Perugia, Italy
Perugia, Italy

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Farruggia P.,Oncoematologia Pediatrica
Medico e Bambino | Year: 2017

Neonatal neutropoenia is not infrequent. Its appearance can be linked to many serious or minor causes and it is necessary to provide an accurate overview in order to make the best decisions on its management. This paper takes into consideration some possible phenomena causing the appearance of neutropoenia in newborns; some of them are little known either by paediatricians or neonatologists. It also provides guidance for possible differential diagnostic criteria as well as information about the therapy, which today often employs the use of Granulocyte-Colony Stimulating Factor (G-CSF).


Zecca M.,Oncoematologia Pediatrica | Strocchio L.,Oncoematologia Pediatrica | Comoli P.,Oncoematologia Pediatrica | Giorgiani G.,Oncoematologia Pediatrica | And 3 more authors.
Biology of Blood and Marrow Transplantation | Year: 2014

We report the outcome of 12 consecutive pediatric patients with Fanconi anemia (FA) who had neither an HLA-identical sibling nor an HLA-matched unrelated donor and who were given Tcell-depleted, CD34+ positively selected cells from a haploidentical related donor after a reduced-intensity, fludarabine-based conditioning regimen. Engraftment was achieved in 9 of 12 patients (75%), and the cumulative incidence of graft rejection was 17% (95% confidence interval [CI], 5% to 59%). Cumulative incidences of grades II to IV acute and chronic graft-versus-host disease were 17% (95% CI, 5% to 59%) and 35% (95% CI, 14% to 89%), respectively. The conditioning regimen was well tolerated, with no fatal regimen-related toxicity and 3 cases of grade III regimen-related toxicity. The cumulative incidence of transplant-related mortality was 17% (95% CI, 5% to 59%). The 5-year overall survival, event-free survival, and disease-free survival were 83% (95% CI, 62% to 100%), 67% (95% CI, 40% to 93%), and 83% (95% CI, 62% to 100%), respectively. These data demonstrate that a fludarabine-based conditioning regimen, followed by infusion of high doses of Tcell-depleted stem cells, is able to ensure engraftment with good overall survival and disease-free survival, confirming the feasibility of haploidentical hematopoietic stem cell transplantation in FA. To the best of our knowledge, this is the largest series of hematopoietic stem cell transplantation from a haploidentical related donor in FA patients reported to date. © 2014 American Society for Blood and Marrow Transplantation.


Zecca M.,Oncoematologia Pediatrica | Balduzzi A.,University of Milan Bicocca | Messina C.,University of Padua | Masetti R.,University of Bologna | And 9 more authors.
Blood | Year: 2011

Acute lymphoblastic leukemia (ALL) in second complete remission is one of the most common indications for allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients. We compared the outcome after HCST of adolescents, aged 14 to 18 years, with that of children (ie, patients < 14 years of age). Enrolled in the study were 395 patients given the allograft between January 1990 and December 2007; both children (334) and adolescents (61) were transplanted in the same pediatric institutions. All patients received a myeloablative regimen that included total body irradiation in the majority of them. The donor was an HLA-identical sibling for 199 patients and an unrelated volunteer in the remaining 196 patients. Children and adolescents had a comparable cumulative incidence of transplantation-related mortality, disease recurrence, and of both acute and chronic graft-versus-host disease. The 10-year probability of overall survival and event-free survival for the whole cohort of patients were 57% (95% confidence interval, 52%-62%) and 54% (95% confidence interval, 49%-59%), respectively, with no difference between children and adolescents. This study documents that adolescents with ALL in second complete remission given HSCT in pediatric centers have an outcome that does not differ from that of patients younger than 14 years of age. © 2011 by The American Society of Hematology.


