Publications by authors named "Filomena Pierri"

34 Publications

HAPLOIDENTICAL α/β T-CELL AND B-CELL STEM CELL TRANSPLANTATION IN SEVERE MEVALONATE KINASE DEFICIENCY.

Rheumatology (Oxford) 2021 Jan 7. Epub 2021 Jan 7.

Centro Malattie Auto-infiammatorie e Immunodeficienze, Istituto G Gaslini, Genova, Italy.

Objective: Mevalonic aciduria (MA) represents the most severe of mevalonate kinase deficiency (MKD). Patients with MA have an incomplete response even to high doses of anti-cytokine drugs as anakinra or canakinumab and stem cell transplantation (SCT) represents a possible therapy for this severe disease.

Methods: We report the first two children affected by severe MKD who received haploidentical (haplo) α/β T cell and B cell depleted SCT. Both patients received treosulfan based conditioning regimen and one received a second haplo-SCT for secondary rejection of the first.

Results: Both patients obtained a stable full donor engraftment with a complete regression of clinical and biochemical inflammatory signs, without acute organ toxicity or acute and chronic GvHD. In both, the urinary excretion of mevalonic acid remained high in post transplant in the absence of any inflammatory signs.

Conclusion: Haploidentical α/β T cell and B cell depleted SCT represents a potential curative strategy in patients affected by MKD. The persistence of urinary excretion of mevalonic acid after SCT, probably related to the ubiquitous expression of MVK enzyme, suggests that these patients should be carefully monitored after SCT to exclude MKD clinical recurrence. Prophylaxis with anakinra in the acute phase after transplant could represent a safe and effective approach. Further biological studies are required to clarify the pathophysiology of inflammatory attacks in MKD in order to better define the therapeutic role of SCT.
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http://dx.doi.org/10.1093/rheumatology/keaa912DOI Listing
January 2021

Thalidomide as treatment of crohn-like disease occurred after allogeneic hematopoietic stem cell transplantation in a pediatric patient.

Pediatr Transplant 2020 Dec 12:e13941. Epub 2020 Dec 12.

Hematopoetic Stem Cell Transplant Unit, Hematology-Oncology, IRCSS, Institute G. Gaslini, Genova, Italy.

Background: Autoimmune diseases may occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and inflammatory bowel disease (IBD or Crohn disease) is rarely described. We describe a child who developed CD after allo-HSCT, successfully treated with thalidomide.

Case Report: A child affected by mucopolysaccharidosis type I received two allogeneic HSCTs for rejection after the first one. After cutaneous and intestinal chronic GvHD and 6 months after HSCT, the patients developed a trilinear autoimmune cytopenia successfully treated with rituximab and sirolimus. Due to persisting intestinal symptoms, colonoscopies were performed and histological findings demonstrated a picture of CD. Based on this observation and according to the recommendations for the treatment of CD, thalidomide was started. A complete stable clinical response was obtained 8 weeks after start of thalidomide. Colonoscopy performed 4.8 years later demonstrated a complete endoscopic and histological remission of CD.

Discussion: In this case, the diagnosis of CD after HSCT was based on histological findings. Indeed, repeated colonscopies were necessary for diagnosis, since both clinical and endoscopic features are often common to chronic GvHD and CD. Thalidomide was started at the dose of 1.7 mg/Kg/day, and it was well tolerated. Mild peripheral neurotoxicity occurred 5 years later but disappeared completely with the dose reduction. Currently, the patient is in complete remission from CD, despite the discontinuation of all the immunosuppressive therapies.

Conclusions: Thalidomide could represent a therapeutic option to treat CD as autoimmune disease after allogeneic HSCT.
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http://dx.doi.org/10.1111/petr.13941DOI Listing
December 2020

Spontaneous pregnancy after hematopoietic stem cell transplantation for chronic granulomatous disease.

Pediatr Blood Cancer 2021 Apr 28;68(4):e28783. Epub 2020 Oct 28.

Hematopoietic Stem Cell Transplant Unit, Department of Hematology and Oncology, IRCCS Istituto Giannina Gaslini, Genova, Italy.

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http://dx.doi.org/10.1002/pbc.28783DOI Listing
April 2021

Resistance to Antibiotics of Uropathogen Bacteria Isolated From Urine and Blood in Pediatric Cancer Patients: A Single Center, 12-year Study.

Pediatr Infect Dis J 2020 12;39(12):1106-1110

From the IRCCS Istituto Giannina Gaslini, Genova, Italy.

Resistant pathogens have become a major healthcare problem in children with cancer, causing different kinds of infections such as the bloodstream ones, most common, and most frequently described and the urinary tract ones, of which less data are available. We analyzed and compared the proportions, and the trends of resistance in pathogens isolated from blood and urines in children with cancer followed in IRCCS Istituto Giannina Gaslini, Genova, Italy, from January 2007 to December 2018. Overall, 345 strains detected in urines and 282 in bloodstream infections were analyzed. Enterobacteriales were the most frequently isolated pathogens. During the study period in urines, there was a significant increase of resistance to ceftazidime, ciprofloxacin, piperacillin/tazobactam, and trimethoprim-sulfamethoxazole, but pathogens from blood were significantly more frequently resistant to amikacin, piperacillin/tazobactam, and combination therapy piperacillin/tazobactam+amikacin, even if with a decreasing trend during the study period. These data confirm the importance of surveillance of isolated microorganism and antibiotic resistance in cancer children.
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http://dx.doi.org/10.1097/INF.0000000000002854DOI Listing
December 2020

Gastrointestinal Hemorrhage: A Manifestation of the Telomere Biology Disorders.

