 88 in the 15 mg/kg ATLG group were included in the analysis. The median follow-up for the whole study population was 3·4 years (IQR 1·7-5·1). The 100-day cumulative incidence of grade II-IV acute GVHD was 36% (95% CI 28-48) in the 15 mg/kg ATLG group and 29% (20-40) in the 30 mg/kg ATLG group (hazard ratio [HR] 0·74, 95% CI 0·44-1·25; p=0·26). The cumulative incidence of non-relapse mortality was 9% (5-18) in the 15 mg/kg ATLG group and 19% (12-30) in the 30 mg/kg ATLG group (HR 2·08, 0·89-4·96; p=0·092). Cumulative incidence of disease recurrence was 15% (12-24): 14% (8-23) in the 15 mg/kg ATLG group versus 20% (13-31) in the 30 mg/kg ATLG group (HR 1·54, 0·74-3·21; p=0·25). The 5-year overall survival probability was 70% (62-77) for the whole study population: 78% (69-87) in the 15 mg/kg ATLG group versus 62% (50-73) in the 30 mg/kg ATLG group (HR 1·80, 1·01-3·20; p=0·045). The 5-year event-free survival was 77% for children in the 15 mg/kg ATLG group versus 61% in the 30 mg/kg ATLG group (HR 1·87, 1·07-3·28; p=0·028). Children with haematological malignancies transplanted from unrelated donors selected through high-resolution HLA-typing benefit from the use of a 15 mg/kg ATLG dose in comparison with a 30 mg/kg ATLG dose. ATLG at 15 mg/kg should thus be regarded as the standard serotherapy regimen for unrelated donor allogeneic HSCT in this patient population. Future randomised studies will continue to aim to optimise patient outcome and strategies to prevent acute GVHD occurrence. Fresenius/Neovii Biotech.
T-Acute Lymphoblastic Leukemia (T-ALL) remains a subgroup of pediatric ALL, with a lower response... more T-Acute Lymphoblastic Leukemia (T-ALL) remains a subgroup of pediatric ALL, with a lower response to standard chemotherapy. Some recent studies established the fundamental role of epigenetic aberrations such as DNA hypermethylation, to influence patients' outcome and response to chemotherapy. Moreover, L-asparaginase is an important chemotherapeutic agent for treatment of ALL and resistance to this drug has been linked to ASNS expression, which can be silenced through methylation. Therefore, we tested whether the sensitivity of T-ALL cell lines towards L-asparaginase is correlated to the epigenetic status of ASNS gene and whether the sensitivity can be modified by concurrent demethylating treatment. Hence we treated different T-ALL cell lines with L-asparaginase and correlated different responses to the treatment with ASNS expression. Then we demonstrated that the ASNS expression was dependent on the methylation status of the promoter. Finally we showed that, despite the demethy...
TW2003, the third Italian prospective study on Wilms tumor, aimed to improve survival in patients... more TW2003, the third Italian prospective study on Wilms tumor, aimed to improve survival in patients with stage III-IV tumors, de-escalate therapy for stage I-II nonanaplastic tumors, refine the risk stratification of therapy, and develop a national infrastructure for biobanking and central pathology review. TW2003 recruited children 18 years old or younger with primary intrarenal tumors. Local physicians chose nephrectomy with or without preoperative chemotherapy as the initial treatment based on the risk of unsafe and/or incomplete immediate surgery. The main drivers for adjuvant therapy were tumor stage and diffuse anaplasia. A new risk stratification schema was investigated, incorporating patient age, reason for stage III designation and completeness of lung nodule response in stage IV disease. We report on 453 patients with unilateral Wilms tumor. Preoperative chemotherapy was administered to 42% of patients. The 5-year event-free survival and overall survival rates were 89.1% (95...
Despite remarkable progress in polychemotherapy protocols, pediatric B-cell acute lymphoblastic l... more Despite remarkable progress in polychemotherapy protocols, pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains fatal in around 20% of cases. Hence, novel targeted therapies are needed for patients with poor prognosis. Glucocorticoids (GCs) are drugs commonly administrated for B-ALL treatment. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling pathway is frequently observed in B-ALL and contributes to GC-resistance. Here, we analyzed for the first time to our knowledge, the therapeutic potential of pan and isoform-selective PI3K p110 inhibitors, alone or combined with dexamethasone (DEX), in B-ALL leukemia cell lines and patient samples. We found that a pan PI3K p110 inhibitor displayed the most powerful cytotoxic effects in B-ALL cells, by inducing cell cycle arrest and apoptosis. Both a pan PI3K p110 inhibitor and a dual γ/δ PI3K p110 inhibitor sensitized B-ALL cells to DEX by restoring nuclear translocation of the GC recept...
