Publications by authors named "Anna Pegoraro"

26 Publications

  • Page 1 of 1

P2X7 Receptor in Hematological Malignancies.

Front Cell Dev Biol 2021 5;9:645605. Epub 2021 Mar 5.

Department of Medical Sciences, University of Ferrara, Ferrara, Italy.

The P2X7 receptor is an ion channel gated by the nucleotide ATP, known for its role in immune responses and recently emerging as a critical onco-promoting factor. Lymphocytes, myeloid cells, and their precursors were among the first cells proved to express a functional P2X7 receptor; therefore, it is not surprising that lymphoproliferative and myeloproliferative diseases, also known as hematological malignancies, were shown to be related in their insurgence and progression to P2X7 alterations. Here, we overview established and recent literature relating P2X7 with the biological mechanisms underlying leukemias, lymphomas, and multiple myeloma development. Particular attention is paid to studies published in the very recent past correlating P2X7 with ATP concentration in the leukemic microenvironment and P2X7 overexpression to acute myeloid leukemia aggressiveness and response to chemotherapy. The described literature strongly suggests that P2X7 and its genetic variants could be regarded as potential new biomarkers in hematological malignancies and that both P2X7 antagonists and agonists could emerge as new therapeutic tools alone or in combination with traditional chemotherapy.
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http://dx.doi.org/10.3389/fcell.2021.645605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982859PMC
March 2021

P2X7 Variants in Oncogenesis.

Cells 2021 Jan 19;10(1). Epub 2021 Jan 19.

Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy.

The P2X7 receptor for extracellular ATP is a well-established mediator of tumoral development and progression both in solid cancers and hematological malignancies. The human P2X7 gene is highly polymorphic, and several splice variants of the receptor have been identified in time. P2X7 single-nucleotide polymorphisms (SNPs) have been broadly analyzed by studies relating them to pathologies as different as infectious, inflammatory, nervous, and bone diseases, among which cancer is included. Moreover, in the last years, an increasing number of reports concentrated on P2X7 splice variants' different roles and their implications in pathological conditions, including oncogenesis. Here, we give an overview of established and recent literature demonstrating a role for human P2X7 gene products in oncological conditions, mainly focusing on current data emerging on P2X7 isoform B and nfP2X7. We explored the role of these and other genetic variants of P2X7 in cancer insurgence, dissemination, and progression, as well as the effect of chemotherapy on isoforms expression. The described literature strongly suggests that P2X7 variants are potential new biomarkers and therapeutical targets in oncological conditions and that their study in carcinogenesis deserves to be further pursued.
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http://dx.doi.org/10.3390/cells10010189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832898PMC
January 2021

Differential sensitivity of acute myeloid leukemia cells to daunorubicin depends on P2X7A versus P2X7B receptor expression.

Cell Death Dis 2020 10 18;11(10):876. Epub 2020 Oct 18.

Department of Medical Sciences, University of Ferrara, 44121, Ferrara, Italy.

Acute myeloid leukemia (AML) is a common adult leukemia often arising from a preexistent myelodysplastic syndrome (MDS). High mortality rates of AML are caused by relapse and chemoresistance; therefore, we analyzed the role of P2X7 receptor (P2X7R) splice variants A and B in AML progression and response to chemotherapy. The expression of P2X7RA and P2X7RB was investigated in samples obtained from MDS and AML untreated subjects or AML patients in relapse or remission after chemotherapy. Both P2X7RA and P2X7RB were overexpressed in AML versus MDS suggesting a disease-promoting function. However, in relapsing patients, P2X7RA was downmodulated, while P2X7RB was upmodulated. Treatment with daunorubicin (DNR), one of the main chemotherapeutics for AML, upregulated P2X7RB expression while reducing P2X7RA mRNA in AML blasts. Interestingly, DNR administration also caused ATP release from AML blasts suggesting that, following chemotherapy, activation of the receptor isoforms via their agonist will be responsible for the differential survival of blasts overexpressing P2X7RA versus P2X7RB. Indeed, AML blasts expressing high levels of P2X7RA were more prone to cell death if exposed to DNR, while those overexpressing P2X7RB were more vital and even protected against DNR toxicity. These data were reproducible also in HEK-293 cells separately expressing P2X7RA and B. P2X7RA facilitation of DNR toxicity was in part due to increased uptake of the drug inside the cell that was lost upon P2X7RB expression. Finally, in an AML xenograft model administration of DNR or the P2X7R antagonist, AZ10606120 significantly reduced leukemic growth and coadministration of the drugs proved more efficacious than single treatment as it reduced both P2X7RA and P2X7RB levels and downmodulated c-myc oncogene. Taken together, our data suggest P2X7RA and P2X7RB as potential prognostic markers for AML and P2X7RB as a therapeutic target to overcome chemoresistance in AML relapsing patients.
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http://dx.doi.org/10.1038/s41419-020-03058-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569086PMC
October 2020

The Impact of Chemotherapy after Pediatric Malignancy on Humoral Immunity to Vaccine-Preventable Diseases.