J Pediatr 2021 Mar 21;230:55-61.e4. Epub 2020 Sep 21.

Section of Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX.

Objective: To describe the clinical features, therapeutic interventions, and patient outcomes of gastrointestinal (GI) hemorrhage in individuals with a telomere biology disorder, including dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome, Revesz syndrome, and Coats plus.

Study Design: Clinical Care Consortium for Telomere Associated Ailments members were invited to contribute data on individuals with telomere biology disorders at their institutions who experienced GI bleeding. Patient demographic, laboratory, imaging, procedural, and treatment information and outcomes were extracted from the medical record.

Results: Sixteen patients who experienced GI hemorrhage were identified at 11 centers. Among 14 patients who underwent genetic testing, 8 had mutations in TINF2, 4 had mutations in CTC1 or STN1, and 1 patient each had a mutation in TERC and RTEL1. Ten patients had a history of hematopoietic cell transplantation. The patients with Coats plus and those without Coats plus had similar clinical features and courses. Angiodysplasia of the stomach and/or small bowel was described in 8 of the 12 patients who underwent endoscopy; only 4 had esophageal varices. Various medical interventions were trialed. No single intervention was uniformly associated with cessation of bleeding, although 1 patient had a sustained response to treatment with bevacizumab. Recurrence was common, and the overall long-term outcome for affected patients was poor.

Conclusions: GI bleeding in patients with telomere biology disorders is associated with significant morbidity and with vascular ectasias rather than varices.
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http://dx.doi.org/10.1016/j.jpeds.2020.09.038DOI Listing
March 2021

The passage from bone marrow niche to bloodstream triggers the metabolic impairment in Fanconi Anemia mononuclear cells.

Redox Biol 2020 09 23;36:101618. Epub 2020 Jun 23.

Experimental Medicine Department, University of Genova, Genoa, Italy.

Fanconi Anemia (FA) is a disease characterized by bone marrow (BM) failure and aplastic anemia. In addition to a defective DNA repair system, other mechanisms are involved in its pathogenesis, such as defective mitochondrial metabolism, accumulation of lipids, and increment of oxidative stress production. To better understand the role of these metabolic alterations in the process of HSC maturation in FA, we evaluated several biochemical and cellular parameters on mononuclear cells isolated from the bone marrow of FA patients or healthy donors. To mimic the cellular residence in the BM niche or their exit from the BM niche to the bloodstream, cells have been grown in hypoxic or normoxic conditions, respectively. The data show that, in normoxic conditions, a switch from anaerobic to aerobic metabolism occurs both in healthy and in pathological samples. However, in FA cells this change is associated with altered oxidative phosphorylation, the increment of oxidative stress production, no activation of the endogenous antioxidant defenses and arrest in the G2M phase of the cell cycle. By contrast, FA cells grown in hypoxic conditions do not show cell cycle and metabolic alterations in comparison to the healthy control, maintaining both an anaerobic flux. The data reported herein suggests that the passage from the BM niche to the bloodstream represents a crucial point in the FA pathogenesis associated with mitochondrial dysfunction.
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http://dx.doi.org/10.1016/j.redox.2020.101618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327247PMC
September 2020

Haploidentical hematopoietic stem cell transplantation in aplastic anemia: a systematic review and meta-analysis of clinical outcome on behalf of the severe aplastic anemia working party of the European group for blood and marrow transplantation (SAAWP of EBMT).

Bone Marrow Transplant 2020 10 28;55(10):1906-1917. Epub 2020 Apr 28.

King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Aplastic anemia (AA) is a serious hematological disorder, which is solely cured by hematopoietic stem cell transplantation (HSCT). Haploidentical HSCT is an emerging modality with encouraging outcomes in several blood conditions. The present study aims to comprehensively assess the feasibility and safety of haploidentical HSCT in patients with severe and very severe AA. It is a systematic review and meta-analysis of studies related to haploidentical stem cell transplantation in idiopathic AA investigating rates of successful engraftment, acute graft-versus-host disease (aGvHD), chronic GvHD (cGvHD), transplant-related mortality (TRM), and posttransplantation viral infections (including cytomegalovirus [CMV]) in patients with AA. The effects of reduced-intensity conditioning (RIC) and nonmyeloablative conditioning (NMA), as well as various GvHD prophylaxis regimens on these outcomes were evaluated. In total 15 studies were identified, (577 patients, 58.9% males), successful engraftment was observed in 97.3% of patients (95% CI, 95.9-98.7) while grades II-IV aGvHD and cGvHD were reported in 26.6% and 25.0%, respectively. The pooled incidence of TRM was 6.7% per year (95% CI, 4.0-9.4). RIC regimens were associated with higher proportions of successful engraftment (97.7% vs 91.7%, P = 0.03) and aGvHD (29.5% vs 18.7%, P = 0.008) when compared with NMA regimens with no differences in cGvHD or mortality incidence. When compared with methotrexate-containing regimens and other regimens, posttransplant cyclophosphamide-containing regimens reduced the rates of aGvHD (28.6%, 27.8%, and 12.8%, respectively, P = 0.02), CMV viremia (55.7%, 38.6%, and 10.4%, respectively, P < 0.001), and CMV disease in initially viremic patients (2.1%, 33.0%, and 0%, respectively, P < 0.001). We have concluded that Haploidentical HSCT was associated with promising outcomes in terms of successful engraftment and reduced complications. Future prospective trials are needed to identify the preferred conditioning regimen, GvHD prophylaxis, and graft source in the setting of haploidentical transplant for AA.
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http://dx.doi.org/10.1038/s41409-020-0897-2DOI Listing
October 2020

Outcome of patients with Fanconi anemia developing myelodysplasia and acute leukemia who received allogeneic hematopoietic stem cell transplantation: A retrospective analysis on behalf of EBMT group.

