Publications by authors named "Davide Zanon"

40 Publications

A child with green urine after a diagnostic enema: Answers.

Pediatr Nephrol 2021 Mar 17. Epub 2021 Mar 17.

University of Trieste, Trieste, Italy.

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http://dx.doi.org/10.1007/s00467-021-05035-6DOI Listing
March 2021

A child with green urine after a diagnostic enema: Questions.

Pediatr Nephrol 2021 Mar 17. Epub 2021 Mar 17.

University of Trieste, Trieste, Italy.

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http://dx.doi.org/10.1007/s00467-021-05028-5DOI Listing
March 2021

Post-HSCT graft failure due to refractory human cytomegalovirus successfully treated with haploidentical donor-derived immunoglobulins and stem cell graft infusion: A case report.

Antiviral Res 2021 04 9;188:105024. Epub 2021 Feb 9.

Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste, Italy. Electronic address:

Background: Human cytomegalovirus (HCMV) remains an important cause of transplant-related morbidity and mortality. The incidence of HCMV recurrence in the donor seronegative (D-)/recipient seropositive (R+) group is significantly higher than in other serostatus combinations as a result of a lack of pre-existing HCMV-specific memory T-lymphocytes in the donor, coupled with the eradication of the recipient's cellular immunity due to the conditioning regimen.

Case Presentation: We describe the case of an 8-year-old βE-thalassemic girl from Bangladesh who was seropositive for human cytomegalovirus (HCMV) and underwent hematopoietic stem cell transplantation from a HLA-matched, unrelated, HCMV-seronegative donor. Despite administering antiviral prophylaxis with commercial pooled anti-HCMV immunoglobulin (Ig) from day +1, the post-transplant course was complicated by prompt viral reactivation, and foscarnet therapy was initiated. The virus was refractory to treatment, leading rapidly to complete bone marrow failure, and targeted immunotherapy was proposed as a second-line therapy. Hypothesizing that the patient and her relatives may have been exposed to similar HCMV strains, we selected the patient's mother, who presented a high HCMV antibody titer, as the donor of virus strain-specific anti-HCMV Ig and T-lymphocytes. Complete viral clearance was achieved after two transfusions of the mother's plasma. Subsequently, the patient underwent a haploidentical rescue transplant, promptly reaching full hematological recovery.

Conclusion: These findings suggest that treatment with virus strain-specific Ig may offer a new therapeutic option for critically ill patients.
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http://dx.doi.org/10.1016/j.antiviral.2021.105024DOI Listing
April 2021

Area-under-the-Curve-Based Mycophenolate Mofetil Dosage May Contribute to Decrease the Incidence of Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients.

J Clin Med 2021 Jan 21;10(3). Epub 2021 Jan 21.

Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Via dell'Istria 65/1, 34137 Trieste, Italy.

Acute graft-versus-host disease (GvHD) remains the second leading cause of death, after disease relapse, in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). The medical records of 112 pediatric patients who underwent allo-HSCT from matched unrelated and haploidentical donors were analyzed. Patients were divided into two groups, according to the GvHD prophylactic regimen used. In the control group, GvHD prophylaxis consisted of cyclosporine A (CsA) and methotrexate (MTX) or CsA and mycophenolate mofetil (MMF) at a standard daily dose of 30 mg/kg. All subjects in the study group received tacrolimus (FK506) and MMF. In this group, MMF was subjected to therapeutic drug monitoring (TDM) through mycophenolic acid (MPA) area under the curve AUC. We found a statistically significant difference in both overall acute GvHD ( < 0.0001) and overall chronic GvHD ( < 0.05) incidence between the study and the control group. The initial daily MMF dose and the age at transplant in the study group proved to be inversely correlated (r = -0.523, < 0.0001). The children under six years of age required a significantly higher daily MMF dose ( < 0.008). This study showed that pharmacological monitoring of MPA AUC concentration allowed a reduction in the incidence of acute and chronic GvHD. MMF showed age-dependent pharmacokinetics due to greater drug clearance in younger children.
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http://dx.doi.org/10.3390/jcm10030406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865591PMC
January 2021

Standard treatment-refractory cytomegalovirus encephalitis unmasked by immune reconstitution inflammatory syndrome and successfully treated with virus-specific hyperimmune globulin.

Clin Transl Immunology 2020 17;9(11):e1201. Epub 2020 Nov 17.

University of Parma Parma Italy.

Objectives: Cytomegalovirus (CMV)-related encephalitis is a rare but potentially life-threatening complication of CMV infection in immunocompromised patients. The high mortality rate is associated with deficient immune system reconstitution after hematopoietic stem cell transplant (HSCT) and poor bioavailability of antiviral drugs in cerebrospinal fluid (CSF). CMV-related central nervous system (CNS) infection may occur with aspecific symptoms, without evidence of either blood viral load or magnetic resonance imaging (MRI) signs of encephalitis.

Methods: Here, we describe a 10-year-old girl who underwent an allogeneic HSCT and subsequently developed CMV encephalitis. Because of the absence of CMV antigen in the blood, the diagnosis of encephalitis was proposed only after a delay, following the onset of immune reconstitution inflammatory syndrome (IRIS). Two months of combined dual antiviral therapy with ganciclovir and foscarnet proved ineffective against CMV and caused significant bone marrow and renal toxicity. To avoid further toxicity, the girl was given daily treatment with CMV-hyperimmune globulins alone.

Results: After three weeks, the CSF viral load dropped significantly and was undetectable within three more weeks. In the meantime, the renal impairment resolved, and there was a complete bone marrow recovery.