Since 1972, children affected by cancer took advantage from multi-centric diagnostic and therapeu... more Since 1972, children affected by cancer took advantage from multi-centric diagnostic and therapeutic protocols produced by the Italian Association of paediatric haematology and oncology (AIEOP). At the beginning, these protocols were used in few well-trained centres, later in almost all Italian haemato-oncological centres. The need of a careful monitoring of his own activity induced AIEOP to achieve, in 1989, an Italian hospital- based registry (database Mod.1.01) of malignant tumours diagnosed and treated in the participating centres, with the aim to quantify the number of cases diagnosed and treated in the different centres, the agreement (or not) to official diagnostic- therapeutic protocols, and the extraregional migration. The database Mod.1.01, which is available via web to the current 55 AIEOP centres since 2000, recruits annually about 1,400 children (0-14 years) and 200 adolescents (15-19 years). While the first accounts for over 90% of expected subjects, the latter are onl...
The aim of this study was the application of complementarity-determining region-3 spectratyping a... more The aim of this study was the application of complementarity-determining region-3 spectratyping analysis to determine T-cell-repertoire complexity and to detect T-cell-clone expansion, as a measure of immune response in nonfunctioning kidney transplants (group hemodialysis-transplant [HD-Tx]), nontransplanted dialysis patients (group hemodialysis [HD]), and normal subjects as controls (group C). Analysis of T-cell receptor (TCR) diversity by spectratyping was applied to peripheral blood samples collected from 21 subjects: eight in group HD-Tx, seven in group HD, and six in group C. Considering the extent of the skew in TCR variable region repertoires as a measure of clonal T cells, we found that the number of altered spectra showed a progressive increase from normal subjects to dialysis patients and to nonfunctioning kidney transplants, respectively. Healthy subjects had the lowest number of altered spectra, and patients with nonfunctioning kidney transplants the highest. Difference...
Myoepithelial neoplasms (MN) are rare and not well-circumstanced entities displaying a heterogene... more Myoepithelial neoplasms (MN) are rare and not well-circumstanced entities displaying a heterogeneous spectrum of genetic abnormalities, including EWSR1, FUS and PLAG1 rearrangements. However, in the remaining MN no other fusion gene has been described and knowledge concerning secondary acquired molecular alterations is still poor. Therefore, we screened 5 cases of MN of the soft tissue by RNA sequencing with the aim of identifying novel fusion transcripts.A novel SRF-E2F1 fusion was detected in two cases: one was negative for other fusions while the other showed also the presence of FUS-KLF17. The fusion was validated through independent techniques and, in both cases, SRF-E2F1 was detected only in a subclone of the tumoral mass. SRF-E2F1 maintained the coding frame, thus leading to the translation of a chimeric protein containing the DNA-binding domain of SRF and the trans-activation domain of E2F1. Moreover, ectopical expression of SRF-E2F1 demonstrated that the chimeric transcript...
Extraskeletal myxoid chondrosarcoma (EMC) is a very rare sarcoma most often arising in the soft t... more Extraskeletal myxoid chondrosarcoma (EMC) is a very rare sarcoma most often arising in the soft tissue. Rare EMC of the bone have been reported. EMC exhibits distinctive clinico-pathological and genetic features; however, despite the name, it lacks any feature of cartilaginous differentiation. EMC is characterized by the rearrangement of the NR4A3, which, in most cases (about 62-75%), is fused with EWSR1 and less frequently with other partners, including TAF15 (27%), TCF12 (4%), TFG and FUS. We herein report the identification by whole-transcriptome sequencing of HSPA8 as a novel fusion partner of NR4A3 in a case of EMC. FISH analysis confirmed the presence of a genomic HSPA8-NR4A3 translocation in the vast majority of tumour cells. Our findings expand the spectrum of NR4A3 fusion partners involved in EMC pathobiology. This article is protected by copyright. All rights reserved.