Am J Hematol 2020 07 21;95(7):809-816. Epub 2020 Apr 21.

UOC Ematologia, Istituto Giannina Gaslini, Genoa, Italy.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative for bone marrow failure in patients with Fanconi anemia (FA), but the presence of a malignant transformation is associated with a poor prognosis and the management of these patients is still challenging. We analyzed outcome of 74 FA patients with a diagnosis of myelodysplastic syndrome (n = 35), acute leukemia (n = 35) or with cytogenetic abnormalities (n = 4), who underwent allo-HSCT from 1999 to 2016 in EBMT network. Type of diagnosis, pre-HSCT cytoreductive therapies and related toxicities, disease status pre-HSCT, donor type, and conditioning regimen were considered as main variables potentially influencing outcome. The 5-year OS and EFS were 42% (30-53%) and 39% (27-51%), respectively. Patients transplanted in CR showed better OS compared with those transplanted in presence of an active malignant disease (OS:71%[48-95] vs 37% [24-50],P = .04), while none of the other variables considered had an impact. Twenty-two patients received pre-HSCT cytoreduction and 9/22 showed a grade 3-4 toxicity, without any lethal event or negative influence on survival after HSCT(OS:toxicity pre-HSCT 48% [20-75%] vs no-toxicity 51% [25-78%],P = .98). The cumulative incidence of day-100 grade II-IV a-GvHD and of 5-year c-GvHD were 38% (26-50%) and 40% (28-52%). Non-relapse-related mortality and incidence of relapse at 5-years were 40% (29-52%) and 21% (11-30%) respectively, without any significant impact of the tested variables. Causes of death were transplant-related events in most patients (34 out of the 42 deaths, 81%). This analysis confirms the poor outcome of transformed FA patients and identifies the importance of achieving CR pre-HSCT, suggesting that, in a newly diagnosed transformed FA patient, a cytoreductive approach pre-HSCT should be considered if a donor have been secured.
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http://dx.doi.org/10.1002/ajh.25810DOI Listing
July 2020

Association of clinical severity with FANCB variant type in Fanconi anemia.

Blood 2020 04;135(18):1588-1602

Cancer Genomics Unit, Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.

Fanconi anemia (FA) is the most common genetic cause of bone marrow failure and is caused by inherited pathogenic variants in any of 22 genes. Of these, only FANCB is X-linked. We describe a cohort of 19 children with FANCB variants, from 16 families of the International Fanconi Anemia Registry. Those with FANCB deletion or truncation demonstrate earlier-than-average onset of bone marrow failure and more severe congenital abnormalities compared with a large series of FA individuals in published reports. This reflects the indispensable role of FANCB protein in the enzymatic activation of FANCD2 monoubiquitination, an essential step in the repair of DNA interstrand crosslinks. For FANCB missense variants, more variable severity is associated with the extent of residual FANCD2 monoubiquitination activity. We used transcript analysis, genetic complementation, and biochemical reconstitution of FANCD2 monoubiquitination to determine the pathogenicity of each variant. Aberrant splicing and transcript destabilization were associated with 2 missense variants. Individuals carrying missense variants with drastically reduced FANCD2 monoubiquitination in biochemical and/or cell-based assays tended to show earlier onset of hematologic disease and shorter survival. Conversely, variants with near-normal FANCD2 monoubiquitination were associated with more favorable outcome. Our study reveals a genotype-phenotype correlation within the FA-B complementation group of FA, where severity is associated with level of residual FANCD2 monoubiquitination.
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http://dx.doi.org/10.1182/blood.2019003249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193183PMC
April 2020

A 20-year long term experience of the Italian Diamond-Blackfan Anaemia Registry: RPS and RPL genes, different faces of the same disease?

Br J Haematol 2020 07 21;190(1):93-104. Epub 2020 Feb 21.

Department of Public Health and Paediatric Sciences, University of Torino, Turin, Italy.

Diamond-Blackfan anaemia (DBA) is a rare and heterogeneous disease characterised by hypoplastic anaemia, congenital anomalies and a predisposition for malignancies. The aim of this paper is to report the findings from the Italian DBA Registry, and to discuss the Registry's future challenges in tackling this disease. Our 20-year long work allowed the connection of 50 Italian Association of Paediatric Haematology and Oncology (AIEOP) centres and the recruitment of 283 cases. Almost all patients have been characterised at a molecular level (96%, 271/283), finding a causative mutation in 68% (184/271). We confirm the importance of determination of erythrocyte adenosine deaminase activity (eADA) and of ribosomal RNA assay in the diagnostic pipeline and characterisation of a remission state. Patients with mutations in large ribosomal subunit protein (RPL) genes had a significant correlation with the incidence of malformations, higher eADA levels and more severe outcomes, compared to patients with mutations in small ribosomal subunit protein (RPS) genes. Furthermore, as a consequence of our findings, particularly the incidence of malignancies and the high percentage of patients aged >18 years, we stress the importance of collaboration with adult clinicians to guarantee regular multi-specialist follow-up. In conclusion, this study highlights the importance of national registries to increase our understanding and improve management of this complex disease.
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http://dx.doi.org/10.1111/bjh.16508DOI Listing
July 2020

Imatinib melylate as second-line treatment of bronchiolitis obliterans after allogenic hematopoietic stem cell transplantation in children.

Pediatr Pulmonol 2020 03 17;55(3):631-637. Epub 2020 Jan 17.