Conclusion: We suggest that this patient succeeded in achieving CMV CSF clearance with high dose of CMV-hyperimmune globulin, given alone, because of the ability of immunoglobulins to penetrate the blood-brain barrier (BBB).
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http://dx.doi.org/10.1002/cti2.1201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670254PMC
November 2020

Pediatric blinatumomab preparation: Risk assessment on SmPC for software compliance.

J Oncol Pharm Pract 2020 Oct 27:1078155220966394. Epub 2020 Oct 27.

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

Introduction: Blinatumomab is an anticancer drug used in the treatment of Acute Lymphoblastic Leukaemia (ALL) in both adults and children. ALL is the most common form of cancer in children and patients who are refractory to standard treatments have poor prognosis. The preparation of blinatumomab is unique and extremely complex. It's important to carry out any information to identify all the critical issues related to the preparation of blinatumomab: sharing procedure between prescribers, staff of the Centralized Chemotherapy Preparation Unit [Unità Farmaci Antiblastici (UFA)] and administering nurses aimed at reducing the clinical risk related to the management of the drug blinatumomab and to obtain correct prescriptions on the real dose to be prepared, safe worksheets with computer processing of all variables (volumes to be added and corresponding dose of drug) and complete labels containing all the information necessary for the control of the preparation and its correct infusion.

Methods: A computerized process involves the use of specific software to which precise instructions must be given. This study is divided into two phases, the first one focused on the analysis of Summary of Product Characteristics (SmPC) and the extrapolation of any unclear part of SmPC. The second phase involved the manufacturer to answer a questionnaire.

Results: This comparison with the company allowed to perfect the blinatumomab preparation process leading to: 1. allow the patient to be discharged and return a few times for infusions and consequently reduce the number of medical prescriptions; 2. set up the drug for each patient every 4 days; 3. reduce costs related to devices, staff employed.

Conclusion: Computerizing the preparation of anti-blastic drugs is a necessary path for the safety of the patient and all the operators involved, however it may be necessary to make changes in the preparation process to allow the software to work correctly. The comparison between pharmacist, clinician and, where necessary, the manufacturer of the drug, was effective in the preparation of this drug.
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http://dx.doi.org/10.1177/1078155220966394DOI Listing
October 2020

When salt is needed to grow: Questions.

Pediatr Nephrol 2021 May 10;36(5):1129. Epub 2020 Aug 10.

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

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http://dx.doi.org/10.1007/s00467-020-04639-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009779PMC
May 2021

When salt is needed to grow: Answers.

Pediatr Nephrol 2021 May 10;36(5):1131-1132. Epub 2020 Aug 10.

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

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http://dx.doi.org/10.1007/s00467-020-04647-8DOI Listing
May 2021

Pentaglobin Efficacy in Reducing the Incidence of Sepsis and Transplant-Related Mortality in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation: A Retrospective Study.

J Clin Med 2020 05 24;9(5). Epub 2020 May 24.

Institute for Maternal and Child Health - IRCC Burlo Garofolo, via dell'Istria 65/1, 34137 Trieste, Italy.

The 12-month mortality rate in patients undergoing hematopoietic stem cell transplantation (HSCT) remains high, especially with respect to transplant-related mortality (TRM), which includes mortality due to infection complications through the aplasia phase. The aim of this study was to determine whether the administration of Pentaglobin could decrease TRM by lowering sepsis onset or weakening sepsis through the aplasia phase. One hundred and ninety-nine pediatric patients who had undergone HSCT were enrolled in our retrospective study. The patients were divided into two groups: the Pentaglobin group, which had received Pentaglobin in addition to the standard antibiotic treatment protocol established for the aplasia phase, and the Control group, which received only the standard treatment. As compared to the control group outcome, Pentaglobin led to a significant decrease in the days of temperature increase ( < 0.001) and a reduced infection-related mortality rate ( = 0.04). In addition, the number of antibiotics used to control infections, and the number of antibiotic therapy changes needed following first-line drug failure, were significantly lowered in the Pentaglobin group as compared to the control group ( < 0.0001). With respect to the onset of new infections following the primary infection detected, the Pentaglobin group showed a significant reduction for bacterial events, as compared to the control group ( < 0.03). Pentaglobin use in patients undergoing HSCT seems to produce a significant decrease in infection-associated TRM rate.
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http://dx.doi.org/10.3390/jcm9051592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291252PMC
May 2020

Rapid recovery of postnivolumab vemurafenib-induced Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome after tocilizumab and infliximab administration.

J Immunother Cancer 2020 02;8(1)

Department of Chemical and Pharmaceutical Sciences, University of Ferrera, Ferrera, Italy.

Background: Immune checkpoint inhibitors such as nivolumab and targeted BRAF inhibitors have dramatically altered the treatment outcomes of metastatic melanoma over the past few years. Skin toxicity is the most common adverse event (AE) related to the commonly used BRAF inhibitor vemurafenib, affecting more than 90% of patients. Vemurafenib-related severe AEs with early onset are reported in patients who were previously treated with anti-programmed cell death-1 (anti PD-1) antibodies. A prolonged administration of systemic steroids is the first-line treatment of severe or life-threatening AEs. We report the case of a woman suffering from vemurafenib-related severe, rapidly worsening Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome, resolved in a few hours after single-dose administration of a combination of TNF-α antagonist infliximab with interleukin (IL)-6 receptor antagonist tocilizumab.

