Publications by authors named "Maria Caterina Putti"

70 Publications

Oncological Children and Well-Being: Occupational Performance and HRQOL Change after Fine Motor Skills Stimulation Activities.

Pediatr Rep 2021 Jul 5;13(3):383-400. Epub 2021 Jul 5.

Province College for Health-Care Professions Claudiana, 39100 Bozen, Italy.

Cancer children experience long periods of hospitalization, which are associated with limited performance in several developmental domains and participation restrictions in age appropriate occupations. Fine motor abilities represent building blocks in performing daily life skills and have been found to be closely connected with later academic success. Moreover, medical and psychological sequelae for cancer inpatients may result in diminished daily activities functioning, poor perceived health related quality of life (HRQOL), and increase the likelihood of long-term impairments. This study examines the variations in the occupational performance of children hospitalized for acute lymphoblastic leukemia (ALL) after their participation to a stimulation program designed to enhance fine motor skills. Parents reported significant gains in children's motor functioning, a slight improvement in overall occupational performance related to an increase in the area of productivity and self-care, and a better quality of life perception following the stimulation activities. Feasibility of the stimulation program in a health care setting are discussed evaluating its benefits for cancer children and their families.
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http://dx.doi.org/10.3390/pediatric13030046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293420PMC
July 2021

CD56, HLA-DR, and CD45 recognize a subtype of childhood AML harboring CBFA2T3-GLIS2 fusion transcript.

Cytometry A 2021 Apr 2. Epub 2021 Apr 2.

Pediatric Hemato Oncology, Maternal and Child Health Department, University of Padua, Padua, Italy.

The presence of CBFA2T3-GLIS2 fusion gene has been identified in childhood Acute Myeloid Leukemia (AML). In view of the genomic studies indicating a distinct gene expression profile, we evaluated the role of immunophenotyping in characterizing a rare subtype of AML-CBFA2T3-GLIS2 rearranged. Immunophenotypic data were obtained by studying a cohort of 20 pediatric CBFA2T3-GLIS2-AML and 77 AML patients not carrying the fusion transcript. Enrolled cases were included in the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP) AML trials and immunophenotypes were compared using different statistical approaches. By multiple computational procedures, we identified two main core antigens responsible for the identification of the CBFA2T3-GLIS2-AML. CD56 showed the highest performance in single marker evaluation (AUC = 0.89) and granted the most accurate prediction when used in combination with HLA-DR (AUC = 0.97) displaying a 93% sensitivity and 99% specificity. We also observed a weak-to-negative CD45 expression, being exceptional in AML. We here provide evidence that the combination of HLA-DR negativity and intense bright CD56 expression detects a rare and aggressive pediatric AML genetic lesion improving the diagnosis performance.
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http://dx.doi.org/10.1002/cyto.a.24339DOI Listing
April 2021

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

Haematologica 2021 Jan 7. Epub 2021 Jan 7.

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

Transfusion-dependent patients typically develop iron-induced cardiomyopathy, liver disease, and endocrine complications. We aimed to estimate the incidence of endocrine disorders in transfusion-dependent thalassemia (TDT) patients during long-term iron-chelation therapy with deferasirox (DFX).We developed a multicentre follow-up study of 426 TDT patients treated with once-daily DFX for a median duration of 8 years, up to 18.5 years. At baseline, 118, 121, and 187 patients had 0, 1, or ≥2 endocrine diseases respectively. 104 additional endocrine diseases were developed during the follow-up. The overall risk of developing a new endocrine complication within 5 years was 9.7% (95%CI=6.3-13.1). Multiple Cox regression analysis identified 3 key predictors: age showed a positive log-linear effect (adjusted HR for 50% increase=1.2, 95%CI=1.1-1.3, P=0.005), the serum concentration of thyrotropin (TSH) showed a positive linear effect (adjusted HR for 1 mIU/L increase=1.3, 95%CI=1.1-1.4, P.
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http://dx.doi.org/10.3324/haematol.2020.272419DOI Listing
January 2021

Systemic Fusariosis: A Rare Complication in Children with Acute Lymphoblastic Leukemia.