Mediterr J Hematol Infect Dis 2020 1;12(1):e2020014. Epub 2020 Mar 1.

Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata Verona, Italy.

Background/aim: The antibody titer of vaccine-preventable diseases in pediatric patients who underwent chemotherapy was assessed in order to evaluate the seroprotection after treatment and the feasibility and the efficacy of a policy of revaccination.

Methods: Serum antibody titers of 55 patients for hepatitis B (HBV), rubella, varicella-zoster (VZV), measles, mumps, polio viruses, () and () were analysed.Results: After chemotherapy, a lack of protective antibody titers against HBV, rubella, VZV, measles, mumps, polio viruses, , and was found in 53%, 45%, 46%, 46%, 43%, 21-26%, 88% and 55% of patients, respectively. In 49 of 55 patients who were tested both before and after chemotherapy for at least a pathogen, the loss of immunity for HBV, rubella, VZV, measles, mumps, polio viruses and was respectively 39%, 43%, 38%, 42%, 32%, 33%, and 80%. A low number of B-lymphocytes was associated with the loss of immunity against measles (p=0.04) whereas a high number of CD8+ T-lymphocytes was associated with the loss of immunity against VZV (p=0.03). A single booster of vaccine dose resulted in a seroprotection for HBV, rubella, VZV, measles, mumps, polio viruses, and in 67%, 83%, 80%, 67%, 33%, 100%, 88% and 67% of patients, respectively.

Conclusions: We confirm that seroprotection for vaccine-preventable diseases is affected by treatment for pediatric malignancy. A single booster dose of vaccine might be a practical way to restore vaccine immunity in patients after chemotherapy.
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http://dx.doi.org/10.4084/MJHID.2020.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059740PMC
March 2020

The P2X7 Receptor 489C>T Gain of Function Polymorphism Favors HHV-6A Infection and Associates With Female Idiopathic Infertility.

Front Pharmacol 2020 21;11:96. Epub 2020 Feb 21.

Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.

The P2X7 receptor (P2X7R) is an ATP-gated ion channel known for its proinflammatory activity. Despite its participation in host defense against pathogens, the role played in viral infections, notably those caused by herpes viruses, has been seldom studied. Here we investigated the effect of P2X7R expression on human herpes virus 6 A (HHV-6A) infection of P2X7R-expressing HEK293 cells. We show that functional P2X7R increases while its blockade decreases viral load. Interestingly, HHV-6A infection was enhanced in HEK293 cells transfected with P2X7R cDNA bearing the gain of function 489C>T SNP (rs208294, replacing a histidine for tyrosine at position 155). The P2X7R 489C>T polymorphism correlated with HHV-6A infection also in a cohort of 50 women affected with idiopathic infertility, a condition previously shown to correlate with HHV-6A infection. None of the infertile women infected by HHV-6A was homozygote for 489CC genotype, while on the contrary HHV-6A infection significantly associated with the presence of the rs208294 allele. Levels of soluble human leukocyte antigen G (sHLA-G), a factor promoting embryo implant, measured in uterine flushings negatively correlated with the 489TT genotype and HHV-6A infection, while proinflammatory cytokines interleukins 1α (IL-1α), 1β (IL-1β), and 8 (IL-8) positively correlated with both the 489T allele presence and viral infection. Taken together these data point to the P2X7R as a new therapeutic target to prevent HHV-6A infection and the associated infertility.
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http://dx.doi.org/10.3389/fphar.2020.00096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046806PMC
February 2020

A Prospective Study of Hematologic Complications and Long-Term Survival of Italian Patients Affected by Shwachman-Diamond Syndrome.

J Pediatr 2020 04 6;219:196-201.e1. Epub 2020 Feb 6.

Cystic Fibrosis Center, Department of Cardiovascular and Thoracic Surgery, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

Objective: To describe the hematologic outcome and long-term survival of patients enrolled in the Shwachman-Diamond syndrome Italian Registry.

Study Design: A retrospective and prospective study of patients recorded in the Shwachman-Diamond syndrome Italian Registry.

Results: The study population included 121 patients, 69 males and 52 females, diagnosed between 1999 and 2018. All patients had the clinical diagnosis confirmed by mutational analysis on the SBDS gene. During the study period, the incidence of SDS was 1 in 153 000 births. The median age of patients with SDS at diagnosis was 1.3 years (range, 0-35.6 years). At the first hematologic assessment, severe neutropenia was present in 25.8%, thrombocytopenia in 25.5%, and anemia in 4.6% of patients. A normal karyotype was found in 40 of 79 patients, assessed whereas the most frequent cytogenetic abnormalities were isochromosome 7 and interstitial deletion of the long arm of chromosome 20. The cumulative incidence of severe neutropenia, thrombocytopenia, and anemia at 30 years of age were 59.9%, 66.8%, and 20.2%, respectively. The 20-year cumulative incidence of myelodysplastic syndrome/leukemia and of bone marrow failure/severe cytopenia was 9.8% and 9.9%, respectively. Fifteen of 121 patients (12.4%) underwent allogeneic stem cell transplantation. Fifteen patients (12.4%) died; the probability of overall survival at 10 and 20 years was 95.7% and 87.4%, respectively.