Case Presentation: A 41-year-old woman treated with single-agent nivolumab presented with a melanoma progression. Biopsy samples were revised, revealing a BRAF V600E mutation. The patient was started on vemurafenib and cobimetinib treatment only 10 days after the last administration of nivolumab. On the third day of anti-BRAF therapy, profound lymphopenia was detected, and maculopapular eruption appeared afterward. Subsequently, the clinical conditions deteriorated further, and the woman was admitted on an emergency basis with high fever, respiratory and cardiocirculatory failure, diffuse rash, generalized edema, and lymphadenopathy. Diagnosis of DRESS syndrome with overexpressed capillary leakage was made. A single dose of tocilizumab was administered with an improvement of cardiocirculatory and renal function in a few hours. Because of worsening of liver function, skin lesions and mucositis, a single dose of infliximab was prescribed, and dramatic improvement was noted over the next 24 hours. Dabrafenib and trametinib were initiated, and coinciding with washout of infliximab from the patient's blood, the drug toxicity recurred.

Conclusion: Anti-IL-6 and anti-TNF-α target treatment of very severe AEs may afford an immediate resolution of potentially life-threatening symptoms and reduce the duration and the costs of hospitalization. Maintenance of therapeutic infliximab blood concentrations permits an early switch to dabrafenib after vemurafenib-related AEs.
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http://dx.doi.org/10.1136/jitc-2019-000388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057420PMC
February 2020

Hematopoietic stem cell transplantation-induced bone remodeling in autosomal recessive osteopetrosis: Interaction between skeleton and hematopoietic and sensory nervous systems.

Bone 2020 01 6;130:115144. Epub 2019 Nov 6.

Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave, CB 8301, St. Louis, MO 63110, USA. Electronic address:

Objective: Autosomal recessive osteopetrosis (ARO) is a rare congenital disorder of defective bone resorption. The inability of osteoclasts to resorb bone compromises the development of bone marrow cavity, and ultimately, leads to defective hematopoiesis and death within the first decade. The only curative treatment currently available for certain forms of ARO is hematopoietic stem cell transplantation (HSCT). Infants over ten months of age suffering from ARO are defined as patients with advanced disease; HSCT to these patients is associated with high risk of transplant-related mortality (TRM). Because of the extreme variability of ARO clinical phenotypes, the most reliable predictive factor of TRM and graft failure risk is the residual bone marrow space volume.

Case Report: We report clinical and radiological outcomes of one patient affected by ARO and treated with HSCT at advance stage of the disease. We describe the anomalies in various tissues, including bone marrow and bones at the moment of the diagnosis and document their gradual disappearance after HSCT until their complete resolution based on magnetic resonance imaging (MRI) observations. We provided radiological images of the cranial vault bone structure modifications, correlating the radiological appearance of the optical canals and nerves and of the cerebellum with the neurological manifestations of the disease.

Conclusions: Our results demonstrate that MRI is a highly sensitive technique that provides excellent images of bone marrow space before and after HSCT without exposing children to ionizing radiation. MRI also permits us to evaluate post-transplant skeletal remodeling and the deriving changes in the hematopoietic and sensory system.
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http://dx.doi.org/10.1016/j.bone.2019.115144DOI Listing
January 2020

Treatment of hepatitis C in two paediatric patients using sofosbuvir during haematopoietic stem cell transplantation.

Antivir Ther 2019 ;24(8):603-607

Bone Marrow Transplant Unit, Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste, Italy.

We report the first two paediatric cases of sofosbuvir treatment during high-intensity myeloablative conditioning and engraftment phases of haematopoietic stem cell transplantation. These reports highlight the safety of sofosbuvir during all phases of transplantation and the lack of interaction between sofosbuvir and alkylating or immunosuppressive agents.
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http://dx.doi.org/10.3851/IMP3332DOI Listing
October 2020

Design, synthesis and antimycobacterial activity of benzoxazinone derivatives and open-ring analogues: Preliminary data and computational analysis.

Bioorg Med Chem Lett 2019 09 17;29(17):2468-2474. Epub 2019 Jul 17.

Pharmacy and Clinical Pharmacology Department, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Via dell'Istria 65/1, 34137 Trieste, Italy.

This study examines in depth benzoxazine nucleus for antimycobacterial property. We synthesized some benzoxazin-2-one and benzoxazin-3-one derivatives, which were tested for activity against a panel of Mycobacterium tuberculosis (Mtb) strains, including H37Ra, H37Rv and some resistant strains. Several compounds displayed a high antimycobacterial activity and the three isoniazid analogue derivatives 8a-c exhibited a MIC range of 0.125-0.250 μg/mL (0.37-0.75 μM) against strain H37Ra, therefore lower than the isoniazid reference drug. Two benzoxazin-2-one derivatives, 1c and 5j, together with isoniazid-analogue compound 8a, also revealed low MIC values against resistant strains and proved highly selective for mycobacterial cells, compared to mammalian Vero cells. To predict whether molecule 8a is able to interact with the active site of InhA, we docked it into the crystal structure; indeed, during the molecular dynamic simulation the compound never left the protein pocket. The more active compounds were predicted for ADME properties and all proved to be potentially orally active in humans.
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http://dx.doi.org/10.1016/j.bmcl.2019.07.025DOI Listing
September 2019

Discovery of new potent dual sigma receptor/GluN2b ligands with antioxidant property as neuroprotective agents.

Eur J Med Chem 2019 Oct 8;180:268-282. Epub 2019 Jul 8.