J Fungi (Basel) 2020 Oct 9;6(4). Epub 2020 Oct 9.

Maternal and Child Health Department, Pediatric Hematology, Oncology and Stem Cell Transplantation Division, Padua University Hospital, 35128 Padua, Italy.

species are ubiquitous pathogens causing opportunistic infections in immunocompromised patients. Clinical presentation depends on a host's immunity and can be localized or disseminated. Since there are few reports of disseminated fusariosis in children, we described an unusual case of infection in a 9-year-old child with acute lymphoblastic leukemia (ALL). This patient presented a deep wound in the elbow at diagnosis. During the induction phase of chemotherapy, he developed multiple skin lesions and severe pneumonia; was cultured from the skin lesions. He was treated with a high dose of liposomal amphotericin B, followed by voriconazole. Starting from this peculiar case, we collected all patients with acute leukemia affected by infection, treated in the pediatric Onco-Hematology Division of Padua University Hospital during the last 20 years. We identified another six cases: all these patients were affected by acute myeloid leukemia (AML) and five of them presented a relapsed/refractory disease. Two out of seven patients died because of infection; five patients recovered from infection, but three out of seven died because of leukemia. Skin lesions in immunocompromised patients should rise the suspicion of disseminated fusariosis. Furthermore, considering the emergence of filamentous fungi in immunocompromised patients, we all should be aware of infection, reminding us that the diagnosis is important to cure the infection.
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http://dx.doi.org/10.3390/jof6040212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712314PMC
October 2020

The Close Link of Pancreatic Iron With Glucose Metabolism and With Cardiac Complications in Thalassemia Major: A Large, Multicenter Observational Study.

Diabetes Care 2020 11 4;43(11):2830-2839. Epub 2020 Sep 4.

Magnetic Resonance Imaging Unit, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy.

Objective: We systematically explored the link of pancreatic iron with glucose metabolism and with cardiac complications in a cohort of 1,079 patients with thalassemia major (TM) enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) project.

Research Design And Methods: MRI was used to quantify iron overload (T2* technique) and cardiac function (cine images) and to detect macroscopic myocardial fibrosis (late gadolinium enhancement technique). Glucose metabolism was assessed by the oral glucose tolerance test (OGTT).

Results: Patients with normal glucose metabolism showed significantly higher global pancreas T2* values than patients with impaired fasting glucose, impaired glucose tolerance, and diabetes. A pancreas T2* <13.07 ms predicted an abnormal OGTT. A normal pancreas T2* value showed a 100% negative predictive value for disturbances of glucose metabolism and for cardiac iron. Patients with myocardial fibrosis showed significantly lower pancreas T2* values. Patients with cardiac complications had significantly lower pancreas T2* values. No patient with arrhythmias/heart failure had a normal global pancreas T2*.

Conclusions: Pancreatic iron is a powerful predictor not only for glucose metabolism but also for cardiac iron and complications, supporting the close link between pancreatic iron and heart disease and the need to intensify iron chelation therapy to prevent both alterations of glucose metabolism and cardiac iron accumulation.
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http://dx.doi.org/10.2337/dc20-0908DOI Listing
November 2020

Consensus of the Italian Primary Immunodeficiency Network on transition management from pediatric to adult care in patients affected with childhood-onset inborn errors of immunity.

J Allergy Clin Immunol 2020 11 19;146(5):967-983. Epub 2020 Aug 19.

Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Childrens' Hospital, Sapienza, University of Rome, Rome Italy.

