Publications by authors named "Rita Maria Pinto"

13 Publications

  • Page 1 of 1

HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia.

Blood Adv 2021 Mar;5(5):1333-1339

Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS) Bambino Gesù Children's Hospital, Rome, Italy.

We report on the outcome of 24 patients with Fanconi anemia (FA) lacking an HLA matched related or unrelated donor, given an HLA-haploidentical T-cell receptor αβ (TCRαβ+) and CD19+ cell-depleted hematopoietic stem cell transplantation (HSCT) in the context of a prospective, single-center phase 2 trial. Sustained primary engraftment was achieved in 22 (91.6%) of 24 patients, with median time to neutrophil recovery of 12 days (range, 9-15 days) and platelet recovery of 10 days (range, 7-14 days). Cumulative incidences of grade 1 to 2 acute graft-versus-host disease (GVHD) and chronic GVHD were 17.4% (95% confidence interval [CI], 5.5%-35.5%) and 5.5% (95% CI, 0.8%-33.4%), respectively. The conditioning regimen, which included fludarabine, low-dose cyclophosphamide and, in most patients, single-dose irradiation was well tolerated; no fatal transplant-related toxicity was observed. With a median follow-up of 5.2 years (range, 0.3-8.7 years), the overall and event-free survival probabilities were 100% and 86.3% (95% CI, 62.8%-95.4%), respectively (2 graft failures and 1 case of poor graft function were considered as events). The 2 patients who experienced primary graft failure underwent a subsequent successful HSCT from the other parent. This is the first report of FA patients given TCRαβ+/CD19+-depleted haplo-HSCT in the context of a prospective trial, and the largest series of T-cell-depleted haplo-HSCT in FA reported to date. This trial was registered at www.clinicaltrials.gov as #NCT01810120.
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http://dx.doi.org/10.1182/bloodadvances.2020003707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948273PMC
March 2021

Microarray expression studies on bone marrow of patients with Shwachman-Diamond syndrome in relation to deletion of the long arm of chromosome 20, other chromosome anomalies or normal karyotype.

Mol Cytogenet 2020 2;13. Epub 2020 Jan 2.

1Genetica Umana e Medica, Dipartimento di Medicina e Chirurgia, Università dell'Insubria, Via J. H. Dunant, 5, 21100 Varese, Italy.

Background: Clonal chromosome changes are often found in the bone marrow (BM) of patients with Shwachman-Diamond syndrome (SDS). The most frequent ones include an isochromosome of the long arm of chromosome 7, i (7)(q10), and an interstitial deletion of the long arm of chromosome 20, del (20)(q). These two imbalances are mechanisms of somatic genetic rescue. The literature offers few expression studies on SDS.

Results: We report the expression analysis of bone marrow (BM) cells of patients with SDS in relation to normal karyotype or to the presence of clonal chromosome anomalies: del (20)(q) (five cases), i (7)(q10) (one case), and other anomalies (two cases). The study was performed using the microarray technique considering the whole transcriptome (WT) and three gene subsets selected as relevant in BM functions. The expression patterns of nine healthy controls and SDS patients with or without chromosome anomalies in the bone marrow showed clear differences.

Conclusions: There is a significant difference between gene expression in the BM of SDS patients and healthy subjects, both at the WT level and in the selected gene sets. The deletion del (20)(q), with the gene consistently lost, even in patients with the smallest losses of material, changes the transcription pattern: a low proportion of abnormal cells led to a pattern similar to SDS patients without acquired anomalies, whereas a high proportion yields a pattern similar to healthy subjects. Hence, the benign prognostic value of del (20)(q). The case of i (7)(q10) showed a transcription pattern similar to healthy subjects, paralleling the positive prognostic role of this anomaly as well.
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http://dx.doi.org/10.1186/s13039-019-0466-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941278PMC
January 2020

Scrambler therapy efficacy and safety for neuropathic pain correlated with chemotherapy-induced peripheral neuropathy in adolescents: A preliminary study.

Pediatr Blood Cancer 2018 07 6;65(7):e27064. Epub 2018 Apr 6.

Pediatric Emergency Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy, in need of effective treatment. Preliminary data support the efficacy of scrambler therapy (ST), a noninvasive cutaneous electrostimulation device, in adults with CIPN. We test the efficacy, safety, and durability of ST for neuropathic pain in adolescents with CIPN.