SCT Unit- Paediatric Haematology, Oncology Department, IRCCS Istituto Giannina Gaslini, Genova, Italy.

Background: The onset of bronchiolitis obliterans (BO) as a pulmonary manifestation of chronic graft vs host disease dramatically changes the prognosis of children undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed to evaluate the overall survival (OS) of children with BO treated with imatinib mesylate (IM).

Methods: This study included children who underwent allo-HSCTs between January 2000 and December 2016.

Results: Among 345 patients who underwent HSCTs, 293 were evaluable for BO and 26 (8.9%) developed BO. The cumulative incidence of BO was 4.8% (95% confidence interval [CI], 2.8-7.5) at 1 year and 7.7% (95% CI, 5.1-11.1) at 3 years after transplantation. In the group of HSCTs (n = 67) complicated by chronic GvHD (c-GVHD), the incidence rate of BO was 38.8%. In total, 96.1% of patients with BO had c-GvHD worse than moderate grade, which was present in 70.7% of patients without BO (P = .011). The mortality rates were 46.1% in the BO group and 27.4% in the group without BO. Half of the patients with BO (n = 13) received IM, and the overall response rate was 76.9%. Four years after HSCT, OS was 42.6% (95% CI, 18.2-65.3) in the group without IM and 83.3% (95% CI, 27.3-97.5) in the group with IM.

Conclusions: BO after HSCT in the pediatric population has a high incidence and mortality rate. In terms of overall response and tolerability, this study showed relevant improvements in the prognosis of children with BO after the introduction of IM. Further prospective studies among children are needed to confirm these results.
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http://dx.doi.org/10.1002/ppul.24652DOI Listing
March 2020

Unusual Late-onset Enteropathy in a Patient With Lipopolysaccharide-responsive Beige-like Anchor Protein Deficiency.

J Pediatr Hematol Oncol 2020 11;42(8):e768-e771

Haematology Unit.

In recent years, monogenic causes of immune dysregulation syndromes, with variable phenotypes, have been documented. Mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) protein are associated with common variable immunodeficiency, autoimmunity, chronic enteropathy, and immune dysregulation disorders. The LRBA protein prevents degradation of cytotoxic T-lymphocyte antigen 4 (CTLA4) protein, thus inhibiting immune responses. Both LRBA and CTLA4 deficiencies usually present with immune dysregulation, mostly characterized by autoimmunity and lymphoproliferation. In this report, we describe a patient with an atypical clinical onset of LRBA deficiency and the patient's response to abatacept, a fusion protein-drug that mimics the action of CTLA4.
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http://dx.doi.org/10.1097/MPH.0000000000001708DOI Listing
November 2020

Failures of once-a-week trimethoprim-sulfamethoxazole prophylaxis in children undergoing allogeneic hematopoietic stem cell transplant.

Transpl Infect Dis 2020 Feb 27;22(1):e13231. Epub 2019 Dec 27.

Istituto Giannina Gaslini, Ospedale Pediatrico IRCCS, Genova, Italy.

Once-a-week cotrimoxazole is an effective prophylaxis for pneumocystosis during antineoplastic chemotherapy or autologous stem cell transplant. Following allogeneic stem cell transplant, this schedule is at risk of pneumocystosis or neurotoxoplasmosis, as demonstrated by these case reports. Therefore, a 3-times-a-week schedule must be adopted in these patients.
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http://dx.doi.org/10.1111/tid.13231DOI Listing
February 2020

Management of aplastic anemia after failure of frontline immunosuppression.

Expert Rev Hematol 2019 10 24;12(10):809-819. Epub 2019 Jul 24.

Hematology Unit, G. Gaslini Children's Research Hospital , Genova , Italy.

: About 60% of aplastic anemia (AA) patients are in need of further treatment after frontline standard immunosuppressive therapy (IST). This along with the prolonged survival of AA subjects who do not respond to or relapse after this treatment makes management of these patients a rising and very challenging issue. : Literature research, carried out from the most commonly used databases, included the following keywords: aplastic anemia, immunosuppressive treatment, antithymocyte globuline, ciclosporine A, refractory aplastic anemia, relapsing aplastic anemia, hematopoietic stem cell transplantation including haploidentical and cord blood transplantations thrombopoietin mimetics, supportive treatment, chelation and infections. Studies on the treatment of aplastic anemia with different levels of evidence were included. Top level of evidence studies (metanalyses and randomized prospective controlled trials) were a minority because severe AA, particularly in the subset of patients who fail upfront IST, is an extremely rare disease. Guidelines from National Societies and review articles were also included. : The most commonly used treatments after failure of upfront immunosuppression are hematopoietic stem cell transplantation, a second course of immunosuppression and thrombopoietin mimetics alone or in combination with immunosuppression. Other potential options are alemtuzumab, androgens, oral cyclosporine A in monotherapy. Not many comparative studies exist to clearly establish the superiority of one over another strategy. Therefore, the choice of the best treatment for these patients should rely on major driving factors like patient's age and comorbidities, availability of a matched unrelated donor, donor's characteristics and drug-availability.
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http://dx.doi.org/10.1080/17474086.2019.1645003DOI Listing
October 2019

FAS-mediated apoptosis impairment in patients with ALPS/ALPS-like phenotype carrying variants on CASP10 gene.

Br J Haematol 2019 11 15;187(4):502-508. Epub 2019 Jul 15.