Medical advances have dramatically improved the long-term prognosis of children and adolescents with inborn errors of immunity (IEIs). Transfer of the medical care of individuals with pediatric IEIs to adult facilities is also a complex task because of the large number of distinct disorders, which requires involvement of patients and both pediatric and adult care providers. To date, there is no consensus on the optimal pathway of the transitional care process and no specific data are available in the literature regarding patients with IEIs. We aimed to develop a consensus statement on the transition process to adult health care services for patients with IEIs. Physicians from major Italian Primary Immunodeficiency Network centers formulated and answered questions after examining the currently published literature on the transition from childhood to adulthood. The authors voted on each recommendation. The most frequent IEIs sharing common main clinical problems requiring full attention during the transitional phase were categorized into different groups of clinically related disorders. For each group of clinically related disorders, physicians from major Italian Primary Immunodeficiency Network institutions focused on selected clinical issues representing the clinical hallmark during early adulthood.
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http://dx.doi.org/10.1016/j.jaci.2020.08.010DOI Listing
November 2020

The Italian Registry for Primary Immunodeficiencies (Italian Primary Immunodeficiency Network; IPINet): Twenty Years of Experience (1999-2019).

J Clin Immunol 2020 10 15;40(7):1026-1037. Epub 2020 Aug 15.

Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy.

Primary immunodeficiencies (PIDs) are heterogeneous disorders, characterized by variable clinical and immunological features. National PID registries offer useful insights on the epidemiology, diagnosis, and natural history of these disorders. In 1999, the Italian network for primary immunodeficiencies (IPINet) was established. We report on data collected from the IPINet registry after 20 years of activity. A total of 3352 pediatric and adult patients affected with PIDs are registered in the database. In Italy, a regional distribution trend of PID diagnosis was observed. Based on the updated IUIS classification of 2019, PID distribution in Italy showed that predominantly antibody deficiencies account for the majority of cases (63%), followed by combined immunodeficiencies with associated or syndromic features (22.5%). The overall age at diagnosis was younger for male patients. The minimal prevalence of PIDs in Italy resulted in 5.1 per 100.000 habitants. Mortality was similar to other European registries (4.2%). Immunoglobulin replacement treatment was prescribed to less than one third of the patient cohort. Collectively, this is the first comprehensive description of the PID epidemiology in Italy.
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http://dx.doi.org/10.1007/s10875-020-00844-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505879PMC
October 2020

Pediatric Patients Treated for Leukemia Back to School: A Mixed-Method Analysis of Narratives about Daily Life and Illness Experience.

Behav Sci (Basel) 2020 Jul 1;10(7). Epub 2020 Jul 1.

Pediatric Hematology, Oncology and Stem Cell Transplant Center, Department of Woman's and Child's Health, University of Padua, 35128 Padua, Italy.

In the last few years, more children and adolescents healed from leukemia go back to their daily life, even if they can show some psycho-social difficulties. The study adopted semi-structured interviews and a mixed-method approach to examine the narratives of 75 children and adolescents about their return to school post 2-years treatment for leukemia. The aims are to collect their illness experiences, to understand how they feel about school and daily routines and to identify the best socio-demographic and illness predictors of a good re-adaptation to school and daily life. The results show that by increasing age and when the pediatric patient have received a hematopoietic stem cell transplantation, at the stop-therapy time, her/his perception about relationships at school and academic performance decrease, especially if his/her feelings about the disease and follow-up visits are negative.
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http://dx.doi.org/10.3390/bs10070107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407376PMC
July 2020

Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial.

Lancet Haematol 2020 Jun;7(6):e469-e478

Fondazione per la Ricerca Farmacologica Gianni Benzi Onlus, Valenzano, Italy.

Background: Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox.

Methods: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512.

Findings: 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had β-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group.

Interpretation: In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group.

Funding: EU Seventh Framework Programme.
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http://dx.doi.org/10.1016/S2352-3026(20)30100-9DOI Listing
June 2020

Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis.