Conclusions: Despite an improvement in survival, hematologic complications still cause death in patients with SDS. Further studies are needed to optimize type and modality of hematopoietic stem cell transplantation and to assess the long-term outcome in nontransplanted patients.
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http://dx.doi.org/10.1016/j.jpeds.2019.12.041DOI Listing
April 2020

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

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

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

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

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

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

Detection of Extracellular ATP in the Tumor Microenvironment, Using the pmeLUC Biosensor.

Methods Mol Biol 2020 ;2041:183-195

Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.

ATP is one of the main components of the tumor microenvironment, where it affects cell growth, tumor progression and antitumor immune response. The development of the pmeLUC probe, a luciferase engineered to be expressed on the outer facet of the plasma membrane, allowed real-time measurement of extracellular ATP in vitro and in vivo systems, among which the tumor microenvironment. Here we describe the experimental procedures to measure extracellular ATP levels in the tumor microenvironment of three different cancer models generated by the implant of pmeLUC-expressing tumor cells into the appropriate mice strain: ACN human neuroblastoma (nude/nude mice host), WEHI-3B murine leukemia (BALB/c host), and B16F10 murine melanoma (C57Bl/6 host). The procedure to obtain stable expression of pmeLUC in different cell types and methods for the measurement of extracellular ATP with pmeLUC in vitro are also described.
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http://dx.doi.org/10.1007/978-1-4939-9717-6_13DOI Listing
April 2020

Role of the P2X7 receptor in tumor-associated inflammation.

Curr Opin Pharmacol 2019 08 25;47:59-64. Epub 2019 Mar 25.

Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Italy.

Inflammation is constantly associated to cancer. Malignant tumors often develop at sites of chronic inflammation, and inflammation promotes tumor progression. But, at the same time, inflammation is crucial for anti-tumor immune response. Many factors are responsible for this 'Dr Jekyll/Mr Hyde' roles of inflammation, among which one that is attracting increasing attention is the P2X7 receptor (P2X7R). This receptor is expressed by most malignant tumors and widely diffused in innate and adaptive immune cells, where it supports proliferation, chemotaxis, growth factor, and cytokine release. P2X7R-targeting may offer novel avenues for anti-cancer therapeutic intervention, but might also impair host anti-tumor responses. This short review highlights recent findings on the dual role of the P2X7R in cancer-associated inflammation.
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http://dx.doi.org/10.1016/j.coph.2019.02.012DOI Listing
August 2019

The P2X7 receptor modulates immune cells infiltration, ectonucleotidases expression and extracellular ATP levels in the tumor microenvironment.

Oncogene 2019 05 17;38(19):3636-3650. Epub 2019 Jan 17.

Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Via Luigi Borsari, 46, 44121, Ferrara, Italy.

In the tumor microenvironment (TME) ATP and its receptor P2X7 exert a pivotal influence on cancer growth and tumor-host interactions. Here we analyzed the different effect of P2X7 genetic deficiency versus its antagonism on response against P2X7-expressing implanted tumors. We focused on immune cell expression of ATP degrading enzymes CD39 and CD73 and in vivo measured TME's ATP. The immune infiltrate of tumors growing in P2X7 null mice shows a decrease in CD8 cells and an increased number of Tregs, overexpressing the fitness markers OX40, PD-1, and CD73. A similar Treg phenotype is also present in the spleen of tumor-bearing P2X7 null mice and it is paralleled by a decrease in proinflammatory cytokines and an increase in TGF-β. Differently, systemic administration of the P2X7 blocker A740003 in wild-type mice left unaltered the number of tumor-infiltrating CD8 and Treg lymphocytes but increased CD4 effector cells and decreased their expression of CD39 and CD73. P2X7 blockade did not affect spleen immune cell composition or ectonucleotidase expression but increased circulating INF-γ. Augmented CD73 in P2X7 null mice was mirrored by a decrease in TME ATP concentration and nucleotide reduced secretion from immune cells. On the contrary, TME ATP levels remained unaltered upon P2X7 antagonism, owing to release of ATP from cancerous cells and diminished ectonucleotidase expression by CD4 and dendritic cells. These data point at P2X7 receptor as a key determinant of TME composition due to its combined action on immune cell infiltrate, ectonucleotidases, and ATP release.
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http://dx.doi.org/10.1038/s41388-019-0684-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756114PMC
May 2019

ATP Release from Chemotherapy-Treated Dying Leukemia Cells Elicits an Immune Suppressive Effect by Increasing Regulatory T Cells and Tolerogenic Dendritic Cells.