Patients And Methods: We studied nine pediatric patients with cancer and CIPN who received ST for pain control. Each patient received 45-min daily sessions for 10 consecutive days as a first step, but some of them required additional treatment.

Results: Pain significantly improved comparing Numeric Rate Scale after 10 days of ST (9.22 ± 0.83 vs. 2.33 ± 2.34; P < 0.001) and at the end of the optimized cycle (EOC) (9.22 ± 0.83 vs. 0.11 ± 0.33, P < 0.001). The improvement in quality of life was significantly reached on pain interference with general activity (8.67 ± 1.66 vs. 3.33 ± 2.12, P < 0.0001), mood (8.33 ± 3.32 vs. 2.78 ± 2.82, P < 0.0005), walking ability (10.00 vs. 2.78 ± 1.22, P < 0.0001), sleep (7.56 ± 2.24 vs. 2.67 ± 1.41, P < 0.001), and relations with people (7.89 ± 2.03 vs. 2.11 ± 2.03, P < 0.0002; Lansky score 26.7 ± 13.2 vs. 10 days of ST 57.8 ± 13.9, P < 0.001; 26.7 ± 13.2 vs. EOC 71.1 ± 16.2, P < 0.001).

Conclusion: Based on these preliminary data, ST could be a good choice for adolescents with CIPN for whom pain control is difficult. ST caused total relief or dramatic reduction in CIPN pain and an improvement in quality of life, durable in follow-up. It caused no detected side effects, and can be retrained successfully. Further larger studies should be performed to confirm our promising preliminary data in pediatric patients with cancer.
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http://dx.doi.org/10.1002/pbc.27064DOI Listing
July 2018

Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion.

Blood 2017 08 6;130(5):677-685. Epub 2017 Jun 6.

Immunology Research Area, IRCCS Ospedale Bambino Gesù, Rome, Italy.

Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children with acute leukemia (AL) either relapsed or at high-risk of treatment failure. We developed a novel method of graft manipulation based on negative depletion of αβ T and B cells and conducted a prospective trial evaluating the outcome of children with AL transplanted with this approach. Eighty AL children, transplanted between September 2011 and September 2014, were enrolled in the trial. All children were given a fully myeloablative preparative regimen. Anti-T-lymphocyte globulin from day -5 to -3 was used for preventing graft rejection and graft-versus-host disease (GVHD); no patient received any posttransplantation GVHD prophylaxis. Two children experienced primary graft failure. The cumulative incidence of skin-only, grade 1-2 acute GVHD was 30%; no patient developed extensive chronic GVHD. Four patients died, the cumulative incidence of nonrelapse mortality being 5%, whereas 19 relapsed, resulting in a 24% cumulative incidence of relapse. With a median follow-up of 46 months for surviving patients, the 5-year probability of chronic GVHD-free, relapse-free survival (GRFS) is 71%. Total body irradiation-containing preparative regimen was the only variable favorably influencing relapse incidence and GRFS. The outcomes of these 80 patients are comparable to those of 41 and 51 children given transplantation from an HLA-identical sibling or a 10/10 allelic-matched unrelated donor in the same period. These data indicate that haplo-HSCT after αβ T- and B-cell depletion represents a competitive alternative for children with AL in need of urgent allograft. This trial was registered at www.clinicaltrials.gov as #NCT01810120.
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http://dx.doi.org/10.1182/blood-2017-04-779769DOI Listing
August 2017

NK cell effector functions in a Chédiak-Higashi patient undergoing cord blood transplantation: Effects of in vitro treatment with IL-2.

Immunol Lett 2016 12 2;180:46-53. Epub 2016 Nov 2.

Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" University of Rome, Italy.