Strocchio L.,Oncoematologia Pediatrica | Zecca M.,Oncoematologia Pediatrica | Comoli P.,Oncoematologia Pediatrica | Mina T.,Oncoematologia Pediatrica | And 4 more authors.
British Journal of Haematology | Year: 2015

Although allogeneic haematopoietic stem cell transplantation (HSCT) still represents the only consolidated possibility of cure for sickle cell disease (SCD) patients, its use has been limited by the risk of morbidity and mortality associated with conventional myeloablative therapy. The introduction of treosulfan to replace busulfan in conditioning regimens has recently been explored by virtue of its lower toxicity profile. We report our experience with a treosulfan/thiotepa/fludarabine conditioning for human leucocyte antigen (HLA)-matched sibling or unrelated donor-HSCT in 15 children with SCD, and compare patient outcomes with those of a historical cohort (15 patients) given a busulfan-based regimen. Engraftment was achieved in 28 out of 30 patients (93%), with one case of graft failure in either group. The conditioning regimen was well tolerated in both groups, with no cases of grade III-IV regimen-related toxicity. The 7-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 100% and 93%, respectively, with a 93% DFS in both busulfan and treosulfan groups. No SCD-related adverse events occurred after engraftment in patients with complete or mixed donor chimerism. This retrospective analysis suggests that a treosulfan-based conditioning regimen is able to ensure engraftment with excellent OS/DFS and low regimen-related toxicity in patients with SCD. © 2015 John Wiley & Sons Ltd.


Buontempo F.,University of Bologna | Orsini E.,University of Bologna | Martins L.R.,University of Lisbon | Antunes I.,University of Lisbon | And 17 more authors.
Leukemia | Year: 2014

Constitutively active casein kinase 2 (CK2) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL). CK2 phosphorylates PTEN (phosphatase and tensin homolog) tumor suppressor, resulting in PTEN stabilization and functional inactivation. Downregulation of PTEN activity has an impact on PI3K/Akt/mTOR signaling, which is of fundamental importance for T-ALL cell survival. These observations lend compelling weight to the application of CK2 inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of CX-4945 - a novel, highly specific, orally available, ATP-competitive inhibitor of CK2α. We show that CX-4945 treatment induced apoptosis in T-ALL cell lines and patient T lymphoblasts. CX-4945 downregulated PI3K/Akt/mTOR signaling in leukemic cells. Notably, CX-4945 affected the unfolded protein response (UPR), as demonstrated by a significant decrease in the levels of the main UPR regulator GRP78/BIP, and led to apoptosis via upregulation of the ER stress/UPR cell death mediators IRE1α and CHOP. In vivo administration of CX-4945 to a subcutaneous xenotransplant model of human T-ALL significantly delayed tumor growth. Our findings indicate that modulation of the ER stress/UPR signaling through CK2 inhibition could be exploited for inducing apoptosis in T-ALL cells and that CX-4945 may be an efficient treatment for those T-ALLs displaying upregulation of CK2α/PI3K/Akt/mTOR signaling. © 2014 Macmillan Publishers Limited.


Evangelisti C.,University of Bologna | Evangelisti C.,National Research Council Italy | Evangelisti C.,Muscoloskeletal Cell Biology Laboratory | Teti G.,University of Bologna | And 13 more authors.
Oncotarget | Year: 2014

Sphingosine 1-phosphate (S1P) is a bioactive lipid that is formed by the phosphorylation of sphingosine and catalysed by sphingosine kinase 1 (SK1) or sphingosine kinase 2 (SK2). Sphingosine kinases play a fundamental role in many signaling pathways associated with cancer, suggesting that proteins belonging to this signaling network represent potential therapeutic targets. Over the last years, many improvements have been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL); however, novel and less toxic therapies are still needed, especially for relapsing and chemo-resistant patients. Here, we analyzed the therapeutic potential of SKi and ROMe, a sphingosine kinase 1 and 2 inhibitor and SK2-selective inhibitor, respectively. While SKi induced apoptosis, ROMe initiated an autophagic cell death in our in vitro cell models. SKi treatment induced an increase in SK1 protein levels in Molt-4 cells, whereas it activated the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) pathway in Jurkat and CEM-R cells as protective mechanisms in a sub-population of T-ALL cells. Interestingly, we observed a synergistic effect of SKi with the classical chemotherapeutic drug vincristine. In addition, we reported that SKi affected signaling cascades implicated in survival, proliferation and stress response of cells. These findings indicate that SK1 or SK2 represent potential targets for treating T-ALL.