Letter to the Editors: Concerning "Divergent clinical outcomes of alphaglucosidase enzyme replace... more Letter to the Editors: Concerning "Divergent clinical outcomes of alphaglucosidase enzyme replacement therapy in two siblings with infantile-onset Pompe disease treated in the symptomatic or pre-symptomatic state" by Takashi M et al. Dear Editors, We read with interest the article by Takashi M et al. that recently appeared in MGM Report. Because many open issues remain about the outcome of infantile Pompe disease (IPD), we describe here our experience with two IPD siblings born to related parents and treated with enzyme replacement therapy (ERT) in the symptomatic and the pre-symptomatic state. In the symptomatic child with severe respiratory insufficiency and hypertrophic cardiomyopathy, no detectable alpha-glucosidase acid (GAA) activity and homozygous substitution c.1A N G on the GAA gene, ERT (α-glucosidase, 20 mg/kg) was started at 6 months of age. Cardiomyopathy improved but not muscular function, and he underwent tracheostomy and gastrostomy. Early evaluation of IPD in his newborn sister showed hypertrophic cardiomyopathy, absent plasma GAA activity, CRIM negative (CN) status and the same genotype. As reported by Banugaria et al. [1], we performed immune tolerance induction (ITI) with rituximab and methotrexate and intravenous immunoglobulin before ERT (at 30 days). Her cardiomyopathy resolved after 1.5 months, and respiratory and neurological examinations appeared normal at the last evaluation (7 months). ERT effectively and rapidly reduces glycogen cardiac accumulation [2,3,4], regardless of CRIM status, but its early commencement does not prevent later anti-rhGAA IgG antibody formation [1,5,6]. Thus, in our older case, as in his sister, ERT effectively reduced cardiomyopathy, but anti-rhGAA IgG production reduced the therapeutic efficacy, worsening the neuromuscular outcome. Patients described by M. Takashi could be CRIM positive due to the presence of a missense mutation. Therefore, their outcome would depend more on the age at the start of ERT than on the CRIM status. We think that IPD patients should be screened as early as possible for CRIM status before ERT. In CN patients, it is important to do ITI and ERT to reduce anti-rhGAA IgG [7] production and to improve the natural history.
CBFA2T3-GLIS2 is a fusion gene found in 17% of non-Down syndrome acute megakaryoblastic leukemia ... more CBFA2T3-GLIS2 is a fusion gene found in 17% of non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL, FAB M7) and in 8% of pediatric cytogenetically normal acute myeloid leukemia (CN-AML, in association with several French-American-British (FAB) subtypes). Children with AML harboring this aberration have a poor outcome, regardless of the FAB subtype. This fusion gene drives a peculiar expression pattern and leads to overexpression of some of Hedgehog-related genes. GLI-similar protein 2 (GLIS2) is closely related to the GLI family, the final effectors of classic Hedgehog pathway. These observations lend compelling support to the application of GLI inhibitors in the treatment of AML with the aberration CBFA2T3-GLIS2. GANT61 is, nowadays, the most potent inhibitor of GLI family proteins. We exposed to GANT61 AML cell lines and primary cells positive and negative for CBFA2T3-GLIS2 and analyzed the effect on cellular viability, induction of apoptosis, cell cycle, and expression...
La maggior parte dei contributi che riguardano la relazione tra operatore sanitario e paziente ha... more La maggior parte dei contributi che riguardano la relazione tra operatore sanitario e paziente ha reso evidente la necessitŕ di approfondire un aspetto importante della formazione dell'operatore, quello che riguarda l'acquisizione di abilitŕ a prestare attenzione alla "risonanza emotiva" suscitata dalla relazione con l'altro. A questo proposito č in corso una ricerca presso il reparto di Oncologia pediatrica dell'ospedale Sant'Orsola di Bologna che ha tra gli obiettivi quello di verificare il grado di coerenza, nel colloquio clinico tra medico e genitore del giovane paziente, della risposta emozionale non verbale del medico, con i segnali espressivo-emozionali prodotti dal genitore. I risultati confermano che la maggior parte dei segnali non verbali e delle espressioni prodotte dal medico hanno, soprattutto, funzione comunicativo- relazionale e non esprimono emozioni in sintonia con quelle espresse dal genitore. Tale aspetto si puň considerare indicativ...