Department of Chemistry and Pharmaceutical Sciences, Piazzale Europa 1- Via Giorgieri 1, University of Trieste, 34127, Trieste, Italy.

Among several potential applications, sigma receptors (σRs) can be used as neuroprotective agents, antiamnesic, antipsychotics and against other neurodegenerative disorders. On the other hands, antagonists of the GluN2b-subunit-containing-N-methyl-D-aspartate (NMDA) receptors are of major interest for the same purpose, being this subunit expressed in specific areas of the central nervous system and responsible for the excitatory regulation of nerve cells. Under these premises, we have synthesized and biologically tested novel hybrid derivatives obtained from the combination of phenyloxadiazolone and dihydroquinolinone scaffolds with different amine moieties, peculiar of σ2R ligands. Most of the new ligands exhibited a pan-affinity towards both σR subtypes and high affinity against GluN2b subunit. The most promising compounds belong to the dihydroquinolinone series, with the best affinity profile for the cyclohexylpiperazine derivative 28. Investigation on their biological activity showed that the new compounds were able to protect SH-SY5Y cells against oxidative stress induced by hydrogen peroxide treatment. These results proved that our dual σR/GluN2b ligands have beneficial effects in a model of neuronal oxidative stress and can represent strong candidate pharmacotherapeutic agents for minimizing oxidative stress-induced neuronal injuries.
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http://dx.doi.org/10.1016/j.ejmech.2019.07.012DOI Listing
October 2019

Stability of a novel Lidocaine, Adrenaline and Tetracaine sterile thermosensitive gel: A ready-to-use formulation.

Eur J Pharm Sci 2019 Aug 21;136:104962. Epub 2019 Jun 21.

Department of Chemistry and Pharmaceutical Sciences, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy.

Background: Superficial wounds that require suturing are often the reason children visit the Paediatric Emergency Department. Suturing is usually accompanied by perilesional administration of lidocaine, a local anaesthetic drug that improves pain tolerance. In paediatric patients, this approach has a low compliance because lidocaine has to be injected, which in children generates fear and anxiety, a sterile anaesthetic gel could improve the child compliance.

Objective: To develop a sterile and stable sterile gel capable of remaining in place over time for topical anaesthesia.

Method: Different formulations were analysed by HPLC, by UV and fluorimetric detection. Two different sterilisation methods were tested.

Main Outcome: To maintain the original stability of the gel also after sterilisation process.

Results: Four different gels were prepared and analysed; the most stable gel lasts over 3 months with a degradation less than 10%.

Conclusion: The use of Poloxamer 407 guarantees stability of the preparation, showing a reduction in oxidative reaction, and gives the gel the right texture for application to a bleeding wound.
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http://dx.doi.org/10.1016/j.ejps.2019.104962DOI Listing
August 2019

Drop of Butyrylcholinesterase Activity after Cyclophosphamide Conditioning as a Predictive Marker of Liver Transplant-Related Complications and Its Correlation with Transplant-Related Mortality in Pediatric Hematopoietic Stem Cell Recipients.

J Clin Med 2019 Jun 10;8(6). Epub 2019 Jun 10.

Department of Transfusion Medicine, ASUITS, Piazza dell'Ospitale 1, 34129 Trieste, Italy.

Transplant-related liver complications are a potentially fatal condition of hematopoietic stem cell transplantation (HSCT) in pediatric patients, actually representing one of the main factors involved in transplant-related mortality (TRM). The search for a specific marker capable of predicting the development of this condition is a relevant clinical issue. We have observed a variable reduction in serum butyrylcholinesterase (BChE) activity after a cyclophosphamide-containing conditioning regimen. This study aims to determine the cutoff of BChE activity reduction that might be a specific prognostic marker for liver complications after HSCT. Our results show that the reduction of BChE values below 2000 U/L the day before the transplantation is an indicator strongly associated with the transplant-related liver complications ( < 0.0001). The incidence of overall survival at 1 year was significantly higher in the BChE > 2000 U/L group compared to the BChE < 2000 U/L group (84.7% versus 58.5%, < 0.001), while the TRM rate was significantly lower (8.1% versus 23.1%, < 0.05). None of the patients undergoing prophylaxis with defibrotide developed severe liver complications. Starting defibrotide treatment at the first signs of hepatic dysfunction in patients with particularly low BChE activity levels reduces severe liver transplant-related complications.
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http://dx.doi.org/10.3390/jcm8060825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617182PMC
June 2019

Monocyte-predominant engraftment, cytokine levels and early transplant-related complications in pediatric hematopoietic stem cell recipients.

Cancer Med 2019 03 28;8(3):890-901. Epub 2019 Jan 28.

Department of Medicine and Surgery, University of Parma, Parma, Italy.

Myeloablative conditioning is a well-established procedure that precedes hematopoietic stem cell transplantation (HSCT), particularly in pediatric patients. In the period directly following transplantation, several factors may contribute to complications that lead to the activation or damage of endothelial cells, involved in the pathogenesis of vascular endothelial syndromes (VES). However, to date, sufficiently specific and sensitive diagnostic markers for the various forms of VES have not been identified. This was a retrospective single-center study of patients who underwent allogeneic HSCT. For this cohort of patients, parameters including type of engraftment, donor characteristics, and cytokine production were measured and correlated with a high prevalence of short-term complications after HSCT. The aim of this study was to identify specific parameters useful for improving diagnostics and predicting adverse effects in VES. We confirmed that monocyte-predominant engraftment was related to a higher risk for an early transplant-related complication termed sinusoidal obstruction syndrome (SOS). The increased production of specific cytokines, in particular RANTES, represents a marker associated with prevalent engraftment. In addition, patients undergoing prophylaxis with defibrotide had "classical" engraftment, a common cytokine profile and a lower incidence of life-threatening transplant-related complications. The beneficial effect of defibrotide might be a starting point for developing selective prophylaxis for patients with monocyte engraftment to prevent severe early transplant-related complications.
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http://dx.doi.org/10.1002/cam4.1912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434198PMC
March 2019

Complete Remission of a Refractory Acute Myeloid Leukemia with Myelodysplastic- and Monosomy 7-Related Changes after a Combined Conditioning Regimen of Plerixafor, Cytarabine and Melphalan in a 4-Year-Old Boy: A Case Report and Review of Literature.

