Publications by authors named "Gabriella Casazza"

18 Publications

  • Page 1 of 1

Toxocariasis in a Child with Autism Spectrum Disorder.

Int J Environ Res Public Health 2021 01 2;18(1). Epub 2021 Jan 2.

Department of Translational Research, N.T.M.S., University of Pisa, 56126 Pisa, Italy.

A boy affected by autism spectrum disorder was admitted for persistent high fever, without shiver, for two weeks. The boy referred to abdominal pain, in the first week of fever, and to mild anorexia in the last days before admittance to our hospital centre. The father reported that the boy suffered by geophagia and coprophagia and he has been going to a didactical farm (where he has been exposed to several kinds of animals) to improve his neuropsychiatric condition. Blood analysis shows severe eosinophilia and high levels of total IgE, and abdominal echocardiography showed hepatic lesions. Enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) confirmed the suspicion of toxocariasis, linked to the habit of the boy to ingest ground or animal faeces in a didactic farm frequented by the boy. Treatment with albendazole and prednisone was administered with a rapid improvement of the symptoms and the laboratory findings and significant reduction of the hepatic lesion.
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http://dx.doi.org/10.3390/ijerph18010283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795894PMC
January 2021

Activated Phosphoinositide 3-Kinase Delta Syndrome 1: Clinical and Immunological Data from an Italian Cohort of Patients.

J Clin Med 2020 Oct 17;9(10). Epub 2020 Oct 17.

Pediatrics Clinic and "A. Nocivelli" Institute for Molecular Medicine, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Brescia, 25123 Brescia, Italy.

Activated phosphoinositide 3-kinase delta syndrome 1 (APDS-1) is a recently described inborn error of immunity caused by monoallelic gain-of-function mutations in the gene. We reviewed for the first time medical records and laboratory data of eight Italian APDS-1 patients. Recurrent sinopulmonary infections were the most common clinical feature at onset of disease. Seven patients presented lymphoproliferative disease, at onset or during follow-up, one of which resembled hemophagocytic lymphohistiocytosis (HLH). Genetic analysis of the gene revealed three novel mutations: functional testing confirmed their activating nature. In the remaining patients, the previously reported variants .E1021K ( = 4) and .E525A ( = 1) were identified. Six patients were started on immunoglobulin replacement treatment (IgRT). One patient successfully underwent hematopoietic stem cell transplantation (HSCT), with good chimerism and no GVHD at 21 months post-HSCT. APDS-1 is a combined immune deficiency with a wide variety of clinical manifestations and a complex immunological presentation. Besides IgRT, specific therapies targeting the PI3Kδ pathway will most likely become a valid aid for the amelioration of patients' clinical management and their quality of life.
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http://dx.doi.org/10.3390/jcm9103335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603210PMC
October 2020

Preliminary Study on β3-Adrenoreceptor as Predictor Marker of Relapse in Ewing Sarcoma Patients.

Biomedicines 2020 Oct 13;8(10). Epub 2020 Oct 13.

Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, 50139 Florence, Italy.

Ewing sarcoma (EWS) is a paediatric aggressive malignant tumour of bones and soft tissues. Multidisciplinary chemotherapies, surgical resection, and radiation represent the only strategies counteracting the disease, however spreading and relapse of disease still remain a clinical issue. Circulating tumour cells (CTCs) are an important feature of EWS but the prognostic significance has not been, yet, clarified. CTCs have been found both in patients with localized disease and in those who recur or metastasize. The identification of markers that can detect recurrences and metastasis remains an important challenge for research. Unfortunately, even most of patients with localized cancer relapsed and the reason has not yet been fully understood. In this clinical study on EWS patients, we evaluated the expression of CD99 antigen and beta-3 adrenergic receptor (β3-AR) on CTCs and bioptic derived cells by flow cytometry. The preliminary data revealed a higher β3-AR expression on cells derived from metastatic or relapsed patients, suggesting a role for the β3-AR as a possible predictive maker of disease recurrence in both patients with metastatic and localized disease.
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http://dx.doi.org/10.3390/biomedicines8100413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600453PMC
October 2020

β3-Adrenoreceptor Blockade Induces Stem Cells Differentiation in Melanoma Microenvironment.

Int J Mol Sci 2020 Feb 20;21(4). Epub 2020 Feb 20.

Hematology-Oncology Department, "Anna Meyer Children's Hospital", 50139 Florence, Italy.