Many studies have reported a more favorable outcome in younger patients with Hodgkin lymphoma (HL... more Many studies have reported a more favorable outcome in younger patients with Hodgkin lymphoma (HL). The aims of this study were to find an appropriate age cutoff able to identify low-risk children and to describe the natural history of 135 very young patients affected by classic HL (cHL). The best age cutoff was identified at 7 years of age. EFS (p = .0451) and PFS (p = .00921) were significantly better in the group of younger patients. The OS rate at 10 years was 97.0% in the younger group and 92.5% in the older one (p = .0448). However, age was not found to be an independent prognostic factor in multivariate analysis and the better prognosis in younger patients seems to be related to more favorable disease characteristics at presentation.
A wait and see approach for desmoid tumors (DT) has become part of the routine treatment strategy... more A wait and see approach for desmoid tumors (DT) has become part of the routine treatment strategy. However, predictive factors to select the risk of progressive disease are still lacking. A translational project was run in order to identify genomic signatures in patients enrolled within an Italian prospective observational study. Among 12 DT patients (10 CTNNB1-mutated and 2 wild type) enrolled from our institution only two patients (17%) showed a progressive disease. Tumor biopsies were collected for whole exome sequencing. Overall, DT exhibited low somatic sequence mutation rate and no additional recurrent mutation was found. In the two wild type (WT) cases, two novel alterations were detected: a complex deletion of APC and a pathogenic mutation of LAMTOR2. Focusing on WT DT subtype, deep sequencing of CTNNB1, APC and LAMTOR2 was conducted on a retrospective series of 11 WT DT using a targeted approach. No other mutation of LAMTOR2 was detected, while APC was mutated in two cases....
Bronchiectasis in pediatric age is a heterogeneous disease associated with significant morbidity.... more Bronchiectasis in pediatric age is a heterogeneous disease associated with significant morbidity.The most common medical conditions leading to bronchial damage are previous pneumonia and recurrent lower airway infections followed by underlying diseases such as immune-deficiencies, congenital airway defects, recurrent aspirations and mucociliary clearance disorders.The most frequent symptom is chronic wet cough. The introduction of high-resolution computed tomography (HRCT) has improved the time of diagnosis allowing earlier treatment.However, the term "bronchiectasis" in pediatric age should be used with caution, since some lesions highlighted with HRCT may improve or regress. The use of chest magnetic resonance imaging (MRI) as a radiation-free technique for the assessment and follow-up of lung abnormalities in non-Cystic Fibrosis chronic lung disease is promising.Non-Cystic Fibrosis Bronchiectasis management needs a multi-disciplinary team. Antibiotics and airway clearan...
The inflammatory myofibroblastic tumor (IMT) is a rare lesion of unclear etiology and variable cl... more The inflammatory myofibroblastic tumor (IMT) is a rare lesion of unclear etiology and variable clinical course, consisting of a proliferation of fibroblasts and myofibroblasts, mixed with inflammatory cells. Synonyms of IMT are inflammatory pseudotumor and plasma cell granuloma reflecting the alleged inflammatory nature attributed to this lesion, even though this heterogeneity in the disease denomination is probably involved in a dispersion of the literature data. Among primary pulmonary neoplasms, it represents the most frequent endobronchial tumor of childhood and beyond the lung it has been described mainly in the bladder, mediastinum and mesentery. Despite having a tendency for local recurrence, the risk of distant metastasis is low. Clinical presentation depends on localization therefore lung peripheral lesions are often asymptomatic resulting in a delayed diagnosis. Radiological findings can suggest the diagnosis that must be confirmed by histopathology assessment. The tumor h...