NK cell cytotoxicity in Chédiak-Higashi syndrome (CHS) is strongly impaired as lytic granules are not released upon NK-target cell contact, contributing to several defects typical of this severe immunodeficiency. Correction of NK cell defects in CHS should improve the outcome of hematopoietic stem-cell transplantation, proposed as therapy. We investigated NK cell functions in a CHS patient before and after cord-blood transplantation, and the ability of in vitro IL-2 treatment to restore them. Before the transplant, the strong defect in NK cell-mediated natural and antibody-dependent cytotoxicity, as well as in IFN-γ production, could be restored up to normal levels by in vitro IL-2 treatment. This cytokine also caused the appearance of smaller lysosomal granules and their orientation towards the NK-target cell contact area, thus suggesting that IL-2 had a more general capacity to restore NK cell effector functions. Moreover after the transplant, although the successful engraftment, NK cell cytotoxicity resulted still partially impaired at one year, almost normal at ten years and, anyhow, fully recovered by in vitro IL-2 treatment. Taken together, our results indicate that IL-2 had a wide capacity to restore NK cell effector functions, being able to reverse the altered cytotoxic activity, lytic granule pattern, and cytokine production observed in the CHS patient.
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http://dx.doi.org/10.1016/j.imlet.2016.10.009DOI Listing
December 2016

Parental origin of the deletion del(20q) in Shwachman-Diamond patients and loss of the paternally derived allele of the imprinted L3MBTL1 gene.

Genes Chromosomes Cancer 2017 01 21;56(1):51-58. Epub 2016 Sep 21.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Shwachman-Diamond syndrome (SDS) (OMIM 260400) is a rare autosomal recessive disease characterized by exocrine pancreatic insufficiency, skeletal, and hematological abnormalities and bone marrow (BM) dysfunction. Mutations in the SBDS gene cause SDS. Clonal chromosome anomalies are often present in BM, i(7)(q10) and del(20q) being the most frequent ones. We collected 6 SDS cases with del(20q): a cluster of imprinted genes, including L3MBTL1 and SGK2 is present in the deleted region. Only the paternal allele is expressed for these genes. Based on these data, we made the hypothesis that the loss of this region, in relation to parental origin of deletion, may be of relevance for the hematological phenotype. By comparing hematological data of our 6 cases with a group of 20 SDS patients without evidence of del(20q) in BM, we observed a significant difference for Hb levels (P < 0.012), and a difference slightly above the significance level for RBC counts (P < 0.053): in both cases the values were higher in patients with del(20q). We also report preliminary evidence for an increased number of BFU-E colonies in cases with paternal deletion, data on the presence of the deletion in colonies and in mature circulating lymphocytes. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/gcc.22401DOI Listing
January 2017

Farber disease in infancy resembling juvenile idiopathic arthritis: identification of two new mutations and a good early response to allogeneic haematopoietic stem cell transplantation.

Rheumatology (Oxford) 2014 Aug 10;53(8):1533-4. Epub 2014 Mar 10.

Clinica Pediatrica De Marchi, UOS Reumatologia Pediatrica, U.O. Pediatria 2, Fondazione IRCCS Cà Granda, Milano, Department of Pediatric Hematology-Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Bambino Gesù Children's Hospital, Rome, Mauro Baschirotto Institute for Rare Diseases, Genetics Unit, Costozza di Longare, Vicenza and Pediatrics Department, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1093/rheumatology/keu010DOI Listing
August 2014

Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan.

Blood 2012 Jul 29;120(2):473-6. Epub 2012 May 29.

Department of Pediatric Hematology-Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Bambino Gesù Children's Hospital, Piazzale S Onofrio, Rome, Italy.

Sixty thalassemia patients (median age, 7 years; range, 1-37) underwent allogeneic hematopoietic stem cell transplantation (HSCT) after a preparation combining thiotepa, treosulfan, and fludarabine. Before HSCT, 27 children were assigned to risk class 1 of the Pesaro classification, 17 to class 2, and 4 to class 3; 12 patients were adults. Twenty patients were transplanted from an HLA-identical sibling and 40 from an unrelated donor. The cumulative incidence of graft failure and transplantation-related mortality was 9% and 7%, respectively. Eight patients experienced grade II-IV acute GVHD, the cumulative incidence being 14%. Among 56 patients at risk, 1 developed limited chronic GVHD. With a median follow-up of 36 months (range, 4-72), the 5-year probability of survival and thalassemia-free survival are 93% and 84%, respectively. Neither the class of risk nor the donor used influenced outcome. This treosulfan-based preparation proved to be safe and effective for thalassemia patients given allogeneic HSCT.
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http://dx.doi.org/10.1182/blood-2012-04-423822DOI Listing
July 2012

Pre-transplant manipulation processing of umbilical cord blood units: Efficacy of Rubinstein's thawing technique used in 40 transplantation procedures.