Front Immunol 2017 22;8:1918. Epub 2017 Dec 22.

Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology L. and A. Seràgnoli, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Chemotherapy-induced immunogenic cell death can favor dendritic cell (DC) cross-priming of tumor-associated antigens for T cell activation thanks to the release of damage-associated molecular patterns, including ATP. Here, we tested the hypothesis that in acute myeloid leukemia (AML), ATP release, along with its well-known immune stimulatory effect, may also contribute to the generation of an immune suppressive microenvironment. In a cohort of AML patients, undergoing combined daunorubicin and cytarabine chemotherapy, a population of T regulatory cells (Tregs) with suppressive phenotype, expressing the immune checkpoint programmed cell death protein 1 (PD-1), was significantly increased. Moving from these results, initial data showed that daunorubicin was more effective than cytarabine in modulating DC function toward Tregs induction and such difference was correlated with the higher capacity of daunorubicin to induce ATP release from treated AML cells. DCs cultured with daunorubicin-treated AML cells upregulated indoleamine 2,3-dioxygenase 1 (IDO1), which induced anti-leukemia Tregs. These data were confirmed as daunorubicin-treated mice show an increase in extracellular ATP levels with increased number of Tregs, expressing PD-1 and IDO1CD39 DCs. Notably, daunorubicin failed to induce Tregs and tolerogenic DCs in mice lacking the ATP receptor P2X7. Our data indicate that ATP release from chemotherapy-treated dying cells contributes to create an immune suppressive microenvironment in AML.
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http://dx.doi.org/10.3389/fimmu.2017.01918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744438PMC
December 2017

The P2X7 receptor: A main player in inflammation.

Biochem Pharmacol 2018 05 27;151:234-244. Epub 2017 Dec 27.

Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy. Electronic address:

Damage associated molecular patterns (DAMPs) are intracellular molecules released from infected or injured cells to activate inflammatory and reparatory responses. One of the most ancient and conserved DAMPs is extracellular ATP that exerts its phlogistic activity mainly through activation of the P2X7 receptor (P2X7R). The P2X7R is an ATP gated ion channel, expressed by most immune cells, including the monocyte-derived cell lineages, T and B lymphocytes and their precursors. Here we give an overview of recent and established literature on the role of P2X7R in septic and sterile inflammation. P2X7R ability in restraining intracellular bacteria and parasite infection by modulation of the immune response are described, with particular focus on Mycobacteria and Plasmodium. Emerging literature on the role of P2X7 in viral infections such as HIV-1 is also briefly covered. Finally, we describe the numerous intracellular pathways related to inflammation and activated by the P2X7R, including the NLRP3 inflammasome, NF-kB, NFAT, GSK3β and VEGF, and discuss the involvement of P2X7R in chronic diseases. The possible therapeutic applications of P2X7R antagonists are also described.
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http://dx.doi.org/10.1016/j.bcp.2017.12.021DOI Listing
May 2018

ECIL guidelines for the prevention, diagnosis and treatment of BK polyomavirus-associated haemorrhagic cystitis in haematopoietic stem cell transplant recipients.

J Antimicrob Chemother 2018 Jan;73(1):12-21

Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, Petersplatz 10; CH-4009 Basel, Switzerland.

Objectives: To define guidelines for BK polyomavirus (BKPyV)-associated haemorrhagic cystitis (BKPyV-HC) after paediatric and adult HSCT.

Methods: Review of English literature and evidence-based recommendations by expert consensus.

Results: BKPyV-HC occurs in 8%-25% of paediatric and 7%-54% of adult recipients undergoing allogeneic HSCT. Diagnosis requires the triad of cystitis, macro-haematuria and high urine BKPyV loads >7 log10 copies/mL, and exclusion of other relevant aetiologies. BKPyV viraemia is frequent and may serve as a more specific semiquantitative follow-up marker. No randomized controlled trials are available to inform antiviral prophylaxis or treatment. However, hyper-hydration and/or bladder irrigation showed limited prophylactic value. Fluoroquinolones are not effective for prophylaxis or treatment, but rather increase antibiotic resistance. Hyperbaric oxygen or fibrin glue is marginally effective based on small case series from correspondingly equipped centres. Although cidofovir has been reported to improve and/or reduce BKPyV viraemia or viruria, the current data do not support its regular use.

Conclusions: BKPyV-HC remains a disabling unmet clinical need in HSCT that requires novel approaches supported by proper clinical trials.
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http://dx.doi.org/10.1093/jac/dkx324DOI Listing
January 2018

A retrospective study of paroxysmal nocturnal hemoglobinuria in pediatric and adolescent patients.

Blood Cells Mol Dis 2017 05 18;64:45-50. Epub 2017 Mar 18.