Although there is an increasing evidence that cancer stem cell (CSC) niches in the tumor microenvironment (TME) plays a crucial role in sustaining solid tumors progression, several molecular players involved in this regulation still remain unknown. The role of β-adrenergic signaling in enhancing tumor growth through β2-adrenoreceptors (β2-ARs) has been confirmed in different cancer models, but the role played by the β3-adrenergic receptor (β3-AR) has recently emerged. Previous studies showed that β3-AR promotes cancer growth through the activation of different stromal cells in the TME, and leads to melanoma malignancy progression through inflammation, angiogenesis, and immunotolerance. Here we show that in B16 melanoma-bearing mice, the pharmacological β3-AR blockade is able to reduce the expression of CSC markers, and to induce a differentiated phenotype of hematopoietic subpopulations in TME. In particular, cytofluorimetric analysis (FACS) of the tumor mass shows that β3-AR antagonist SR59230A promotes hematopoietic differentiation as indicated by increased ratios of lymphoid/hematopoietic stem cells (HSCs) and of myeloid progenitor cells/HSCs, and increases the number of Ter119 and natural killer (NK) precursor cells, and of granulocyte precursors, indicating active hematopoiesis within the tumor tissue. Moreover, pharmacological antagonism of β3-AR induces mesenchymal stem cell (MSC) differentiation into adipocytes subtracting a potential renewal of the stem compartment by these cells. Here we demonstrate that β3-AR blockade in the TME by inducing the differentiation of different stromal cells at the expense of stemness traits could possibly have a favorable effect on the control of melanoma progression.
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http://dx.doi.org/10.3390/ijms21041420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073111PMC
February 2020

β3-adrenoreceptor blockade reduces tumor growth and increases neuronal differentiation in neuroblastoma via SK2/S1P modulation.

Oncogene 2020 01 2;39(2):368-384. Epub 2019 Sep 2.

Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy.

Neuroblastoma (NB) is the most frequently observed among extracranial pediatric solid tumors. It displays an extreme clinical heterogeneity, in particular for the presentation at diagnosis and response to treatment, often depending on cancer cell differentiation/stemness. The frequent presence of elevated hematic and urinary levels of catecholamines in patients affected by NB suggests that the dissection of adrenergic system is crucial for a better understanding of this cancer. β3-adrenoreceptor (β3-AR) is the last identified member of adrenergic receptors, involved in different tumor conditions, such as melanoma. Multiple studies have shown that the dysregulation of the bioactive lipid sphingosine 1-phosphate (S1P) metabolism and signaling is involved in many pathological diseases including cancer. However, whether S1P is crucial for NB progression and aggressiveness is still under investigation. Here we provide experimental evidence that β3-AR is expressed in NB, both human specimens and cell lines, where it is critically involved in the activation of proliferation and the regulation between stemness/differentiation, via its functional cross-talk with sphingosine kinase 2 (SK2)/S1P receptor 2 (S1P) axis. The specific antagonism of β3-AR by SR59230A inhibits NB growth and tumor progression, by switching from stemness to cell differentiation both in vivo and in vitro through the specific blockade of SK2/S1P signaling.
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http://dx.doi.org/10.1038/s41388-019-0993-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949192PMC
January 2020

Unrelated donor vs HLA-haploidentical α/β T-cell- and B-cell-depleted HSCT in children with acute leukemia.

Blood 2018 12 22;132(24):2594-2607. Epub 2018 Oct 22.

Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ospedale Bambino Gesù, Rome, Italy.

Traditionally, hematopoietic stem cell transplantation (HSCT) from both HLA-matched related and unrelated donors (UD) has been used for treating children with acute leukemia (AL) in need of an allograft. Recently, HLA-haploidentical HSCT after αβ T-cell/B-cell depletion (αβhaplo-HSCT) was shown to be effective in single-center studies. Here, we report the first multicenter retrospective analysis of 127 matched UD (MUD), 118 mismatched UD (MMUD), and 98 αβhaplo-HSCT recipients, transplanted between 2010 and 2015, in 13 Italian centers. All these AL children were transplanted in morphological remission after a myeloablative conditioning regimen. Graft failure occurred in 2% each of UD-HSCT and αβhaplo-HSCT groups. In MUD vs MMUD-HSCT recipients, the cumulative incidence of grade II to IV and grade III to IV acute graft-versus-host disease (GVHD) was 35% vs 44% and 6% vs 18%, respectively, compared with 16% and 0% in αβhaplo-HSCT recipients ( < .001). Children treated with αβhaplo-HSCT also had a significantly lower incidence of overall and extensive chronic GVHD ( < .01). Eight (6%) MUD, 32 (28%) MMUD, and 9 (9%) αβhaplo-HSCT patients died of transplant-related complications. With a median follow-up of 3.3 years, the 5-year probability of leukemia-free survival in the 3 groups was 67%, 55%, and 62%, respectively. In the 3 groups, chronic GVHD-free/relapse-free (GRFS) probability of survival was 61%, 34%, and 58%, respectively ( < .001). When compared with patients given MMUD-HSCT, αβhaplo-HSCT recipients had a lower cumulative incidence of nonrelapse mortality and a better GRFS ( < .001). These data indicate that αβhaplo-HSCT is a suitable therapeutic option for children with AL in need of transplantation, especially when an allele-matched UD is not available.
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http://dx.doi.org/10.1182/blood-2018-07-861575DOI Listing
December 2018