Transfus Apher Sci 2010 Oct 3;43(2):173-8. Epub 2010 Aug 3.

Immunohematology Section, SIMT Bambino Gesù Pediatric Hospital, Tor Vergata University, Rome, Italy.

Background: Umbilical cord blood (UCB) is a valid alternative to be used in transplanted patients. Limitations of the use of stem cells depends on the small number of cells available; this is the reason why UCB can be used only in very low-weight patients. In this study we have evaluated the efficacy of cellular manipulation before transplant and in particular, before thawing the units through the Rubinstein method.

Methods: We have evaluated the results obtained after thawing 40 UCB to be used for as many patients affected by several pathologies (21 ALL, 6 AML, 3 MDS, 2 LNH, 2 histiocytosis, 2 β-thalassemia, 1 Chédiak-Higashi syndrome, 1 Fanconi anemia, 1 Wiskott-Aldrich syndrome and 1 Omenn syndrome).

Results: After thawing, nucleated cells (NC) mean recovery was 76.81% (SD±15.41). The quantity of NC obtained was 124.29×107 (SD±43.18) and in only 5 cases the number of NC after the procedure was lower than the requested graft dose. Among the last ones, in two cases only we did not achieve the target after manipulation. The post-manipulation cellular viability was 83.48% (SD±10.6). For all the units shipment complied with all the necessary procedures; in fact the temperature never rose above -120°C.

Conclusion: In our study we highlighted the efficacy of UCB thawing technique, with the same method defined in 1995 at the New York Blood Centre that guarantees an excellent NC recovery and maintains a high level of cell viability.
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http://dx.doi.org/10.1016/j.transci.2010.07.005DOI Listing
October 2010

RABGAP1L gene rearrangement resulting from a der(Y)t(Y;1)(q12;q25) in acute myeloid leukemia arising in a child with Klinefelter syndrome.

Virchows Arch 2009 Mar 28;454(3):311-6. Epub 2009 Jan 28.

Cytogenetics and Molecular Genetics, Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165, Rome, Italy.

In this study, we report the molecular cytogenetic characterization of an acute myeloid leukemia with a der(Y)t(Y;1)(q12;q25) in bone marrow cells in a child with Klinefelter syndrome. Conventional cytogenetics demonstrated the unbalanced translocation, i.e., a trisomic 1q25-qter juxtaposed to Yq12 replaced the terminal segment of chromosome Y was acquired and present only on bone marrow cells. Fluorescence in situ hybridization showed that the breakpoint at 1q25 disrupted RABGAP1L, a strongly expressed gene in CFU-GEMM, erythroid cells, and megakaryocytes, while the Yq12 breakpoint fell within the heterochromatic region. As der(Y)t(Y;1)(q12;q25) was an isolated cytogenetic change, RABGAP1L rearrangement as well as gene(s) dosage effects correlated to 1q25-qter trisomy, and Yq12-qter loss may make a major contribution to leukemogenesis and/or disease progression.
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http://dx.doi.org/10.1007/s00428-009-0732-zDOI Listing
March 2009

Allogeneic bone marrow transplantation for infantile globoid-cell leukodystrophy (Krabbe's disease).

Pediatr Transplant 2002 Oct;6(5):427-31

Bone Marrow Transplant Unit, Hematology Division, Bambino Gesù Children's Hospital IRCCS, Piazza Sant'Onofrio, 400165 Rome, Italy.

A 4-month-old-girl affected by early expression of Krabbe's disease was treated with allogeneic bone marrow transplantation (BMT). The stem cell donor was her heterozygous HLA-identical mother. The central nervous system (CNS) involvement at diagnosis was evident, but minimal. After BMT the child presented a severe hypotonia and an acute tetraventricular hydrocephalus; she died 180 days after the BMT with progressive severe neurologic deterioration. Leukocyte galactocerebrosidase (GALC) activity was present at donor levels 20 days after BMT. Full donor chimerism was evident 18 days after BMT. This report confirms that in early onset "Krabbe's syndrome" if the diagnosis is delayed after the birth, the progression of the neurologic deterioration is not reversed by BMT. It is to be demonstrated if a very early hemopoietic stem cell transplantation during the first weeks of life, could be appropriate and efficacious.
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http://dx.doi.org/10.1034/j.1399-3046.2002.02026.xDOI Listing
October 2002