U.O.C Oncoematologia Pediatrica-AOUI Verona, P.le L.A. Scuro 10, 37134 Verona, Italy.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease, especially in children, characterized by intravascular hemolysis, thrombotic events, serious infections and bone marrow failure. We describe 16 patients who were diagnosed with PNH in childhood or adolescence. The time interval between the onset of symptoms and the PNH diagnosis and its treatment were compared in patients with classic PNH versus PNH associated with bone marrow disorder (PNH/BMD). A greater delay in diagnosis was observed in classic PNH compared to PNH/BMD patients. The first group of patients had higher levels of LDH, total bilirubin and absolute reticulocyte count and a bigger PNH clone size compared to PNH/BMD patients; also thrombotic events were observed only in the classic form of PNH. Conversely, PNH/BMD patients showed lower median levels of platelets. Apart from standard supportive measures, four patients with classic PNH received eculizumab whereas four patients with PNH/BMD underwent hematopoietic stem cell transplantation. Our series confirm that the most frequent presentation of PNH in the pediatric-adolescent age is PNH/BMD. The delay between the onset of symptoms and PNH diagnosis is relevant principally in the classic form. Moreover, our study showed that any case of unexpected thrombosis represents a criterium to perform a PNH screening.
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http://dx.doi.org/10.1016/j.bcmd.2017.03.006DOI Listing
May 2017

The Use of Splenectomy to Manage Platelet Transfusion Refractoriness due to Anti-Human Leukocyte Antibodies in Allogeneic Stem Cell Transplantation.

Pediatr Rep 2016 Mar 31;8(1):6159. Epub 2016 Mar 31.

Department of Pediatric Hematology Oncology, Verona, Italy.

In patients undergoing hematopoietic stem cell transplantation (HSCT), refractoriness to platelet transfusion has been associated with graft failure, delayed engraftment, early mortality and decreased overall survival. Therapeutic strategies include plasma exchange, immunoglobulins, rituximab, and splenectomy. We describe here three patients with refractoriness to platelet transfusion due to anti-human leukocyte antibodies who were splenectomized before HSCT (two cases) and after HSCT (one case) due to the lack of efficacy of other therapies. Splenectomy was uneventful. All three patients achieved a full donor engraftment. We suggest that splenectomy is feasible and effective in HSCT patients to reduce the risk of graft failure or delayed engraftment.
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http://dx.doi.org/10.4081/pr.2016.6159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821215PMC
March 2016

A comprehensive approach to the prevention of central venous catheter complications: results of 10-year prospective surveillance in pediatric hematology-oncology patients.

Ann Hematol 2016 Apr 10;95(5):817-25. Epub 2016 Mar 10.

Pediatric Hematology and Oncology, Azienda Ospedaliera Universitaria Integrata, Piazzale L.A. Scuro, 10, Policlinico G.B. Rossi, 37134, Verona, Italy.

We report our decennial experience with 1161 newly-placed long-term central venous catheters inserted in 919 hematology-oncology patients for a total of 413,901 CVC-days of observation. Most of the CVCs were partially-implanted, open-ended, Broviac-Hickman type of CVC (95 %). One thousand and twenty-four complications were recorded equal to 2.47 per 1000 CVC-days. The frequency of complications per CVC, the rate of episodes per 1000 CVC-days, and removal rate were malfunction/occlusion 42 %, 1.18/1000, and 2.3 %; mechanical (dislodgement/rupture/kinking) 18.3 %, 0.51/1000, and 77.4 %; bacteremia 14.8 %, 0.42/1000, and 18.6 %; exit-site/tunnel infection 11.5 %, 0.32/1000, and 9.7 %; thrombosis 0.86 %, 0.02/1000, and 30 %; pneumothorax 0.52 %, 0.01/1000, and 0. In multivariate analysis, the risk factors were for mechanical complications, a younger age <6.1 years at CVC insertion (HR 1.8, p = 0.0006); for bacteremia, a double lumen CVC (HR 3.1, p < 0.0001) and the surgical modality of CVC insertion (HR 1.5, p = 0.03); for exit-site/tunnel infection, a double lumen CVC (HR 2.1, p = 0.0003) and a diagnosis of leukemia or lymphoma (HR 1.8, p = 0.01); for malfunction/occlusion, an age <6.1 years (HR 1.6, p = 0.0003), the diagnosis of leukemia or lymphoma (HR 1.9, p < 0.0001) and double lumen CVC (HR 1.33, p = 0.023). The cumulative incidence of premature CVC removal was 29.2 % and the risk factors associated with this event were the surgical modality of CVC insertion (HR 1.4, p = 0.0153) and an age at CVC positioning less than 6.1 years (HR 1.6, p = 0.0025). We conclude that a best-practice set of rules resulted in reduced CVC complications.
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http://dx.doi.org/10.1007/s00277-016-2634-xDOI Listing
April 2016

A Prospective Study on the Predictive Value of Plasma BK Virus-DNA Load for Hemorrhagic Cystitis in Pediatric Patients After Stem Cell Transplantation.