Hypomorphic FANCA mutations correlate with mild mitochondrial and clinical phenotype in Fanconi anemia.

Haematologica 2018 03 21;103(3):417-426. Epub 2017 Dec 21.

Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy

Fanconi anemia is a rare disease characterized by congenital malformations, aplastic anemia, and predisposition to cancer. Despite the consolidated role of the Fanconi anemia proteins in DNA repair, their involvement in mitochondrial function is emerging. The purpose of this work was to assess whether the mitochondrial phenotype, independent of genomic integrity, could correlate with patient phenotype. We evaluated mitochondrial and clinical features of 11 affected individuals homozygous or compound heterozygous for p.His913Pro and p.Arg951Gln/Trp, the two residues of FANCA that are more frequently affected in our cohort of patients. Although p.His913Pro and p.Arg951Gln proteins are stably expressed in cytoplasm, they are unable to migrate in the nucleus, preventing cells from repairing DNA. In these cells, the electron transfer between respiring complex I-III is reduced and the ATP/AMP ratio is impaired with defective ATP production and AMP accumulation. These activities are intermediate between those observed in wild-type and FANCA-/- cells, suggesting that the variants at residues His913 and Arg951 are hypomorphic mutations. Consistent with these findings, the clinical phenotype of most of the patients carrying these mutations is mild. These data further support the recent finding that the Fanconi anemia proteins play a role in mitochondria, and open up possibilities for genotype/phenotype studies based on novel mitochondrial criteria.
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http://dx.doi.org/10.3324/haematol.2017.176131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830397PMC
March 2018

Somatic, hematologic phenotype, long-term outcome, and effect of hematopoietic stem cell transplantation. An analysis of 97 Fanconi anemia patients from the Italian national database on behalf of the Marrow Failure Study Group of the AIEOP (Italian Association of Pediatric Hematology-Oncology).

Am J Hematol 2016 07 24;91(7):666-71. Epub 2016 Apr 24.

Hematology Unit, Gaslini Institute, Genova, Italy.

We analyzed 97 Fanconi anemia patients from a clinic/biological database for genotype, somatic, and hematologic phenotype, adverse hematological events, solid tumors, and treatment. Seventy-two patients belonged to complementation group A. Eighty percent of patients presented with mild/moderate somatic phenotype and most with cytopenia. No correlation was seen between somatic/hematologic phenotype and number of missense mutations of FANCA alleles. Over follow-up, 33% of patients improved or maintained mild/moderate cytopenia or normal blood count, whereas remaining worsened cytopenia. Eleven patients developed a hematological adverse event (MDS, AML, pathological cytogenetics) and three developed solid tumors. 10 years cumulative risk of death of the whole cohort was 25.6% with median follow-up 5.8 years. In patients eligible to hematopoietic stem cell transplantation because of moderate cytopenia, mortality was significantly higher in subjects transplanted from matched unrelated donor over nontransplanted subjects, whereas there was no significant difference between matched sibling donor transplants and nontransplanted patients. In patients eligible to transplant because of severe cytopenia and clonal disease, mortality risk was not significantly different in transplanted from matched unrelated versus matched sibling donor versus nontransplanted subjects. The decision to transplant should rely on various elements including, type of donor, HLA matching, patient comorbidities, impairment, and clonal evolution of hematopoiesis. Am. J. Hematol. 91:666-671, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajh.24373DOI Listing
July 2016

Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology.

Haematologica 2014 Jun 28;99(6):1022-31. Epub 2014 Feb 28.