N Engl J Med 2020 05;382(19):1811-1822

From the Department of Pediatrics, Sapienza, University of Rome (F.L.), and the Department of Pediatric Hematology-Oncology (F.L.) and Division of Rheumatology (F.D.B.), IRCCS Bambino Gesù Children's Hospital, Rome, Pediatric Hematology-Oncology, Woman and Child Hospital, Azienda Ospedaliera Universitaria Integrata, Verona (S.C.), the Pediatric Hematology-Oncology Unit, Department of Pediatrics, University of Milano-Bicocca, Monza Brianza per il Bambino e la sua Mamma Foundation, Monza (C.R.), the Clinic of Pediatric Hematology-Oncology, University Hospital of Padova, Padua (M.-C.P.), and the Division of Pediatric Onco-Hematology, Regina Margherita Hospital, Turin (F.F.) - all in Italy; the Divisions of Immunobiology and Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics (M.B.J.), and the Division of Rheumatology (A.G.), Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine (M.B.J.) - all in Cincinnati; the Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston (C.A.); the Department of Hematology, Great Ormond Street Hospital for Children, London (A.R.); the Department of Pediatric Hematology-Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston (B.D.); the Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora (T.P.G.); the Departments of Pediatric Hematology-Oncology and Hematology and Oncology, Fundación para la Investigación Biomédica Hospital Infantil Universitario Niño Jesús, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid (J.S.), and the Department of Pediatric Hematology and Oncology, Hospital Universitari Vall d'Hebron, Barcelona (J.-L.D.D.); the Department of Pediatric Hematology and Oncology, University Children's Hospital, Muenster, Germany (M.A.); the Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ (M.H.); NovImmune, Plan-les-Ouates, Switzerland (G.L., M.B., C.M.); and MnS Modelling and Simulation, Dinant, Belgium (P.J.).

Background: Primary hemophagocytic lymphohistiocytosis is a rare syndrome characterized by immune dysregulation and hyperinflammation. It typically manifests in infancy and is associated with high mortality.

Methods: We investigated the efficacy and safety of emapalumab (a human anti-interferon-γ antibody), administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving patients who had received conventional therapy before enrollment (previously treated patients) and previously untreated patients who were 18 years of age or younger and had primary hemophagocytic lymphohistiocytosis. The patients could enter a long-term follow-up study until 1 year after allogeneic hematopoietic stem-cell transplantation or until 1 year after the last dose of emapalumab, if transplantation was not performed. The planned 8-week treatment period could be shortened or extended if needed according to the timing of transplantation. The primary efficacy end point was the overall response, which was assessed in the previously treated patients according to objective clinical and laboratory criteria.

Results: At the cutoff date of July 20, 2017, a total of 34 patients (27 previously treated patients and 7 previously untreated patients) had received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40% (P = 0.02 and P = 0.005, respectively). In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis.

Conclusions: Emapalumab was an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis. (Funded by NovImmune and the European Commission; NI-0501-04 and NI-0501-05 ClinicalTrials.gov numbers, NCT01818492 and NCT02069899.).
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http://dx.doi.org/10.1056/NEJMoa1911326DOI Listing
May 2020

Health Locus of Control in Parents of Children with Leukemia and Associations with Their Life Perceptions and Depression Symptomatology.

Children (Basel) 2020 May 1;7(5). Epub 2020 May 1.

Pediatric Hematology, Oncology and Stem Cell Transplant Center, Department of Woman's and Child's Health, University of Padua, 35128 Padua, Italy.

In childhood cancer, parents have an important role in the promotion of their children's wellbeing and in their adoption of a locus of control style towards their children's health. The current study aimed at identifying types of locus of control in parents of children with leukemia and the possible association with depressive symptomatology and current life perception. One hundred and four parents were recruited at the Hematology-Oncology Clinic of the Department of Woman's and Child's Health, University of Padua, one month after a leukemia diagnosis. Participants were Caucasian with a mean age of 37.28 years (SD = 5.89), mostly mothers (87.5%) and with a mean of 12.16 years of education (SD = 3.82). After signing the informed consent, they filled in the Ladder of Life, the Brief Symptom Inventory-18 and the Parental Health Locus of Control (PHLOC) questionnaires. Paired-samples -test ( = -14.42; df = 103; = 0.0001) showed that parents of children with leukemia were more inclined to have an external locus of control than an internal one. The hierarchical regression analysis model (R = 0.34; F = 4.32; = 0.0001) identified health professional influence (ß = -0.28; = 0.004), current life perception (ß = -0.3; = 0.013) and future life perception (ß = -0.26; = 0.012) as significant predictors of parental depression. Current life perception was best predicted (R = 0.25; F = 3.96; = 0.01) by the parental influence locus of control style (ß = 0.25; = 0.03). Improving trust in the medical staff care and strengthening the internal locus of control in parents could be a preventive program to cope with parental depression symptomatology.
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http://dx.doi.org/10.3390/children7050040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278609PMC
May 2020

Long-term follow-up of 168 patients with X-linked agammaglobulinemia reveals increased morbidity and mortality.