A three-miRNA-based expression signature at diagnosis can predict occurrence of relapse in childr... more A three-miRNA-based expression signature at diagnosis can predict occurrence of relapse in children with t(8;21) RUNX1-RUNX1T1 acute myeloid leukaemia Children with acute myeloid leukaemia (AML) harbouring CBF anomalies notoriously have a more favourable prognosis than other AML cytogenetic subgroups. In the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP)-AML 2002/01 protocol, these patients were allocated to the standard-risk (SR) group and all achieved morphological complete remission (CR) after induction therapy (Pession et al, 2013; Manara et al, 2014). However, approximately one-third of themin particular those harbouring t(8;21)RUNX1/ RUNX1T1relapsed (Pession et al, 2013). These results prompted us to refine the definition of SR, trying to identify those t(8;21) AML patients who could be pre-emptively directed to an increased chemotherapy treatment or to allogeneic haematopoietic stem cell transplantation to properly tackle their higher risk to relapse. To this purpose, we performed, for the first time, a retrospective analysis to identify a prognostic model, based on micro RNA (miRNA) expression, capable of enhancing the prediction of recurrence in paediatric t(8;21) AML patients. We determined the miRNA expression profile of 33 patients enrolled in AIEOP AML 2002/01. In our cohort, 14 out of 33 (42Á4%) patients suffered relapse after a median time of 280 days and 6 of them Fig 1. miRNAs expression in t(8;21)RUNX1/RUNX1T1 patients. (A) Supervised hierarchical clustering analysis (Spearman Rank correlation distance) using the 115 differentially expressed miRNAs (Kruskal-Wallis test, P < 0Á05) identified among t(8;21)RUNX1/RUNX1T1 de novo acute myeloid leukaemia (AML) patients who did (red bar) or did not (green bar) experience leukaemia relapse. (B) Cumulative incidence of relapse (CIR) in t(8;21) AML patients stratified according to miRNA expression in the Training (N = 17) and Validation (N = 16) sets. Significant differences between groups were assessed by the Gray test with P-value < 0Á05.
A 3-year-old girl with Spinal Muscular Atrophy type I presented with a right pneumonia. On physic... more A 3-year-old girl with Spinal Muscular Atrophy type I presented with a right pneumonia. On physical examination pulmonary auscultation revealed an asymmetry of breath sounds between the 2 hemithoraces, owing to decreased breath sounds in the right hemithorax. Blood tests were normal. The initial working diagnosis was a suspected area of mucus accumulation. A treatment with Free Aspire was started. Within a few days, the girl was discharged with a normal physical examination and X-ray study result. Spinal Muscular Atrophy is a rare neuromuscular disorder characterized by loss of motor neurons and progressive muscle wasting. Cough in these patients result ineffective. Free-Aspire is an electromedical machine for removing bronchoalveolar secretions. The case show that Free Aspire in patients with ineffective cough and impaired removal of secretions is a safe and effective device for the removal of bronchial secretions and could be an another help in the management of airway clearance.
Background: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory arthritis of unknown or... more Background: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory arthritis of unknown origin which can be considered an autoimmune disease (AD). The aim of this study is to analyse the presence of two or more autoimmune diseases (polyautoimmunity) in patients suffering from JIA and to evaluate the occurrence of ADs in their families. Methods: Seventy-nine patients diagnosed with JIA aged 0-21 years, admitted to the Paediatric Rheumatology Unit, Sant'Orsola-Malpighi Hospital, Bologna were screened for ADs. Parents were asked about the presence of ADs in the living relatives of first and second degree. Results: Twelve of 79 patients (15.2%) had at least 1 AD associated with JIA. Eight patients (10.1%) suffered from autoimmune thyroid disease (AITD), three patients had celiac disease, three patients suffered from psoriasis, one from alopecia and 1 from insulin-dependent diabetes mellitus. The average age at diagnosis was 13.2 years and the cumulative incidence of AITD was 36%. Seventy-six families were studied for a total of 438 relatives. The prevalence of ADs was 13%, greater in first-degree relatives (16.7%) than in second-degree ones (11.1%). The most common AD was AITD; there was no difference in JIA's age of presentation between patients with positive and negative familiarity with ADs (p > 0.05). Conclusion: Children and adolescents with JIA present a high autoimmunity burden, most commonly represented by AITD. Familial autoimmunity is not negligible in patients suffering from JIA (almost 50% of patients have at least one relative with an AD) and it should always be carefully examined.