Cancers (Basel) 2018 Aug 27;10(9). Epub 2018 Aug 27.

Bone Marrow Transplant Unit, Institute for Maternal and Child Health-IRCCS Burlo Garofolo, via dell'Istria 65/1, 34137 Trieste, Italy.

Acute myeloid leukemia with myelodysplastic changes and monosomy 7 is a rare form of pediatric leukemia associated with very poor disease-free survival. The refractoriness of the disease is due to the protection offered by the bone marrow niche, making leukemic stem cells impervious to whatever chemotherapy or myeloablative regimen is chosen. Using a mobilizing agent for haematopoietic stem cells, Plerixafor, could sensitise leukemic cells to the myeloablative therapy. This approach was not previously used in a pediatric population, and in adult populations, was used in combination with busulphan with no difference in overall survival. We describe the case of a 4-year-old boy affected by refractory acute myeloid leukemia with myelodysplastic changes and monosomy 7. The child had never achieved a remission. We proposed a combined time-scheduled scheme of therapy with plerixafor and melphalan. Combining pharmacokinetics of plerixafor with pharmacokinetics and rapid and elevated myeloablative potential of melphalan in high dosage (200 mg/m²), we succeeded in mobilizing more than 85% of stem blasts immediately before infusion of Melphalan. The count of residual blasts after 8 h from melphalan infusion was only 1.3 cells/μL. The child achieved an engraftment at day +32 with full donor chimerism. Sixteen months after haematopoietic stem cell transplantation (HSCT), he is well and in complete remission. Our case suggests that the use of plerixafor before a conditioning therapy with melphalan could induce remission in acute myeloid leukemia refractory to the usual conditioning therapy in pediatric patients. This work adds strength to the body of knowledge regarding the "personalized" conditioning regimen for high-risk leukemic patients.
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http://dx.doi.org/10.3390/cancers10090291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162695PMC
August 2018

Administering analgesia sublingually is a suitable option for children with acute abdominal pain in the emergency department.

Acta Paediatr 2019 01 17;108(1):143-148. Epub 2018 Aug 17.

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

Aim: Acute abdominal pain is a frequent complaint in children attending emergency departments. The aim of this study was to investigate the pain score reductions when children with acute abdominal pain received medication sublingually.

Methods: We carried out a multicentre randomised controlled trial in three children's hospitals in Italy between March 2015 and June 2017. Children from four to 18 years of age with acute abdominal pain were recruited if their self-reported pain was at least six on a scale from 0-10. The children were randomised to receive ketorolac 0.5 mg/kg (n = 70) or tramadol 2 mg/kg (n = 70) sublingually or a melt in the mouth powder of 20 mg/kg paracetamol (n = 70). The main study outcome was the pain scores for the three drugs after two hours.

Results: The 210 children (58.6% girls) had a median age of 12 years with an interquartile range of 9-14.3. The median pain scores at two hours were not significantly different between ketorolac 2.0 (interquartile ranges, IQR 0.0-4.3) and tramadol 3.0 (IQR 1.0-5.0) vs paracetamol 3.0 (IQR 0.8-5.0). The median pain reductions were all 5.0 points.

Conclusion: Delivering analgesia sublingually was a suitable option for pain relief in children with acute abdominal pain in the emergency department.
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http://dx.doi.org/10.1111/apa.14514DOI Listing
January 2019

Total body irradiation and iron chelation treatment are associated with pancreatic injury following pediatric hematopoietic stem cell transplantation.

Oncotarget 2018 Apr 13;9(28):19543-19554. Epub 2018 Apr 13.

Pediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Bergamo, Italy.

Whereas many studies have addressed the risk of organ dysfunction following hematopoietic stem cell transplantation (HSCT), little is known about pancreatic susceptibility in this setting. We aimed to investigate the effect of iron overload (IO) and total body irradiation (TBI) on pancreatic function of children undergoing HSCT. We retrospectively evaluated children admitted between 2012-2016 fulfilling the following criteria: normal pancreatic iron concentration (PIC), regular pancreatic function before HSCT, availability of abdominal magnetic resonance imaging with gradient-recalled-echo sequences and a full set of biochemical markers of IO and pancreatic function performed before HSCT and at discharge. We divided the patients according to the use of TBI or myeloablative chemotherapy (MCHT) in the conditioning regimen. All patients with severe IO or moderate IO with a high risk of engraftment delay or transplantation-related complications underwent chelation therapy with deferoxamine (DFO) from the first day of conditioning to discharge. 63 patients had a HSCT in the study period, 13 did not fulfill the inclusion criteria; 50 (25 in each group) are included in the analysis, and did not show differences at baseline evaluation. At follow up testing the TBI group showed a significantly higher PIC (107,8±100,3 μmol/g vs 28,4±37,9 in MCHT group, p<0,0001). In the TBI group the patients who had DFO treatment had higher PIC (223,2±48,8 μmol/g vs 55,7±10,5 without DFO treatment, p<0,0001), and all patients having PIC >100 μmol/g at follow up had DFO-based chelation therapy, versus 26% of those with lower PIC (p<0,0001). The number of patients presenting exocrine pancreatic dysfunctions one month after transplantation was significantly higher in the TBI group (48% vs 4%; p<0.0001). The mean pancreatic volume reduction was significantly greater in the TBI group (39,1% vs 0,9% in the MCHT group; p<0,05), and was significantly worse on those who received DFO therapy. Based on our data, we suggest that TBI is detrimental for pancreatic functions, and speculate that DFO may contribute to the rapid pancreatic IO observed in these patients.
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http://dx.doi.org/10.18632/oncotarget.24646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929407PMC
April 2018