Department of Medical Sciences, University of Trieste, Italy Pediatric Onco-Hematology, "Azienda Ospedaliero Universitaria Pisana", Pisa, Italy

Fanconi anemia is an inherited disease characterized by congenital malformations, pancytopenia, cancer predisposition, and sensitivity to cross-linking agents. The molecular diagnosis of Fanconi anemia is relatively complex for several aspects including genetic heterogeneity with mutations in at least 16 different genes. In this paper, we report the mutations identified in 100 unrelated probands enrolled into the National Network of the Italian Association of Pediatric Hematoly and Oncology. In approximately half of these cases, mutational screening was carried out after retroviral complementation analyses or protein analysis. In the other half, the analysis was performed on the most frequently mutated genes or using a next generation sequencing approach. We identified 108 distinct variants of the FANCA, FANCG, FANCC, FANCD2, and FANCB genes in 85, 9, 3, 2, and 1 families, respectively. Despite the relatively high number of private mutations, 45 of which are novel Fanconi anemia alleles, 26% of the FANCA alleles are due to 5 distinct mutations. Most of the mutations are large genomic deletions and nonsense or frameshift mutations, although we identified a series of missense mutations, whose pathogenetic role was not always certain. The molecular diagnosis of Fanconi anemia is still a tiered procedure that requires identifying candidate genes to avoid useless sequencing. Introduction of next generation sequencing strategies will greatly improve the diagnostic process, allowing a rapid analysis of all the genes.
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http://dx.doi.org/10.3324/haematol.2014.104224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040906PMC
June 2014

Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study.

Blood 2014 Mar 10;123(10):1470-8. Epub 2014 Jan 10.

Department of Pediatrics, Ospedale S. Gerardo, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy;

The outcome of high-risk (HR) acute lymphoblastic leukemia patients enrolled in the AIEOP-BFM ALL 2000 study in Italy is described. HR criteria were minimal residual disease (MRD) levels ≥10(-3) at day 78 (MRD-HR), no complete remission (CR) at day 33, t(4;11) translocation, and prednisone poor response (PPR). Treatment (2 years) included protocol I, 3 polychemotherapy blocks, delayed intensification (protocol IIx2 or IIIx3), cranial radiotherapy, and maintenance. A total of 312 HR patients had a 5-year event-free survival (EFS) of 58.9% (standard error [SE] = 2.8) and an overall survival of 68.9% (SE = 2.6). In hierarchical order, EFS was 45.9% (4.4) in 132 MRD-HR patients, 41.2% (11.9) in 17 patients with no CR at day 33, 36.4% (14.5) in 11 patients with t(4;11), and 74.0% (3.6) in 152 HR patients only for PPR. No statistically significant difference was found for disease-free survival in patients with very HR features [MRD-HR, no CR at day 33, t(4;11) translocation], given hematopoietic stem cell transplantation (HSCT) (n = 66) or chemotherapy only (n = 88), after adjusting for waiting time to HSCT (5.7 months). Patients at HR only for PPR have a favorable outcome. MRD-HR is associated with poor outcome despite intensive treatment and/or HSCT and may qualify for innovative therapies. The study was registered at www.clinicaltrials.gov as #NCT00613457.
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http://dx.doi.org/10.1182/blood-2013-10-532598DOI Listing
March 2014

Congenital and acquired neutropenias consensus guidelines on therapy and follow-up in childhood from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica).

Am J Hematol 2012 Feb 27;87(2):238-43. Epub 2011 Dec 27.

Haematology Unit, G. Gaslini Children's Hospital, Genova, Italy.

The management of congenital and acquired neutropenias presents some differences according to the type of the disease. Treatment with recombinant human granulocyte-colony stimulating factor (G-CSF) is not standardized and scanty data are available on the best schedule to apply. The frequency and the type of longitudinal controls in patients affected with neutropenias are not usually discussed in the literature. The Neutropenia Committee of the Marrow Failure Syndrome Group (MFSG) of the Associazione Italiana di Emato-Oncologia Pediatrica (AIEOP) elaborated this document following design and methodology formerly approved by the AIEOP board. The panel of experts reviewed the literature on the topic and participated in a conference producing a document that includes recommendations on neutropenia treatment and timing of follow-up.
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http://dx.doi.org/10.1002/ajh.22242DOI Listing
February 2012

Foreign children with cancer in Italy.

Ital J Pediatr 2011 Sep 18;37:44. Epub 2011 Sep 18.

Paediatric Oncology-Haematology Lalla Seràgnoli, Policlinico S.Orsola-Malpighi, Bologna, Italy.

Background: There has been a noticeable annual increase in the number of children coming to Italy for medical treatment, just like it has happened in the rest of the European Union. In Italy, the assistance to children suffering from cancer is assured by the current network of 54 centres members of the Italian Association of Paediatric Haematology and Oncology (AIEOP), which has kept records of all demographic and clinical data in the database of Mod.1.01 Registry since 1989.