Although rabbit anti-T-lymphocyte globulin (ATLG) is largely used for the prevention of immune-me... more Although rabbit anti-T-lymphocyte globulin (ATLG) is largely used for the prevention of immune-mediated complications in patients given allogeneic haemopoietic stem-cell transplantation (HSCT) from an unrelated donor, the optimum dose of this drug in children is still undefined. We aimed to test whether a higher dose of ATLG was superior to a lower dose for prevention of grade II-IV acute graft-versus-host disease (GVHD). We conducted a multicentre, randomised, open-label, phase 3 trial in seven Italian centres comparing two different doses of ATLG (30 mg/kg vs 15 mg/kg, given intravenously over 3 days, from day -4 to -2) in children (aged 0-18 years) with haematological malignancies transplanted from an unrelated donor, selected using high-resolution typing for HLA-class I/II loci. All patients received a myeloablative regimen and cyclosporine-A plus short-term methotrexate as post-transplantation GVHD prophylaxis. Patients were randomly assigned (1:1) to either of the two groups and were stratified by the degree of HLA-compatibility with their donor, the source of haemopoietic stem cells used (bone marrow vs peripheral blood stem cells), and the disease risk category. The randomisation was open label; all investigators were aware of the treatment allocation. The primary endpoint of the study was 100-day cumulative incidence of grade II-IV acute GVHD. Statistical analyses were done according to the per-protocol principle. Other outcomes included cumulative incidence of chronic GVHD, non-relapse mortality, disease recurrence, and probability of overall survival and event-free survival. This study was registered with ClinicalTrials.gov, number NCT00934557. Between Jan 15, 2008, and Sept 25, 2012, 89 patients were randomly assigned to the 30 mg/kg ATLG group and 91 to the 15 mg/kg ATLG group; 84 patients in the 30 mg/kg ATLG group and 88 in the 15 mg/kg ATLG group were included in the analysis. The median follow-up for the whole study population was 3·4 years (IQR 1·7-5·1). The 100-day cumulative incidence of grade II-IV acute GVHD was 36% (95% CI 28-48) in the 15 mg/kg ATLG group and 29% (20-40) in the 30 mg/kg ATLG group (hazard ratio [HR] 0·74, 95% CI 0·44-1·25; p=0·26). The cumulative incidence of non-relapse mortality was 9% (5-18) in the 15 mg/kg ATLG group and 19% (12-30) in the 30 mg/kg ATLG group (HR 2·08, 0·89-4·96; p=0·092). Cumulative incidence of disease recurrence was 15% (12-24): 14% (8-23) in the 15 mg/kg ATLG group versus 20% (13-31) in the 30 mg/kg ATLG group (HR 1·54, 0·74-3·21; p=0·25). The 5-year overall survival probability was 70% (62-77) for the whole study population: 78% (69-87) in the 15 mg/kg ATLG group versus 62% (50-73) in the 30 mg/kg ATLG group (HR 1·80, 1·01-3·20; p=0·045). The 5-year event-free survival was 77% for children in the 15 mg/kg ATLG group versus 61% in the 30 mg/kg ATLG group (HR 1·87, 1·07-3·28; p=0·028). Children with haematological malignancies transplanted from unrelated donors selected through high-resolution HLA-typing benefit from the use of a 15 mg/kg ATLG dose in comparison with a 30 mg/kg ATLG dose. ATLG at 15 mg/kg should thus be regarded as the standard serotherapy regimen for unrelated donor allogeneic HSCT in this patient population. Future randomised studies will continue to aim to optimise patient outcome and strategies to prevent acute GVHD occurrence. Fresenius/Neovii Biotech.
T-Acute Lymphoblastic Leukemia (T-ALL) remains a subgroup of pediatric ALL, with a lower response... more T-Acute Lymphoblastic Leukemia (T-ALL) remains a subgroup of pediatric ALL, with a lower response to standard chemotherapy. Some recent studies established the fundamental role of epigenetic aberrations such as DNA hypermethylation, to influence patients' outcome and response to chemotherapy. Moreover, L-asparaginase is an important chemotherapeutic agent for treatment of ALL and resistance to this drug has been linked to ASNS expression, which can be silenced through methylation. Therefore, we tested whether the sensitivity of T-ALL cell lines towards L-asparaginase is correlated to the epigenetic status of ASNS gene and whether the sensitivity can be modified by concurrent demethylating treatment. Hence we treated different T-ALL cell lines with L-asparaginase and correlated different responses to the treatment with ASNS expression. Then we demonstrated that the ASNS expression was dependent on the methylation status of the promoter. Finally we showed that, despite the demethy...