Haematology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Autoimmune lymphoproliferative syndrome (ALPS) is a congenital disorder that results in an apoptosis impairment of lymphocytes, leading to chronic lymphoproliferation and autoimmunity, mainly autoimmune cytopenias. FAS gene defects are often responsible for the disease, the phenotype of which can vary from asymptomatic/mild forms to severe disease. More rarely, defects are associated to  other genes involved in apoptosis pathway, such as CASP10. Few data are available on CASP10-mutated patients. To date, two CASP10 mutations have been recognized as pathogenic (I406L and L258F) and others have been reported with controversial result on their pathogenicity (V410l, Y446C) or are known to be polymorphic variants (L522l). In this study, we evaluated apoptosis function in patients with an ALPS/ALPS-like phenotype carrying CASP10 variants. Molecular findings were obtained by next generation sequencing analysis of genes involved in immune dysregulation syndromes. Functional studies were performed after inducing apoptosis by FAS-ligand/TRIAL stimulation and analysing cell death and the function of CASP10, CASP8 and PARP proteins. We identified 6 patients with an ALPS (n = 2) or ALPS-like (n = 4) phenotype, carrying I406L (n = 1),V410l (n = 2),Y446C (n = 1) heterozygous CASP10 variants or the L522l polymorphisms (n = 2) associated with another polymorphic homozygote variant on CASP8 or a compound heterozygous mutation on TNFRSF13C. Apoptosis was impaired in all patients showing that such variants may play a role in the development of clinical phenotype.
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http://dx.doi.org/10.1111/bjh.16098DOI Listing
November 2019

Aplastic Anemia & MDS International Foundation (AA&MDSIF): Bone Marrow Failure Disease Scientific Symposium 2018.

Leuk Res 2019 05 20;80:19-25. Epub 2019 Mar 20.

Hematology Unit, IRCSS, Istituto Giannina Gaslini, Via Gerolamo Gaslini, 5, 16147, Genoa, Italy. Electronic address:

The bone marrow failure (BMF) syndromes are a group of rare disorders characterized by ineffective hematopoiesis resulting from deficiencies in the hematopoietic stem cell compartment. Although these diseases are typically acquired, some forms (e.g., Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome) are inherited. Patients with BMF syndromes can develop peripheral blood cytopenias and pancytopenia, and their disease can ultimately progress to acute myelogenous leukemia (AML). Research around the world is shedding light on the biology of the BMF syndromes, their clinical effects, and novel treatments. The Aplastic Anemia and MDS International Foundation (AAMDSIF) is an independent nonprofit organization whose mission is to help patients and family members cope with BMF syndromes. This report summarizes presentations on the latest scientific discoveries in BMF syndromes from the Sixth International Bone Marrow Failure Disease Scientific Symposium sponsored by AAMDSIF on March 22-23, 2018, in Rockville, Maryland.
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http://dx.doi.org/10.1016/j.leukres.2019.03.003DOI Listing
May 2019

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

Brachiocephalic vein for percutaneous ultrasound-guided central line positioning in children: A 20-month preliminary experience with 109 procedures.

Pediatr Blood Cancer 2017 02 31;64(2):330-335. Epub 2016 Aug 31.

Giannina Gaslini Institute, Genoa, Italy.

Background: Ultrasound-guided (USG) cannulation of the brachiocephalic vein (BCV) is gaining worldwide consensus for central venous access in children. This study reports a 20-month experience with this approach in children.

Methods: All patients who underwent percutaneous USG central venous catheter (CVC) positioning in the BCV between August 2013 and March 2015 have been included. Devices inserted during this period were open-ended, either single or double-lumen tunneled CVC. Our series was divided into three consecutive study periods in order to determine the relative incidence of repositioning and complications.

Results: During the study period, a total of 95 patients underwent 109 CVC insertions in the BCV. The median length of CVC duration was 230 days for a total of 23,212 catheter days. No major intraoperative complications occurred. Overall rate of CVC-related postoperative complications requiring repositioning or precocious removal was 0.90 per 1,000 catheter days and involved 21 CVC (19%, 95% confidence interval 13-28). These included 18 dislodgments, two infections, and one malfunction. Double-lumen CVCs represented the only significant risk factor for complications (52% complications-three per 1,000 catheter days).

Conclusion: USG supraclavicular cannulation of the BCV represents a safe approach for central line placement in children. It proved to be versatile, as it can be used in premature infants as well as in adolescents. Provided it is adopted by operators experienced in USG cannulation, we strongly suggest to resort to this approach as a first-line choice in children undergoing tunnelled central line placement for long-lasting therapy.
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http://dx.doi.org/10.1002/pbc.26202DOI Listing
February 2017

Acute lymphoblastic leukemia in the context of RASopathies.

Eur J Med Genet 2016 Mar 5;59(3):173-8. Epub 2016 Feb 5.

Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, Paris, France; INSERM UMR 1141, Université Paris Diderot, Sorbonne-Paris-Cité, Paris, France.

Noonan syndrome is associated with a range of malignancies including acute lymphoblastic leukemia (ALL). However, little information is available regarding the frequency, natural history, characteristics and prognosis of ALL in Noonan syndrome or RASopathies in general. Cross-referencing data from a large prospective cohort of 1176 patients having a molecularly confirmed RASopathy with data from the French childhood cancer registry allowed us to identify ALL in 6 (0.5%) patients including 4/778 (0.5%) with a germline PTPN11 mutation and 2/94 (2.1%) with a germline SOS1 mutation. None of the patients of our series with CFC syndrome (with germline BRAF or MAP2K1/MAP2K2 mutation - n = 121) or Costello syndrome (with HRAS mutation - n = 35) had an ALL. A total of 19 Noonan-ALL were gathered by adding our patients to those of the International Berlin-Munster-Frankfurt (I-BFM) study group and previously reported patients. Strikingly, all Noonan-associated ALL were B-cell precursor ALL, and high hyperdiploidy with more than 50 chromosomes was found in the leukemia cells of 13/17 (76%) patients with available genetics data. Our data suggest that children with Noonan syndrome are at higher risk to develop ALL. Like what is observed for somatic PTPN11 mutations, NS is preferentially associated with the development of hyperdiploid ALL that will usually respond well to chemotherapy. However, Noonan syndrome patients seem to have a propensity to develop post therapy myelodysplasia that can eventually be fatal. Hence, one should be particularly cautious when treating these patients.
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http://dx.doi.org/10.1016/j.ejmg.2016.01.003DOI Listing
March 2016

Utility of intranasal Ketamine and Midazolam to perform gastric aspirates in children: a double-blind, placebo controlled, randomized study.