Multicenter randomized, double-blind controlled trial to evaluate the efficacy of laser therapy for the treatment of severe oral mucositis induced by chemotherapy in children: laMPO RCT.

Pediatr Blood Cancer 2018 08 4;65(8):e27098. Epub 2018 May 4.

Pediatric Hemato-Oncology Unit, IRCCS materno infantile Burlo Garofolo, Trieste, Italy.

Objectives: To demonstrate the efficacy of laser photobiomodulation (PBM) compared to that of placebo on severe oral mucositis (OM) in pediatric oncology patients. The primary objective was the reduction of OM grade (World Health Organization [WHO] scale) 7 days after starting PBM. Secondary objectives were reduction of pain, analgesic consumption, and incidence of side effects.

Methods: One hundred and one children with WHO grade > 2 chemotherapy-induced OM were enrolled in eight Italian hospitals. Patients were randomized to either PBM or sham treatment for four consecutive days (days +1 to +4). On days +4, +7, and +11, OM grade, pain (following a 0-10 numeric pain rating scale, NRS) and need for analgesics were evaluated by an operator blinded to treatment.

Results: Fifty-one patients were allocated to the PBM group, and 50 were allocated to the sham group. In total, 93.7% of PBM patients and 72% of sham patients had OM grade < 3 WHO on day +7 (P = 0.01). A significant reduction of pain was registered on day +7 in the PBM versus sham group (NRS 1 [0-3] vs. 2.5 [1-5], P < 0.006). Reduced use of analgesics was reported in the PBM group, although it was not statistically significant. No significant adverse events attributable to treatment were recorded.

Conclusions: PBM is a safe, feasible, and effective treatment for children affected by chemotherapy-induced OM, as it accelerates mucosal recovery and reduces pain.
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http://dx.doi.org/10.1002/pbc.27098DOI Listing
August 2018

MRI-based evaluation of multiorgan iron overload is a predictor of adverse outcomes in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation.

Oncotarget 2017 Oct 5;8(45):79650-79661. Epub 2017 Jul 5.

Department of Radiology, Institute for Maternal and Child Health-IRCCS Burlo Garofolo, 34137 Trieste, Italy.

The medical records of 44 pediatric patients who underwent allogeneic transplantation from 2011 to 2015 were retrospectively reviewed. Magnetic resonance imaging was used to measure iron concentrations in the liver, spleen, pancreas and bone. These patients were divided into two groups, 18 with non-elevated (< 100 μmol/g; Group 1) liver iron concentration before transplantation and 26 with elevated (> 100 μmol/g; Group 2) concentration . We compared transplant-related outcomes in the two groups. Iron overload was a negative prognostic risk factor for sinusoidal obstruction syndrome (OR = 17), osteoporosis (OR = 6.8), pancreatic insufficiency (OR = 17) and metabolic syndrome (OR = 15.1). No statistically significant differences in overall survival, disease-free survival, relapse incidence and incidence of acute or chronic graft-versus host disease were observed between the two groups. Mean times to engraftment of platelets (43.0 ± 35.3 days vs. 22.1 ± 9.5 days, < 0.05) and neutrophils (23.1 ± 10.4 days vs. 17.8 ± 4.6 days, < 0.05) appear significantly longer in Group 2 than in Group 1. Time to platelet engraftment showed statistically significant correlation with pre-transplant liver ( = 0.5775; < 0.001) and bone iron concentration ( = 0.7305; < 0.001). Post-transplant evaluation pointed out that iron concentration analyzed at the first follow-up peaked in all tissues. The iron accumulation was highest in bone, followed by the spleen, liver and pancreas. One year post transplant 9 of 18 (50%) patients in Group 1 and 6 of 22 (27%) in Group 2 presented with bone and/or spleen iron overload, but not with liver overload. Liver iron concentration is not always a reliable indicator of systemic siderosis or of the efficacy of chelation therapy.
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http://dx.doi.org/10.18632/oncotarget.19021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668078PMC
October 2017

Comparison of Efficacy and Safety of Caspofungin Versus Micafungin in Pediatric Allogeneic Stem Cell Transplant Recipients: A Retrospective Analysis.

Adv Ther 2017 05 20;34(5):1184-1199. Epub 2017 Apr 20.

Pharmacy and Clinical Pharmacology Unit, Institute for Maternal and Child Health Burlo Garofolo, Trieste, Italy.

Introduction: The high morbidity and mortality associated with invasive fungal infections (IFIs) provide the rationale for antifungal prophylaxis in immuno-compromised pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). Caspofungin and micafungin are antifungal agents of interest for prophylaxis of IFIs because of their potency against Candida and minimal toxicity or interactions with other drugs. Few studies have demonstrated the safety and efficacy of such echinocandins as prophylaxis for IFIs in patients undergoing HSCT.