Methods: We used the information stored in the already mentioned database to assess the impact of immigration of foreign children with cancer on centres' activity, with the scope of drawing a map of the assistance to these cases.

Results: Out of 14,738 cases recorded by all centres in the period from 1999 to 2008, 92.2% were born and resident in Italy, 4.1% (608) were born abroad and living abroad and 3.7% (538) were born abroad and living in Italy. Foreign children cases have increased over the years from 2.5% in 1999 to. 8.1% in 2008.Most immigrant children came from Europe (65.7%), whereas patients who came from America, Asia and Oceania amounted to 13.2%, 10.1%, 0.2%, respectively. The immigrant survival rate was lower compared to that of children who were born in Italy. This is especially true for acute lymphoblastic leukaemia patients entered an AIEOP protocol, who showed a 10-years survival rate of 71.0% vs. 80.7% (p < 0.001) for immigrants and patients born in Italy, respectively.

Conclusions: Children and adolescents are an increasingly important part of the immigration phenomenon, which occurs in many parts of the world. In Italy the vast majority of children affected by malignancies are treated in AIEOP centres. Since immigrant children are predominantly treated in northern Italy, these centres have developed a special expertise in treating immigrant patients, which is certainly very useful for the entire AIEOP network.
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http://dx.doi.org/10.1186/1824-7288-37-44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189490PMC
September 2011

Reconstitution rate of absolute CD8+ T lymphocyte counts affects overall survival after pediatric allogeneic hematopoietic stem cell transplantation.

J Pediatr Hematol Oncol 2012 Jan;34(1):29-34

U.O. Oncoematologia Pediatrica †U.O. Immunoematologia S.S.N., Azienda Ospedaliera Universitaria Pisana, Pisa Italy.

Immune reconstitution after allogeneic stem cell transplantation protects against opportunistic infections and disease relapse. Identifying the most protective lymphocyte subset would have implications of adoptive immunotherapy. We followed up a case series of 34 allogeneic transplantations for pediatric leukemias, aplastic anemias, or solid tumors. Regardless of baseline hematologic disorder, the speed of reconstitution of cytotoxic CD8 T lymphocytes and the achieving of the 10th percentile of normal CD4 T lymphocytes (but not B lymphocytes or natural killer cells) conditioned overall survival. The source of hematopoietic stem cells (peripheral blood vs bone marrow) and the occurrence of graft-versus-host disease (either acute or chronic) did not impact on immune reconstitution. Larger case series are needed to confirm the pivotal role of cytotoxic CD8 T lymphocytes in overall survival.
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http://dx.doi.org/10.1097/MPH.0b013e3182127addDOI Listing
January 2012

Treatment of high-risk relapsed Wilms tumor with dose-intensive chemotherapy, marrow-ablative chemotherapy, and autologous hematopoietic stem cell support: experience by the Italian Association of Pediatric Hematology and Oncology.

Pediatr Blood Cancer 2008 Jul;51(1):23-8

Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Background: We evaluated an intensified chemotherapy strategy in children with Wilms tumor who relapsed with high-risk features.

Procedures: From January 2001 to June 2006, we treated 20 consecutive children with reinduction chemotherapy (using ifosfamide/carboplatin/etoposide in 15/20 cases), with (n = 15) or without (n = 5) subsequent high-dose chemotherapy and hematopoietic stem cell support, surgery where feasible, and radiation therapy. The median time to relapse was 10 months after nephrectomy. All but two children initially received doxorubicin as first-line therapy.

Results: All patients were assessed for outcome: 13 are currently alive, 12 of them in remission a median 25 months since their relapse, one with progressing tumor. The treatment was unsuccessful in eight children: the disease progressed during reinduction in three, and relapsed in five. There was one toxic death. All transplanted patients engrafted to a neutrophil count >0.5 x 10(3)/microl after a median 11 days, and to an unsustained platelet count >25,000/microl after a median of 13 days. Three-year disease-free and overall survival rates were 56 +/- 12% and 55 +/- 13%, respectively. Neither recurrence within 12 months of nephrectomy nor extra-lung recurrence negatively affected outcome. A survival advantage was demonstrated in patients without disease evidence prior to transplant.

Conclusion: A disease-free survival rate nearing 50% is a realistic target in children with high-risk recurrent Wilms tumor. The benefit of autologous hematopoietic stem cell transplantation for consolidation deserves to be investigated in a randomized, controlled study.
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http://dx.doi.org/10.1002/pbc.21524DOI Listing
July 2008