BMC Pediatr 2014 Mar 5;14:67. Epub 2014 Mar 5.

Department of Pediatric Sciences, Catholic University of Rome, Largo A, Gemelli, 1, 00168 Rome, Italy.

Background: We performed a prospective, randomized, placebo-controlled study aimed to evaluate the efficacy and safety of a sedation protocol based on intranasal Ketamine and Midazolam (INKM) administered by a mucosal atomizer device in uncooperative children undergoing gastric aspirates for suspected tuberculosis.

Primary Outcome: evaluation of Modified Objective Pain Score (MOPS) reduction in children undergoing INKM compared to the placebo group.

Secondary Outcomes: evaluation of safety of INKM protocol, start time sedation effect, duration of sedation and evaluation of parents and doctors' satisfaction about the procedure.

Methods: In the sedation group, 19 children, mean age 41.5 months, received intranasal Midazolam (0.5 mg/kg) and Ketamine (2 mg/kg). In the placebo group, 17 children received normal saline solution twice in each nostril. The child's degree of sedation was scored using the MOPS. A questionnaire was designed to evaluate the parents' and doctors' opinions on the procedures of both groups.

Results: Fifty-seven gastric washings were performed in the sedation-group, while in the placebo-group we performed 51 gastric aspirates. The degree of sedation achieved by INMK enabled all procedures to be completed without additional drugs. The mean duration of sedation was 71.5 min. Mean MOPS was 3.5 (range 1-8) in the sedation-group, 7.2 (range 4-9) in the placebo-group (p <0.0001). The questionnaire revealed high levels of satisfaction by both doctors and parents in the sedation-group compared to the placebo-group. The only side effect registered was post-sedation agitation in 6 procedures in the sedation group (10.5%).

Conclusions: Our experience suggests that atomized INKM makes gastric aspirates more acceptable and easy to perform in children.

Trial Registration: Unique trial Number: UMIN000010623; Receipt Number: R000012422.
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http://dx.doi.org/10.1186/1471-2431-14-67DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974003PMC
March 2014

Safety and efficacy of propofol administered by paediatricians during procedural sedation in children.

Acta Paediatr 2014 Feb 3;103(2):182-7. Epub 2013 Dec 3.

Department of Paediatrics, Catholic University Medical School, Rome, Italy.

Aim: The aim of this study was to determine the safety and the efficacy of paediatrician-administered propofol in children undergoing different painful procedures.

Methods: We conducted a retrospective study over a 12-year period in three Italian hospitals. A specific training protocol was developed in each institution to train paediatricians administering propofol for painful procedures.

Results: In this study, 36,516 procedural sedations were performed. Deep sedation was achieved in all patients. None of the children experienced severe side effects or prolonged hospitalisation. There were six calls to the emergency team (0.02%): three for prolonged laryngospasm, one for bleeding, one for intestinal perforation and one during lumbar puncture. Nineteen patients (0.05%) developed hypotension requiring saline solution administration, 128 children (0.4%) needed O2 ventilation by face mask, mainly during upper endoscopy, 78 (0.2%) patients experienced laryngospasm, and 15 (0.04%) had bronchospasm. There were no differences in the incidence of major complications among the three hospitals, while minor complications were higher in children undergoing gastroscopy.

Conclusion: This multicentre study demonstrates the safety and the efficacy of paediatrician-administered propofol for procedural sedation in children and highlights the importance of appropriate training for paediatricians to increase the safety of this procedure in children.
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http://dx.doi.org/10.1111/apa.12472DOI Listing
February 2014

Platinum compounds in children with cancer: toxicity and clinical management.

Anticancer Drugs 2013 Nov;24(10):1007-19

Division of Pediatric Oncology, Catholic University of Rome, Rome, Italy.

Platinum compounds are widely used in the treatment of pediatric tumors such as neuroblastoma, germ-cell tumors, osteosarcoma, retinoblastoma, hepatoblastoma, brain tumors (low-grade gliomas and medulloblastoma/PNET), and relapsed and refractory lymphomas. The three major platinum compounds (cisplatin, carboplatin, and oxaliplatin) have a similar pharmacokinetics profile and mechanism of action, but the differences in their chemical structure are responsible for their different antitumor activity and toxicity. In this review, we have described the main characteristics of cisplatin, carboplatin, and oxaliplatin, focusing on their toxic effects and possible strategies to prevent them to improve the clinical outcomes in pediatric cancer patients. The underlying mechanism of each platinum-related toxicity is shown together with the clinical manifestations. Furthermore, possible preventive strategies are suggested to reduce the negative impact of platinum compounds on the quality of life of children with cancer. Cisplatin seems to be mostly ototoxic and nephrotoxic, carboplatin mainly produces myelosuppression, whereas oxaliplatin induces predominantly peripheral sensory neurotoxicity. In contrast, nausea and vomiting can be linked to all platinum compounds, although cisplatin exerts the strongest emetic effect. A correct knowledge of pharmacokinetics and toxicological profile of platinum compounds may aid physicians prevent their toxicity on auditory, nervous, renal, and bone marrow function, improving the quality of life of pediatric cancer patients.
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http://dx.doi.org/10.1097/CAD.0b013e3283650bdaDOI Listing
November 2013

New insights into the molecular mechanisms underlying sensitivity/resistance to the atypical retinoid ST1926 in acute myeloid leukaemia cells: the role of histone H2A.Z, cAMP-dependent protein kinase A and the proteasome.