J Pediatric Infect Dis Soc 2015 Jun 5;4(2):134-42. Epub 2014 Jun 5.

Pediatric Hematology Oncology, Department of Pediatrics.

Background: In hematopoietic stem cell transplantation (HSCT), late hemorrhagic cystitis (HC) has been associated with BK virus (BKV) infection. We assessed the value of plasma BKV load in predicting HC.

Methods: Plasma and urine BKV-DNA load were assessed prospectively in 107 pediatric patients.

Results: Twenty patients developed grade II and III HC, with 100-day cumulative incidence of 18.8%. At diagnosis of HC, the median load of BKV DNA was 2.3 × 10(3) copies/mL. A plasma BKV-DNA load of 10(3) copies/mL had a sensitivity of 100% and a specificity of 86% with a negative predictive value (NPV) of 100% and a positive predictive value (PPV) of 39% for HC. A urine BKV-DNA load of >10(7) copies/mL had a sensitivity of 86% and a specificity of 60% with a NPV of 98% and a PPV of 14% for HC. A BKV load of 10(3) copies/mL on plasma was significantly associated with HC in multivariate analysis (hazard ratio [HR], 6.1; P = .0006). Patients with HC had a significantly higher risk of mortality than patients who did not have HC (HR, 2.6; P = .018).

Conclusions: The above values were used to monitor plasma BKV-DNA load, and they provided a better prediction of patients at risk of HC than urine BKV-DNA load.
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http://dx.doi.org/10.1093/jpids/piu043DOI Listing
June 2015

The role of surgery in the treatment of invasive fungal infection in paediatric haematology patients: a retrospective single-centre survey.

Mycoses 2014 Jul 19;57(7):394-9. Epub 2014 Jan 19.

Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy; Pediatric Hematology Oncology, Department of Pediatrics, University of Padova, Padova, Italy.

Surgery may improve the control of fungal disease and patient survival. The aim of this study was to report a single-centre experience in using surgery for the treatment of paediatric invasive fungal infection (IFI). From 2001 to 2009, 18 paediatric onco-haematology patients underwent 24 surgical procedures as treatment of IFI. At surgery, severe thrombocytopenia and neutropenia were present in four and one episodes respectively. Complications were one pleural effusion, one pleural effusion and surgical wound infection, one pneumothorax with wound dehiscence and one wound dehiscence. None of them required repeat surgery. The median duration of hospitalisation for four complicated procedures was 11 days, range 3-16, and 7 days, range 2-13, for the 20 uncomplicated procedures. No surgery-related deaths occurred. Fourteen patients resumed chemotherapy after a median of 26 days, range 9-77, whereas nine patients underwent hematopoietic stem cell transplantation after a median of 42 days, range 27-110. At 3 months from IFI, 17 patients were alive (94%) and one patient (6%) died from mycosis; the 3-month overall survival (OS) being 94.4%, CI 66.6-99.2. After a median follow-up of 7.1 years (CI 2.8-7.5), the OS was 54.5%, CI 29.2-74.2. Surgery is a feasible and valuable option in paediatric patients because it is associated with a low incidence of complications and an acceptable delay in resuming the chemotherapeutic plan.
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http://dx.doi.org/10.1111/myc.12172DOI Listing
July 2014

A prospective, randomized study of empirical antifungal therapy for the treatment of chemotherapy-induced febrile neutropenia in children.

Br J Haematol 2012 Jul 10;158(2):249-255. Epub 2012 May 10.

Department Paediatric Haematology Oncology, Azienda Ospedaliero-Universitaria Meyer, Firenze, Italy.

Given that the rationale for empirical antifungal therapy in neutropenic children is limited and based on adult patient data, we performed a prospective, randomized, controlled trial that evaluated 110 neutropenic children with persistent fever. Those at high risk for invasive fungal infections (IFI) received caspofungin (Arm C) or liposomal amphotericinB (Arm B); those with a lower risk were randomized to receive Arm B, C, or no antifungal treatment (Arm A). Complete response to empirical antifungal therapy was achieved in 90/104 patients (86·5%): 48/56 at high risk (85·7%) [88·0% in Arm B; 83·9% in Arm C (P = 0·72)], and 42/48 at low risk (87·5%) [87·5% in control Arm A, 80·0% Arm B, 94·1% Arm C; (P = 0·41)]. None of the variables tested by multiple logistic regression analysis showed a significant effect on the probability to achieve complete response. IFI was diagnosed in nine patients (8·2%, 95% confidence interval, 3·8-15·0). This randomized controlled study showed that empirical antifungal therapy was of no advantage in terms of survival without fever and IFI in patients aged <18 years and defined with low risk of IFI. Higher risk patients, including those with relapsed cancer, appear to be the target for empirical antifungal therapy during protracted febrile neutropenia.
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http://dx.doi.org/10.1111/j.1365-2141.2012.09156.xDOI Listing
July 2012

A prospective, multicentre survey on antifungal therapy in neutropenic paediatric haematology patients.