TW2003, the third Italian prospective study on Wilms tumor, aimed to improve survival in patients... more TW2003, the third Italian prospective study on Wilms tumor, aimed to improve survival in patients with stage III-IV tumors, de-escalate therapy for stage I-II nonanaplastic tumors, refine the risk stratification of therapy, and develop a national infrastructure for biobanking and central pathology review. TW2003 recruited children 18 years old or younger with primary intrarenal tumors. Local physicians chose nephrectomy with or without preoperative chemotherapy as the initial treatment based on the risk of unsafe and/or incomplete immediate surgery. The main drivers for adjuvant therapy were tumor stage and diffuse anaplasia. A new risk stratification schema was investigated, incorporating patient age, reason for stage III designation and completeness of lung nodule response in stage IV disease. We report on 453 patients with unilateral Wilms tumor. Preoperative chemotherapy was administered to 42% of patients. The 5-year event-free survival and overall survival rates were 89.1% (95...
Despite remarkable progress in polychemotherapy protocols, pediatric B-cell acute lymphoblastic l... more Despite remarkable progress in polychemotherapy protocols, pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains fatal in around 20% of cases. Hence, novel targeted therapies are needed for patients with poor prognosis. Glucocorticoids (GCs) are drugs commonly administrated for B-ALL treatment. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling pathway is frequently observed in B-ALL and contributes to GC-resistance. Here, we analyzed for the first time to our knowledge, the therapeutic potential of pan and isoform-selective PI3K p110 inhibitors, alone or combined with dexamethasone (DEX), in B-ALL leukemia cell lines and patient samples. We found that a pan PI3K p110 inhibitor displayed the most powerful cytotoxic effects in B-ALL cells, by inducing cell cycle arrest and apoptosis. Both a pan PI3K p110 inhibitor and a dual γ/δ PI3K p110 inhibitor sensitized B-ALL cells to DEX by restoring nuclear translocation of the GC recept...
Since 1972, children affected by cancer took advantage from multi-centric diagnostic and therapeu... more Since 1972, children affected by cancer took advantage from multi-centric diagnostic and therapeutic protocols produced by the Italian Association of paediatric haematology and oncology (AIEOP). At the beginning, these protocols were used in few well-trained centres, later in almost all Italian haemato-oncological centres. The need of a careful monitoring of his own activity induced AIEOP to achieve, in 1989, an Italian hospital- based registry (database Mod.1.01) of malignant tumours diagnosed and treated in the participating centres, with the aim to quantify the number of cases diagnosed and treated in the different centres, the agreement (or not) to official diagnostic- therapeutic protocols, and the extraregional migration. The database Mod.1.01, which is available via web to the current 55 AIEOP centres since 2000, recruits annually about 1,400 children (0-14 years) and 200 adolescents (15-19 years). While the first accounts for over 90% of expected subjects, the latter are onl...
The aim of this study was the application of complementarity-determining region-3 spectratyping a... more The aim of this study was the application of complementarity-determining region-3 spectratyping analysis to determine T-cell-repertoire complexity and to detect T-cell-clone expansion, as a measure of immune response in nonfunctioning kidney transplants (group hemodialysis-transplant [HD-Tx]), nontransplanted dialysis patients (group hemodialysis [HD]), and normal subjects as controls (group C). Analysis of T-cell receptor (TCR) diversity by spectratyping was applied to peripheral blood samples collected from 21 subjects: eight in group HD-Tx, seven in group HD, and six in group C. Considering the extent of the skew in TCR variable region repertoires as a measure of clonal T cells, we found that the number of altered spectra showed a progressive increase from normal subjects to dialysis patients and to nonfunctioning kidney transplants, respectively. Healthy subjects had the lowest number of altered spectra, and patients with nonfunctioning kidney transplants the highest. Difference...
Myoepithelial neoplasms (MN) are rare and not well-circumstanced entities displaying a heterogene... more Myoepithelial neoplasms (MN) are rare and not well-circumstanced entities displaying a heterogeneous spectrum of genetic abnormalities, including EWSR1, FUS and PLAG1 rearrangements. However, in the remaining MN no other fusion gene has been described and knowledge concerning secondary acquired molecular alterations is still poor. Therefore, we screened 5 cases of MN of the soft tissue by RNA sequencing with the aim of identifying novel fusion transcripts.A novel SRF-E2F1 fusion was detected in two cases: one was negative for other fusions while the other showed also the presence of FUS-KLF17. The fusion was validated through independent techniques and, in both cases, SRF-E2F1 was detected only in a subclone of the tumoral mass. SRF-E2F1 maintained the coding frame, thus leading to the translation of a chimeric protein containing the DNA-binding domain of SRF and the trans-activation domain of E2F1. Moreover, ectopical expression of SRF-E2F1 demonstrated that the chimeric transcript...