Eur J Cancer 2013 Apr 11;49(6):1491-500. Epub 2012 Dec 11.

Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy.

ST1926 is an atypical retinoid and a promising anti-tumour agent with selective apoptotic activity on the leukaemic blast. The anti-tumour activity of the compound has been associated with its capacity to induce DNA double stranded breaks. Target profiling by affinity chromatography coupled to mass spectrometry led to the identification of histone H2A.Z as a protein capable of binding ST1926 specifically. The result was confirmed by studies involving Surface Plasmon Resonance (SPR). This indicates that H2A.Z is a primary target of ST1926 and links the perturbations of the histone pathway observed by microarray analysis to the DNA damage and apoptotic responses caused by the atypical retinoid. Comparison of the whole-genome gene-expression profiles of the ST1926-sensitive NB4 and the ST1926-resistant NB4.437r cell lines demonstrated differential expression of numerous genes. Network analysis of the data indicated enrichment of the cellular pathways controlling cAMP (cyclic adenosine-monophosphate)-dependent signal transduction, proteasome-dependent protein degradation and nuclear histones in NB4.437r cells. Pharmacological inhibition of cAMP-dependent protein kinase A with H89 partially reverted resistance of NB4.437r cells to ST1926. Conversely, inhibition of the proteasome with MG132 or bortezomib blocked the apoptotic response afforded by ST1926 in the NB4 cell line. This last effect was associated with a dramatic reduction in the DNA damage caused by the atypical retinoid. The results corroborate the idea that DNA damage is an important determinant of ST1926 apoptotic activity. More importantly, they demonstrate a proactive role of the proteasome in the DNA damaging and ensuing apoptotic response observed upon the challenge of acute myeloid leukaemia cells with ST1926.
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http://dx.doi.org/10.1016/j.ejca.2012.11.013DOI Listing
April 2013

Preclinical evaluation of the novel 7-substituted camptothecin Namitecan (ST1968) in paediatric tumour models.

Cancer Chemother Pharmacol 2012 Dec 25;70(6):811-22. Epub 2012 Sep 25.

Laboratory of Pharmacology, Division of Paediatric Oncology, Catholic University of Rome, Italy.

Purpose: The present study aimed to evaluate the new water soluble camptothecin analogue Namitecan (ST1968) in preclinical paediatric tumour models of the nervous system comprehensive of neuroblastoma, primitive neuroectodermal tumours/PNET and medulloblastoma where the drug was compared to Irinotecan.

Methods: Cellular sensitivity to the drug was assessed by MTT and clonogenic assays. Propidium iodide staining was used for cell cycle perturbation studies. The genotoxic effects were quantified by Comet assay, whereas apoptosis was assessed by PARP cleavage and sub-G1 accumulation. Tumour response was investigated in xenograft models in nude mice.

Results: The cellular response to Namitecan was heterogeneous with IC(50) (2 h) ranging between 0.14 and 13.26 μM, whereas SN38 (the active metabolite of Irinotecan) appeared more effective (IC(50): 0.03-11.7 μM). Interestingly, prolonged drug incubation times up to 72 h enhanced Namitecan cytotoxicity, with similar colony inhibition curves between the two analogues (IC(50), nM-SN38: 0.9 ± 0.2; Namitecan: 0.7 ± 0.4). DNA damage, accumulation in late-S/G2 phases and induction of apoptosis appeared important players of Namitecan cytotoxicity in our models. In vivo, Namitecan was superior to Irinotecan in three out of five xenograft models, with reversible weight loss (10 %). In the sensitive SK-N-AS xenograft, Namitecan showed a high retention in tumours consistently with: high antitumour response, rapid drug-mediated DNA damage (60 % mean TailDNA after 1 h from drug inoculation), persistent cell cycle perturbation (60-40 % G2 accumulation after 48-72 h, respectively) and apoptosis. Studies with Namitecan and platinum agents in this model showed a significant enhancement of antitumour activity of the drugs combination versus single agents.

Conclusions: Our preclinical data strongly support the interest of further investigations on the well-tolerated Namitecan either as a single agent or in combination in paediatric oncology.
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http://dx.doi.org/10.1007/s00280-012-1973-0DOI Listing
December 2012

Expression of liquoral neuroprotection markers in children with acute lymphoblastic leukemia.

Leuk Res 2011 Nov 16;35(11):1467-71. Epub 2011 Aug 16.

Department of Pediatric Neurosciences, Catholic University of Rome, Rome, Italy.

Brain damage related to intrathecal methotrexate in children with acute lymphoblastic leukemia (ALL) is still unclear. Neuroinflammatory mechanisms and intracerebral production of specific biomarkers, play a key role in determining neuroprotective mechanisms after brain injury. To determine whether the CSF concentrations of neuron-specific enolase (NSE), neurotrophic factors and doublecortin (DCX) are influenced by repeated intrathecal methotrexate administrations, we prospectively collected CSF samples from 10 children with ALL and 10 controls. Our results showed an increased expression of the liquoral markers. This up-regulation could be interpreted as a neuroprotective response of the brain against the neuronal damages induced by MTX.
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http://dx.doi.org/10.1016/j.leukres.2011.07.025DOI Listing
November 2011

Effects of nerve growth factor in experimental model of focal microgyria.