Mycoses 2013 Jan 19;56(1):21-5. Epub 2012 Mar 19.

Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

Invasive fungal infections are a frequent complication after intensive chemotherapy. The aims of this prospective study were to describe the use of antifungal therapy and to report which strategy was routinely adopted to guide the introduction of antifungal therapy. A total of 321 febrile episodes in 160 paediatric patients affected by acute leukaemia or non-Hodgkin-lymphoma were investigated. Antifungal therapy was used in 100 of 321 febrile episodes (31%), and classified as empiric in 73 episodes, diagnostic-driven in 25 episodes and targeted in 2 episodes. Switching to a second-line antifungal therapy was needed in 28 of 100 episodes (28%) and was classified as empiric in 10 episodes (36%), diagnostic-driven in 17 episodes (61%) and targeted in 1 episode (4%). In 9 of 28 episodes (32%), switching to a third-line antifungal therapy was performed and was classified as empiric in 2 episodes (22%), diagnostic-driven in 6 episodes (67%) and targeted in 1 episode (11%). Invasive fungal infections was reported in 23 of 100 episodes: confirmed in 4 episodes, probable in 8 episodes, and possible in 11 episodes. Attributable mortality was 2.8%. Antifungal therapy was still used mostly empirically, whereas as fever persisted, its modification was guided by a diagnostic-driven approach.
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http://dx.doi.org/10.1111/j.1439-0507.2012.02187.xDOI Listing
January 2013

Combination antifungal therapy and surgery for the treatment of invasive pulmonary aspergillosis after hematopoietic stem cell transplantation.

Pediatr Rep 2011 Jun;3(2):e18

Pediatric Hematology Oncology, Department of Pediatrics, Padova;

An 8-year old boy, affected by severe aplastic anemia, developed a probable pulmonary invasive aspergillosis (IA) early after a second unrelated allogeneic hematopoietic stem cell transplant (HSCT). He was treated promptly with the combination of liposomal amphotericin B and caspofungin. Despite the initial stabilization, the patient deteriorated and the antifungal therapy was switched to voriconazole and caspofungin. The patient gradually improved and was discharged home on day +29 post-HSCT on oral voriconazole. On day +119, a sudden episode of hemoptysis occurred and a right superior lobectomy was decided to remove the residual aspergilloma. The patient is now alive and well more than 24 months from HSCT. This case demonstrated that antifungal combination therapy and surgery are valid options to cure pulmonary IA even in patients at high-risk and severely immunosuppressed.
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http://dx.doi.org/10.4081/pr.2011.e18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3207306PMC
June 2011

Current evidence of antifungal prophylaxis and therapy in pediatric patients.

Pediatr Rep 2011 Feb;3(1):e6

Pediatric Hematology Oncology and Bone Marrow Unit, Ospedale Infantile Regina Margherita, Torino;

Invasive fungal infections (IFI) are an important complication in pediatric haematological and oncological patients who undergo intensive chemotherapy for leukemia, solid tumour at advanced stage or relapsed, and hematopoietic stem cell transplantation. The incidence of IFI is lower than bacterial infection but mortality rate remains high. This review is designed to help paediatric oncologists in choosing the appropriate anti-fungal strategy and agents for prophylaxis, empirical, pre-emptive and specific therapy on the basis of published evidence.
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http://dx.doi.org/10.4081/pr.2011.e6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103132PMC
February 2011

Prophylaxis and therapy of viral infections in pediatric patients treated for malignancy.

Pediatr Rep 2011 Feb;3(1):e5

Pediatric Hematology Oncology, University of Catania;

Infections are still an important cause of mortality and morbidity in pediatric cancer patients. Most of the febrile episodes in immunocompromised patients are classified as a fever of unknown origin (FUO) while bacteria are the more frequent causes of documented infections. Viral infections are also feared during chemotherapy but less data are available on their incidence and morbidity. We reviewed the literature on incidence, morbidity, and mortality of viral infections in children undergoing chemotherapy and discussed the evidence concerning the prophylaxis and the therapy.
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http://dx.doi.org/10.4081/pr.2011.e5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103130PMC
February 2011

A Phase II study on the safety and efficacy of a single dose of pegfilgrastim for mobilization and transplantation of autologous hematopoietic stem cells in pediatric oncohematology patients.

Transfusion 2011 Nov 4;51(11):2480-7. Epub 2011 May 4.

Pediatric Hematology Oncology, Department of Pediatrics, University of Padova, Padova, Italy.

Background: Limited data are available on the use of pegfilgrastim in pediatric patients as a mobilizing agent in association with chemotherapy.

Study Design And Methods: This was a prospective, multicenter, Phase II study to evaluate the safety and efficacy of a single dose of 100 µg/kg pegfilgrastim in mobilizing peripheral blood stem cells (PBSCs) in pediatric patients. The primary endpoint of the study was the percentage of good mobilizers with pegfilgrastim (blood peak of CD34+ cells ≥ 20 × 10(6) /L). The results were compared with a historical control group.