Methods: This retrospective cohort study compared caspofungin and micafungin for prevention of IFIs in 93 pediatric patients undergoing HSCT for oncological or non-oncological disease. The observation began with the first dose of antifungal agent and ended 3 months after transplantation.

Results: Patients in the micafungin group had a higher overall treatment success rate of 87.2 versus 84.8% in the caspofungin group, but the difference was not significant. There were no statistically significant differences in the incidence or type of proven/probable IFIs between the 2 groups. The low incidence of death did not differ statistically between the groups. Patients in the caspofungin group presented more frequently with fever, during and after neutropenia. In both groups, we observed an expected worsening of blood chemistry parameters. There were no adverse events definitely attributable to the two antifungal agents.

Conclusion: These results demonstrate good efficacy and tolerability for caspofungin and micafungin. However, better results with respect to the incidence and resolution of fever in the micafungin group may suggest its use in preference to that of caspofungin.
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http://dx.doi.org/10.1007/s12325-017-0534-7DOI Listing
May 2017

First-time success with needle procedures was higher with a warm lidocaine and tetracaine patch than an eutectic mixture of lidocaine and prilocaine cream.

Acta Paediatr 2017 May 21;106(5):773-778. Epub 2017 Feb 21.

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

Aim: More than 50% of children report apian during venepuncture or intravenous cannulation and using local anaesthetics before needle procedures can lead to different success rates. This study examined how many needle procedures were successful at the first attempt when children received either a warm lidocaine and tetracaine patch or an eutectic mixture of lidocaine and prilocaine (EMLA) cream.

Methods: We conducted this multicentre randomised controlled trial at three tertiary-level children's hospitals in Italy in 2015. Children aged three to 10 years were enrolled in an emergency department, paediatric day hospital and paediatric ward and randomly allocated to receive a warm lidocaine and tetracaine patch or EMLA cream. The primary outcome was the success rate at the first attempt.

Results: The analysis included 172 children who received a warm lidocaine and tetracaine patch and 167 who received an EMLA cream. The needle procedure was successful at the first attempt in 158 children (92.4%) who received the warm patch and in 142 children (85.0%) who received the cream (p = 0.03). The pain scores were similar in both groups.

Conclusion: This study showed that the first-time needle procedure success was 7.4% higher in children receiving a warm lidocaine and tetracaine patch than EMLA cream.
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http://dx.doi.org/10.1111/apa.13764DOI Listing
May 2017

Oral Ondansetron versus Domperidone for Acute Gastroenteritis in Pediatric Emergency Departments: Multicenter Double Blind Randomized Controlled Trial.

PLoS One 2016 23;11(11):e0165441. Epub 2016 Nov 23.

Clinical Epidemiology and Public Health Research Unit, Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy.

The use of antiemetics for vomiting in acute gastroenteritis in children is still a matter of debate. We conducted a double-blind randomized trial to evaluate whether a single oral dose of ondansetron vs domperidone or placebo improves outcomes in children with gastroenteritis. After failure of initial oral rehydration administration, children aged 1-6 years admitted for gastroenteritis to the pediatric emergency departments of 15 hospitals in Italy were randomized to receive one oral dose of ondansetron (0.15 mg/kg) or domperidone (0.5 mg/kg) or placebo. The primary outcome was the percentage of children receiving nasogastric or intravenous rehydration. A p value of 0.014 was used to indicate statistical significance (and 98.6% CI were calculated) as a result of having carried out two interim analyses. 1,313 children were eligible for the first attempt with oral rehydration solution, which was successful for 832 (63.4%); 356 underwent randomization (the parents of 125 children did not give consent): 118 to placebo, 119 to domperidone, and 119 to ondansetron. Fourteen (11.8%) needed intravenous rehydration in the ondansetron group vs 30 (25.2%) and 34 (28.8%) in the domperidone and placebo groups, respectively. Ondansetron reduced the risk of intravenous rehydration by over 50%, both vs placebo (RR 0.41, 98.6% CI 0.20-0.83) and domperidone (RR 0.47, 98.6% CI 0.23-0.97). No differences for adverse events were seen among groups. In a context of emergency care, 6 out of 10 children aged 1-6 years with vomiting due to gastroenteritis and without severe dehydration can be managed effectively with administration of oral rehydration solution alone. In children who fail oral rehydration, a single oral dose of ondansetron reduces the need for intravenous rehydration and the percentage of children who continue to vomit, thereby facilitating the success of oral rehydration. Domperidone was not effective for the symptomatic treatment of vomiting during acute gastroenteritis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165441PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120790PMC
June 2017

Hepatic Gadolinium Deposition and Reversibility after Contrast Agent-enhanced MR Imaging of Pediatric Hematopoietic Stem Cell Transplant Recipients.

Radiology 2016 11 8;281(2):418-426. Epub 2016 Jun 8.

From the Bone Marrow Transplant Unit (N.M.), Department of Radiology (M.G., F.Z.), Department of Transfusion Medicine (R.S.), and Department of Pharmacy (D.Z.), Institute for Maternal and Child Health-IRCCS Burlo Garofolo, via dell'Istria, 65/1, 34137 Trieste, Italy; and Department of Pathology, Ospedale Beato Papa Giovanni XXIII, Bergamo, Italy (A.S.).