J Allergy Clin Immunol 2020 08 10;146(2):429-437. Epub 2020 Mar 10.

University Department of Pediatrics, Unit of Immune and Infectious Diseases, Bambino Gesù Children's Hospital, University of Rome Tor Vergata, and the Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

Background: X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarce.

Objective: Our aim was to describe the natural history of XLA.

Methods: A nationwide multicenter study based on the Italian Primary Immunodeficiency Network registry was established in 2000 in Italy. Affected patients were enrolled by documenting centers, and the patients' laboratory, clinical, and imaging data were recorded on an annual base.

Results: Data on the patients (N = 168) were derived from a cumulative follow-up of 1370 patient-years, with a mean follow-up of 8.35 years per patient. The mean age at diagnosis decreased after establishment of the Italian Primary Immunodeficiency Network registry (84 months before vs 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 with that for the healthy male Italian population, and it further deteriorated in the presence of chronic lung disease.

Conclusions: This is the first detailed long-term follow-up study for patients with XLA, revealing that although immunoglobulin replacement treatment reduces the incidence of invasive infections, it does not appear to influence the development of chronic lung disease. The overall survival of affected patients is reduced. Further studies are warranted to improve patients' clinical management and increase awareness among physicians.
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http://dx.doi.org/10.1016/j.jaci.2020.03.001DOI Listing
August 2020

CMR for myocardial iron overload quantification: calibration curve from the MIOT Network.

Eur Radiol 2020 Jun 12;30(6):3217-3225. Epub 2020 Feb 12.

MRI Unit, Fondazione G. Monasterio CNR-Regione Toscana, Area della Ricerca S. Cataldo, Via Moruzzi, 1, 56124, Pisa, Italy.

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) (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.
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http://dx.doi.org/10.1007/s00330-020-06668-1DOI Listing
June 2020

Psychological Wellbeing in Adolescents with Leukaemia: A Comparative Study with Typical Development Peers.

Int J Environ Res Public Health 2020 01 16;17(2). Epub 2020 Jan 16.

Department of Child and Woman Health, University of Padua, 35127 Padua, Italy.

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.
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http://dx.doi.org/10.3390/ijerph17020567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014127PMC
January 2020

Mucormycosis with peculiar aortic involvement in a child with acute lymphoblastic leukemia.

Pediatr Hematol Oncol 2020 Mar 17;37(2):164-169. Epub 2019 Dec 17.

Pediatric Onco-Hematology Unit, Department of Women's and Children's Health, University of Padova, Padova, Italy.

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.
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http://dx.doi.org/10.1080/08880018.2019.1691294DOI Listing
March 2020

Pharmacokinetics of Nilotinib in Pediatric Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia or Acute Lymphoblastic Leukemia.

Clin Cancer Res 2020 02 1;26(4):812-820. Epub 2019 Nov 1.

Institute of Cancer and Genomic Sciences, NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, United Kingdom.

Purpose: We investigated nilotinib exposure in pediatric patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) resistant to, relapsed on, refractory to, or intolerant of previous treatment.

Patients And Methods: Fifteen patients (aged 1-<18 years) with CML resistant to or intolerant of imatinib and/or dasatinib ( = 11) or Ph ALL relapsed on or refractory to standard therapy ( = 4) enrolled in this phase I study. Nilotinib (230 mg/m twice daily; equivalent to the adult 400-mg twice-daily dose) was administered orally in 12 or 24 cycles of 28 days. The primary objective was to characterize the pharmacokinetics of nilotinib in pediatric patients.