Lonetti A.,University of Bologna | Antunes I.L.,University of Lisbon | Chiarini F.,National Research Council Italy | Chiarini F.,Muscoloskeletal Cell Biology Laboratory | And 14 more authors.
Leukemia | Year: 2014

Constitutively active phosphoinositide 3-kinase (PI3K) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it upregulates cell proliferation, survival and drug resistance. These observations lend compelling weight to the application of PI3K inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of the pan-PI3K inhibitor NVP-BKM120 (BKM120), an orally bioavailable 2,6-dimorpholino pyrimidine derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. BKM120 treatment resulted in G 2 /M phase cell cycle arrest and apoptosis, being cytotoxic to a panel of T-ALL cell lines and patient T lymphoblasts, and promoting a dose- and time-dependent dephosphorylation of Akt and S6RP. BKM120 maintained its pro-apoptotic activity against Jurkat cells even when cocultured with MS-5 stromal cells, which mimic the bone marrow microenvironment. Remarkably, BKM120 synergized with chemotherapeutic agents currently used for treating T-ALL patients. Moreover, in vivo administration of BKM120 to a subcutaneous xenotransplant model of human T-ALL significantly delayed tumor growth, thus prolonging survival time. Taken together, our findings indicate that BKM120, either alone or in combination with chemotherapeutic drugs, may be an efficient treatment for T-ALLs that have aberrant upregulation of the PI3K signaling pathway. © 2014 Macmillan Publishers Limited.


Pession A.,University of Bologna | Masetti R.,University of Bologna | Rizzari C.,University of Milan Bicocca | Putti M.C.,University of Padua | And 16 more authors.
Blood | Year: 2013

We evaluated the outcome of 482 children with acute myeloid leukemia (AML) enrolled in the Associazione Italiana di Ematologia e Oncologia Pediatrica AML 2002/01 trial. Treatment was stratified according to risk group; hematopoietic stem cell transplantation (HSCT) was used in high-risk (HR) children. Patients with core binding factor leukemia achieving complete remission (CR) after the first induction course were considered standard risk (SR; 99 patients), whereas the others (n 5 383) were assigned to the HR group. Allogeneic (ALLO) or autologous (AUTO) HSCT was employed, respectively, in 141 and 102 HR patients after consolidation therapy. CR, early death, and induction failure rates were 87%, 3%, and 10%, respectively. Relapse occurred in 24%of patients achieving CR. The 8-year overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 68%, 55%, and 63%, respectively. OS, EFS, and DFS for SR and HR patients were 83%, 63%, and 66% and 64%, 53%, and 62%. DFS was 63% and 73% for HR patients given AUTO-HSCT and ALLO-HSCT, respectively. In multivariate analysis, risk group, white blood cell >100 × 109/L at diagnosis, and monosomal karyotype predicted poorer EFS. Risk-oriented treatment and broad use of HSCT result in a long-term EFS comparing favorably with previously published studies on childhood AML. (Blood. 2013; 122(2):170-178) © 2013 by The American Society of Hematology.


Piralla A.,S.S. Virologia Molecolare | Lilleri D.,Laboratori Sperimentali Of Ricerca | Sarasini A.,S.S. Virologia Molecolare | Marchi A.,University of Pavia | And 4 more authors.
Diagnostic Microbiology and Infectious Disease | Year: 2012

The epidemiology of picornavirus infections along with associated risk factors for lower respiratory tract infections (LRTI) and duration of virus shedding were investigated in 985 hospitalized patients in the period October 2008-September 2009. One-third of patients were human rhinovirus (HRV)-positive. Of 336 HRV-associated episodes, 153 (45.5%) were sustained by HRV-A, 31 (9.2%) by HRV-B, and 93 (27.7%) by HRV-C, while 7 episodes showed multiple HRV types and 52 were sustained by undefined HRV species. Independent risk factors for LRTI included high viral load and age less than 5 years. Twenty (2.1%) patients were enterovirus (EV)-positive (12 had EV-68, 7 EV-104, and 1 E-13 infection). Half of the EV-positive patients had a LRTI and were younger with respect to patients with upper RTI (median 18 months versus 37 years; P < 0.001). HRVs are often the cause of LRTI in children less than 5 years, frequently in association with a high viral load. © 2012 Elsevier Inc.

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