Purpose To determine if hepatic gadolinium deposition occurs in pediatric patients with iron overload but normal renal and hepatic function who undergo gadolinium-based contrast agent (GBCA)-enhanced magnetic resonance (MR) imaging. Materials and Methods Design and execution of this study was approved by the Ethical Committee of Institute for Research in Maternal and Child Health Burlo Garofolo of Trieste (reference no. 1105/2015). Because of the retrospective nature of the study, the requirement to obtain informed consent was waived. Twenty-one recipients of allogeneic hematopoietic stem cell transplants who underwent GBCA-enhanced MR imaging for suspected infection or relapse followed by liver biopsy comprised the study group. The number of GBCA-enhanced MR examinations and cumulative gadolinium dose for each patient was analyzed by comparing liver histologic analysis and iron and gadolinium liver concentration (GLC). Eight patients had siderosis and underwent chelation therapy. The study group was compared with four control patients who were never exposed to GBCA. Statistical analysis was performed with Spearman rank coefficient for correlation. Results All 21 patients had positive correlations between GLC and total GBCA dose (r = 0.4486; P < .05) and between GLC and liver iron concentration (r = 0.56; P < .05). Patients who underwent deferoxamine therapy had a significant reduction of GLC (from 0.64 μg/g ± 0.29 to 0.20 μg/g ± 0.17 [standard deviation]; P < .05). Conclusion In the presence of siderosis, a transmetallation mechanism may be set off between ferric ion and gadoterate meglumine. Deferoxamine appears capable of binding to gadolinium ion. Further studies of the safety of GBCAs in severe siderosis are needed. Chelation should be considered in patients with iron overload and a history of GBCA exposure. RSNA, 2016.
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http://dx.doi.org/10.1148/radiol.2016152846DOI Listing
November 2016

Metal accumulation in the renal cortex of a pediatric patient with sickle cell disease: a case report and review of the literature.

J Pediatr Hematol Oncol 2015 May;37(4):311-4

*Pediatric Hemato Oncology Department †Pharmacy and Clinical Pharmacology ‡Laboratory and Molecular Medicine §Department of Radiology, Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste ∥Department of Pathology, Ospedale Beato Papa Giovanni XXIII, Bergamo, Italy.

Background: Sickle cell disease (SCD) is a well-known multisystem illness characterized by vascular injury due to vasoocclusion and hemolysis, as well as infectious complications and iron overload, all of which contribute to high morbidity and mortality rates among children. In these patients, some authors have previously described iron cortical deposition in the kidney. We here report the first case in the literature of a girl affected by SCD showing an anomalous metal and rare element retention in the renal cortex.

Case Presentation: A 10-year-old white girl affected by SCD underwent a routine magnetic resonance imaging investigation that evidenced a reduced signal intensity in the renal cortex, compatible with hemosiderin precipitation. Histologic and elemental analyses of the hepatic and the renal biotic samples, performed with inductively coupled plasma mass spectrometry, revealed that concomitant with the high iron deposition, toxic and potentially carcinogenic elements such as nickel, magnesium, rubidium, and gadolinuim were anomalously retained particularly in the kidney.

Conclusions: The finding of rare and toxic elements in the kidney of SCD patients might be linked to the development of specific neoplastic transformations already described in this patient cohort. To be confirmed, our speculations need to be demonstrated in large sampling of patients.
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http://dx.doi.org/10.1097/MPH.0000000000000322DOI Listing
May 2015

Propranolol for cerebral cavernous angiomatosis: a magic bullet.

Clin Pediatr (Phila) 2014 Feb 25;53(2):189-90. Epub 2013 Jun 25.

1Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy.

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http://dx.doi.org/10.1177/0009922813492885DOI Listing
February 2014

Sublingual ketorolac versus sublingual tramadol for moderate to severe post-traumatic bone pain in children: a double-blind, randomised, controlled trial.

Arch Dis Child 2013 Sep 23;98(9):721-4. Epub 2013 May 23.

Pediatric Emergency Department, Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste, Italy.

Objectives: To assess the effectiveness of sublingual ketorolac versus sublingual tramadol in reducing the pain associated with fracture or dislocation of extremities in children.

Patients And Methods: A double-blind, randomised, controlled, non-inferiority trial was conducted in the paediatric emergency department of a research institute. One hundred and thirty-one children aged 4-17 years with suspected bone fracture or dislocation were enrolled. Eligible children were randomised to ketorolac (0.5 mg/kg) and placebo, or to tramadol (2 mg/kg) and placebo by sublingual administration, using a double-dummy technique. Pain was assessed by the patients every 20 min, for a maximum period of 2 h, using the McGrath scale for patients up to 6 years of age, and the Visual Analogue Scale for those older than 6 years of age.

Results: The mean pain scores fell significantly from eight to four and five in the ketorolac and tramadol groups, respectively, by 100 min (Wilcoxon sign rank test, p<0.001). The mean pain scores for ketorolac were lower than those for tramadol, but these differences were not significant at any time point (Mann-Whitney U Test, p values: 0-20 min: 0.167; 20-40 min: 0.314; 40-60 min: 0.223; 60-80 min: 0.348; 80-100 min: 0.166; 100-120 min: 0.08). The rescue dose of paracetamol-codeine was administered in 2/60 children in the ketorolac group versus 8/65 in the tramadol group (Fisher exact test, p=0.098). There were no statistically significant differences between the two groups in the frequency of adverse effects.

Conclusions: Both sublingual ketorolac and tramadol were equally effective for pain management in children with suspected fractures or dislocations.
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http://dx.doi.org/10.1136/archdischild-2012-303527DOI Listing
September 2013
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