Extraskeletal myxoid chondrosarcoma (EMC) is a very rare sarcoma most often arising in the soft t... more Extraskeletal myxoid chondrosarcoma (EMC) is a very rare sarcoma most often arising in the soft tissue. Rare EMC of the bone have been reported. EMC exhibits distinctive clinico-pathological and genetic features; however, despite the name, it lacks any feature of cartilaginous differentiation. EMC is characterized by the rearrangement of the NR4A3, which, in most cases (about 62-75%), is fused with EWSR1 and less frequently with other partners, including TAF15 (27%), TCF12 (4%), TFG and FUS. We herein report the identification by whole-transcriptome sequencing of HSPA8 as a novel fusion partner of NR4A3 in a case of EMC. FISH analysis confirmed the presence of a genomic HSPA8-NR4A3 translocation in the vast majority of tumour cells. Our findings expand the spectrum of NR4A3 fusion partners involved in EMC pathobiology. This article is protected by copyright. All rights reserved.
Letter to the Editors: Concerning "Divergent clinical outcomes of alphaglucosidase enzyme replace... more Letter to the Editors: Concerning "Divergent clinical outcomes of alphaglucosidase enzyme replacement therapy in two siblings with infantile-onset Pompe disease treated in the symptomatic or pre-symptomatic state" by Takashi M et al. Dear Editors, We read with interest the article by Takashi M et al. that recently appeared in MGM Report. Because many open issues remain about the outcome of infantile Pompe disease (IPD), we describe here our experience with two IPD siblings born to related parents and treated with enzyme replacement therapy (ERT) in the symptomatic and the pre-symptomatic state. In the symptomatic child with severe respiratory insufficiency and hypertrophic cardiomyopathy, no detectable alpha-glucosidase acid (GAA) activity and homozygous substitution c.1A N G on the GAA gene, ERT (α-glucosidase, 20 mg/kg) was started at 6 months of age. Cardiomyopathy improved but not muscular function, and he underwent tracheostomy and gastrostomy. Early evaluation of IPD in his newborn sister showed hypertrophic cardiomyopathy, absent plasma GAA activity, CRIM negative (CN) status and the same genotype. As reported by Banugaria et al. [1], we performed immune tolerance induction (ITI) with rituximab and methotrexate and intravenous immunoglobulin before ERT (at 30 days). Her cardiomyopathy resolved after 1.5 months, and respiratory and neurological examinations appeared normal at the last evaluation (7 months). ERT effectively and rapidly reduces glycogen cardiac accumulation [2,3,4], regardless of CRIM status, but its early commencement does not prevent later anti-rhGAA IgG antibody formation [1,5,6]. Thus, in our older case, as in his sister, ERT effectively reduced cardiomyopathy, but anti-rhGAA IgG production reduced the therapeutic efficacy, worsening the neuromuscular outcome. Patients described by M. Takashi could be CRIM positive due to the presence of a missense mutation. Therefore, their outcome would depend more on the age at the start of ERT than on the CRIM status. We think that IPD patients should be screened as early as possible for CRIM status before ERT. In CN patients, it is important to do ITI and ERT to reduce anti-rhGAA IgG [7] production and to improve the natural history.
CBFA2T3-GLIS2 is a fusion gene found in 17% of non-Down syndrome acute megakaryoblastic leukemia ... more CBFA2T3-GLIS2 is a fusion gene found in 17% of non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL, FAB M7) and in 8% of pediatric cytogenetically normal acute myeloid leukemia (CN-AML, in association with several French-American-British (FAB) subtypes). Children with AML harboring this aberration have a poor outcome, regardless of the FAB subtype. This fusion gene drives a peculiar expression pattern and leads to overexpression of some of Hedgehog-related genes. GLI-similar protein 2 (GLIS2) is closely related to the GLI family, the final effectors of classic Hedgehog pathway. These observations lend compelling support to the application of GLI inhibitors in the treatment of AML with the aberration CBFA2T3-GLIS2. GANT61 is, nowadays, the most potent inhibitor of GLI family proteins. We exposed to GANT61 AML cell lines and primary cells positive and negative for CBFA2T3-GLIS2 and analyzed the effect on cellular viability, induction of apoptosis, cell cycle, and expression...
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