Childs Nerv Syst 2011 Dec 1;27(12):2117-22. Epub 2011 Jul 1.

Department of Pediatric Neurosciences, Gemelli Hospital, Catholic University Medical School, Largo F. Vito, 1-00168 Rome, Italy.

Aim: The effects on neural repair of intraparenchymal nerve growth factor (NGF) administration were evaluated in neonate Wistar rats with experimentally induced focal microgyria.

Methods: A freezing focal polymicrogyric lesion was induced on the frontal cortex in 35 newborn Wistar rats on postnatal day 1. NGF was administered in 15 cases, with 20 pups as controls. Animals were sacrificed at 72 h and 7 days after NGF administration. Real-time PCR was used for the quantification of the expression of TrkA, p75, and doublecortin (DCX) at the level of the cortical lesion in seven different groups of animals: control 72 h (n = 5), control 7 days (n = 5), microgyria 72 h (n = 5), microgyria 7 days (n = 5), microgyria + NGF 72 h (n = 5), microgyria + NGF 7 days (n = 5), and control + NGF (n = 5).

Results: A significant increase in TrkA expression was found in the microgyria + NGF 7 days group compared to the others. TrkA upregulation was already visible 72 h after NGF administration. Unlike TrkA, p75 expression increased in animals subjected to the experimental focal microgyria and decreased markedly after NGF administration. DCX expression in injured animals was observed to increase strongly 7 days after NGF administration compared with other groups.

Conclusions: NGF administration interferes with neural repair mechanisms at the polymicrogyric lesion site by means of TrkA and DCX upregulation which possibly counteracts the process of apoptosis caused by the brain injury.
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http://dx.doi.org/10.1007/s00381-011-1516-8DOI Listing
December 2011

Neuroprotective role of nerve growth factor in hypoxicischemic injury. From brain to skin.

Arch Ital Biol 2011 Jun;149(2):275-82

Department of Pediatric Neuroscience, Catholic University of Rome, Italy.

Hypoxic-ischemic injuries (HII) of the brain, optic pathways, and skin are frequently associated with poor neurological and clinical outcome. Unfortunately, no new therapeutic approaches have been proposed for these conditions. Recently, experimental and clinical studies showed that nerve growth factor (NGF) can improve neurological deficits, visual loss and skin damage after HII. Based on these studies, we report the effects of NGF administration in different lesions of the brain, optic pathways and skin. 2.5S NGF purified and lyophilized from male mouse submaxillary glands was utilized for the treatment. NGF administration was started in absence of recovery after conventional and standardized treatment. One mg NGF was administered via the external catheter into the brain, by drop administration in the eye, and by subcutaneous administration in the skin. We treated 4 patients: 2 children with hypoxic-ischemic brain damage, an adult patient with an optic glioma-induced visual loss and a child with a severe crush syndrome of the lower left limb. After NGF treatment, we observed an amelioration of both neurological and electrophysiological function of the brain, a subjective and objective improvement of visual function, and a gradual improvement of ischemic skin lesion. No side effects were related to NGF treatment in all patients studied. Our observation shows that NGF administration may be an effective and safe adjunct therapy in patients with severe HII. The beneficial and prolonged effect on nerve function suggests a neuroprotective mechanism exerted by NGF on the residual viable neurological pathways of these patients.
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http://dx.doi.org/10.4449/aib.v149i2.1364DOI Listing
June 2011

Enhanced cell cycle perturbation and apoptosis mediate the synergistic effects of ST1926 and ATRA in neuroblastoma preclinical models.

Invest New Drugs 2012 Aug 3;30(4):1319-30. Epub 2011 Jun 3.

Laboratory of Pharmacology, Division of Pediatric Oncology, Catholic University of Rome, L.go A. Gemelli 8, 00168 Rome, Italy.

Retinoic acid therapy is nowadays an important component of treatment for residual disease of stage IV neuroblastoma after multimodal therapy. Nevertheless, arising resistance and treatment toxicity could represent relevant limiting factors. In the present study, we show that retinoic acid enhances the cytostatic and apoptogenic properties of the novel adamantyl retinoid ST1926 in a panel of neuroblastoma cells with different p53 status and caspase 8 expression, resulting in synergistic effects as assessed by Combination Index and Isobologram analysis. Under conditions where the two drugs alone produced no toxic effects, their combination resulted in enhanced G2-M arrest and sub-G1 population as shown by BrdU pulse-chase and labeling experiments. PARP cleavage, caspase 3, 8 and 9 activation and modulation of DR4 and FAS were indicative of enhanced apoptosis triggered by the co-incubation of the two drugs whereas neither ST1926-mediated genotoxic damage nor ATRA-differentiating effects were affected by the combined treatment. Caspase-3 and 8-mediated apoptosis appeared to play an important role in the drugs synergism. In fact, the addition of a pan-caspase inhibitor ZVAD-FMK reverted this effect in SK-N-DZ cells, and synergism was confined to limited drugs doses in HTLA cells not expressing caspase-8. Although not modulated, p53 appeared to enhance cells responsiveness to retinoid/ATRA combination. In vivo studies in the most sensitive neuroblastoma model SK-N-DZ, confirmed enhanced activity of the drugs combination vs single treatments. The study provides important lines of evidence that such a drugs combination could represent a less toxic and more effective approach for maintenance treatment in children with neuroblastoma.
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http://dx.doi.org/10.1007/s10637-011-9689-2DOI Listing
August 2012