Results: The area under the concentration-time curve at steady state was slightly lower in pediatric patients versus adults (14,751.4 vs. 17,102.9 ng/h/mL); the geometric mean ratio (GMR; pediatric:adult) was 0.86 [90% confidence interval (CI), 0.70-1.06]. Body surface area-adjusted systemic clearance was slightly higher in pediatric versus adult patients (GMR, 1.30; 90% CI, 1.04-1.62). Nilotinib was generally well tolerated. The most common adverse events were headache, vomiting, increased blood bilirubin, and rash. Three patients with CML achieved major molecular response, and three with Ph ALL achieved complete remission.

Conclusions: Nilotinib 230 mg/m twice daily in pediatric patients provided a pharmacokinetics and safety profile comparable with the adult reference dose; clinical activity was demonstrated in both CML and Ph ALL. This dose is recommended for further evaluation in pediatric patients. The safety profile was consistent with that in adults.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0090DOI Listing
February 2020

Outcome of adolescent patients with acute lymphoblastic leukaemia aged 10-14 years as compared with those aged 15-17 years: Long-term results of 1094 patients of the AIEOP-BFM ALL 2000 study.

Eur J Cancer 2019 11 17;122:61-71. Epub 2019 Oct 17.

Department of Pediatrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.

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.
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http://dx.doi.org/10.1016/j.ejca.2019.09.004DOI Listing
November 2019

Clinical, Immunological, and Molecular Features of Typical and Atypical Severe Combined Immunodeficiency: Report of the Italian Primary Immunodeficiency Network.

Front Immunol 2019 13;10:1908. Epub 2019 Aug 13.

Department of Pediatric Hematology and Oncology, Bambino Gesù Children's Hospital, Rome, Italy.

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.
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http://dx.doi.org/10.3389/fimmu.2019.01908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700292PMC
September 2020

Contemporary management of essential thrombocythemia in children.

Expert Rev Hematol 2019 05 27;12(5):367-373. Epub 2019 Apr 27.

b Department of Women's and Children's Health, Pediatric Hemato-Oncology , University of Padova , Padova , Italy.

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 10/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.
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http://dx.doi.org/10.1080/17474086.2019.1602034DOI Listing
May 2019

Immunophenotype Anomalies Predict the Development of Autoimmune Cytopenia in 22q11.2 Deletion Syndrome.

J Allergy Clin Immunol Pract 2019 Sep - Oct;7(7):2369-2376. Epub 2019 Mar 26.

University Department of Pediatrics, Unit of Immune and Infectious Diseases, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

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.
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http://dx.doi.org/10.1016/j.jaip.2019.03.014DOI Listing
October 2020

Osteonecrosis in Children and Adolescents With Acute Lymphoblastic Leukemia: Early Diagnosis and New Treatment Strategies.

Anticancer Res 2019 Mar;39(3):1259-1266

Department of Women's and Children's Health, Pediatric Haemato-Oncology, University of Padua, Padua, Italy.

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.
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http://dx.doi.org/10.21873/anticanres.13236DOI Listing
March 2019

Real-Life Management of Children and Adolescents with Chronic Myeloid Leukemia: The Italian Experience.

Acta Haematol 2018 18;140(2):105-111. Epub 2018 Sep 18.

Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto I, Sapienza University, Rome, Italy.

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.
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http://dx.doi.org/10.1159/000491546DOI Listing
June 2019

Identification of a new exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease.

Blood 2018 08 11;132(5):469-483. Epub 2018 Jun 11.

Faculty of Medicine Alexandroupolis, Democritus University of Thrace, Thrace, Greece.

Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau () gene. Since this discovery, additional mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. 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 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 coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other exons. In this study, we show that the mutations induced a dysregulation of 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 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 alterations and reveals a novel complex splicing regulation of the gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway.
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http://dx.doi.org/10.1182/blood-2018-03-838235DOI Listing
August 2018

Can myocardial remodeling be a useful surrogate predictor of myocardial iron load? A 3D echocardiographic multicentric study.

Pediatr Blood Cancer 2018 10 6;65(10):e27272. Epub 2018 Jun 6.

Faculty of Medicine, Cairo University.

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.
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http://dx.doi.org/10.1002/pbc.27272DOI Listing
October 2018
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