Results: Thirty of 36 recruited patients were classified as good mobilizers (83%). The median value of circulating CD34+ at leukapheresis was 143 × 10(6) /L (range, 20 × 10(6) -1988 × 10(6) /L). No significant adverse effects were associated with the use of pegfilgrastim and no patient was withdrawn from using the drug. A blood peak of 20 × 10(6) /L or more CD34+ was observed in 33 of 36 control patients (92%) and the median CD34+ count at leukapheresis was 158 × 10(6) /kg (range, 28 × 10(6) -4529 × 10(6) /kg; p = 0.7). No significant differences were found between the two groups in terms of toxicity or other variables of mobilization. As at October 2008, 23 patients of the pegfilgrastim group and 32 patients of the filgrastim group underwent autologous transplant. No significant differences were found in terms of early toxicity, myeloid recovery, and Day 100 survival.

Conclusion: A single dose of 100 µg/kg pegfilgrastim was safe and effective for PBSC collection in pediatric patients. We suggest that these results support the use of pegfilgrastim for pediatric patients.
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http://dx.doi.org/10.1111/j.1537-2995.2011.03157.xDOI Listing
November 2011

Retrospective survey on the prevalence and outcome of prior autoimmune diseases in patients with aplastic anemia reported to the registry of the European group for blood and marrow transplantation.

Acta Haematol 2010 6;124(1):19-22. Epub 2010 Jul 6.

Pediatric Hematology Oncology, Department of Pediatrics, University of Padua, Padua, Italy.

Background: Aplastic anemia (AA) is rarely described after a diagnosis of autoimmune disease (aID).

Aims: To assess the prevalence of prior aID in patients with AA recorded in the registry of the European Group for Blood and Marrow Transplantation (EBMT) and to evaluate treatment and outcome.

Methods: 1,251 AA patients from 18 EBMT centers were assessed.

Results: Fifty patients (4%) were eligible: 22 males and 28 females with a median age of 46 years at the diagnosis of aID and of 51 years at the diagnosis of AA. Information on the treatment of AA was available in 49 patients: 38 received only immunosuppressive therapy (IST), 8 patients underwent hematopoietic stem cell transplantation (HSCT) - 6 as first-line therapy and 2 after failure of IST - whilst 3 patients had a spontaneous recovery. After a median follow-up of 3.19 years, 32 patients were alive, including 7 of the 8 patients who underwent HSCT. Only 6 of 32 patients who were alive at the last follow-up were receiving IST for AA.

Conclusions: Most cases of AA following aID benefitted from IST or HSCT if a matched donor was available. Further prospective investigation is needed to assess the effects of IST on the outcome of underlying aID.
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http://dx.doi.org/10.1159/000313783DOI Listing
August 2010

A prospective study on modulation of immunosuppression for Epstein-Barr virus reactivation in pediatric patients who underwent unrelated hematopoietic stem-cell transplantation.

Transplantation 2010 Jun;89(12):1533-40

Pediatric Hematology Oncology, Department of Pediatrics, University of Padova, Italy.

Background: Posttransplant lymphoproliferative disease caused by Epstein-Barr virus (EBV-PTLD) is a severe complication after allogeneic hematopoietic stem-cell transplantation (HSCT). We evaluated whether the modulation of immunosuppression (IS) guided by quantitative polymerase chain reaction for EBV (EBV-PCR) was effective as a first-line therapeutic approach for EBV reactivation.

Methods: Eighty-nine pediatric patients who received an HSCT from an unrelated donor were prospectively assessed by quantitative EBV-PCR. The EBV-PCR threshold to modulate IS was set to more than 300 genomic copies (gc)/10 peripheral blood mononuclear cells.

Results: EBV-PCR positivity was observed in 56 (63%) of 89 patients at a median time of 44 days after HSCT. The variables associated with EBV-PCR positivity were bone marrow stem cells (P=0.047) and a lower total dose of nuclear cells reinfused (P=0.03). Thirty-one patients (35%) had more than or equal to 300 gc. IS was withdrawn or reduced in 18 (58%) and 13 (42%) of the 31 patients, respectively. EBV viral load (EBV-VL) less than 300 gc was achieved in 30 of these 31 patients at a median of 25 days. Only 1 (1%) of the 89 patients progressed to EBV-PTLD. The patients with EBV-VL more than 300 gc had a lower incidence of acute graft versus host disease III-IV than patients with EBV-VL less than 300 gc: 13% vs. 36%, P=0.02. No differences in terms of chronic graft versus host disease, overall survival, event-free survival and transplant-related mortality were observed between the two groups.

Conclusions: We conclude that PCR-guided modulation of IS may play a role in early intervention for EBV-PTLD and a prospective, randomized study is needed.
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http://dx.doi.org/10.1097/TP.0b013e3181dd6c0aDOI Listing
June 2010