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Objectives Posterior reversible encephalopathy syndrome (PRES) is one of the most common neurological complications in hematology-oncology pediatric patients. Despite an increasingly recognized occurrence, no clear consensus exists regarding how best to manage the syndrome, because most cases of PRES have reported in single case reports or small series. Aim of this paper is to identify incidence, clinical features, management and outcome of PRES in a large series of hematology-oncology pediatric patients Methods The cases of PRES occurred in twelve centres of the Italian Association of Pediatric Haematology and Oncology were reported Results 124 cases of PRES in 112 pediatric patients were recorded with an incidence of 2.1% and 4.7% respectively in acute lymphoblastic leukemia in first complete remission and hematopoietic stem cell transplantation (HSCT). The majority of cases occurred after a cycle of chemotherapy rather than after stem cell transplant. PRES after chemotherapy significantly differs from that after HSCT for diagnosis, time of presentation, risk factors, management and outcome Conclusions This study demonstrates that PRES is a common neurological complication and occurring preferentially in course of induction treatment of some hematologic malignancies, as ALL and after HSCT. It also highlights great clinical differences in the management and outcome in patients with PRES occurring after chemotherapy or after HSCT This article is protected by copyright. All rights reserved.

Busulphan (BU) is associated with neurotoxicity and risk of seizures. Hence, seizure prophylaxis is routinely utilized during BU administration for stem cell transplantation (SCT). We collected data on the incidence of seizures among children undergoing SCT in Italy. Fourteen pediatric transplantation centers agreed to report unselected data on children receiving BU as part of the conditioning regimen for SCT between 2005 and 2012. Data on 954 pediatric transplantation procedures were collected; of them, 66% of the patients received BU orally, and the remaining 34%, i.v. All the patients received prophylaxis of seizures, according to local protocols, consisting of different schedules and drugs. A total of 13 patients (1.3%) developed seizures; of them, 3 had a history of epilepsy (or other seizure-related pre-existing condition); 3 had documented brain lesions potentially causing seizures per se; 1 had febrile seizures, 1 severe hypo-osmolality. In the remaining 5 patients, seizures were considered not explained and, thus, potentially related to BU administration. The incidence of seizures in children receiving BU-containing regimen was very low (1.3%); furthermore, most of them had at least 1—either pre-existing or concurrent—associated risk factor for seizures.

Leukemic relapse of the eye has sometimes been cured. In this paper we review the cases of leukemic infiltration of the eye tissue with the aim of ascertaining whether an optimal treatment can be suggested. Data from 25 children (16 males, 9 females) with isolated ocular relapse (10 in therapy, 15 off therapy) of acute lymphoblastic leukemia (ALL) in first complete remission are examined. The patients were treated according to different chemotherapy schedules, with (20 pts) or without local radiotherapy (5 pts). Isolated ocular relapse can be successfully treated, especially if it occurs after the withdrawal of therapy; second ocular infiltration was seen only in anterior chamber involvement after low doses of local radiotherapy. While the need for high doses of chemotherapy is not evident, high doses of ocular radiotherapy (20 Gy) seem to be mandatory to cure this leukemic relapse.

A one-year prospective, multicentre surveillance study on aetiology, main clinical features and outcome of bloodstream infections in children with cancer was conducted in 18 paediatric haematology centres belonging to the Italian Association for Paediatric Haematology and Oncology. A total of 191 bloodstream infections were reported during the study period. Of them, 123 (64%) occurred in neutropenic and 68 (36%) in non-neutropenic patients. Gram-positive cocci caused 45% (85/191) of the episodes, gram-negative rods 41% (78/191), and fungi 9% (18/191). The remaining 5% (10/191) of the episodes were poly-microbial infections. A total of 204 pathogens were isolated (46% gram-positive cocci; 44% gram-negative rods; and 10% fungi). The aetiologic distribution was similar among neutropenic and non-neutropenic patients. A correlation between the infection and the presence of an indwelling central venous catheter was found in 20% (23/114) of the episodes among neutropenic patients and in 55% (23/62) among non-neutropenic patients. Gram-negative micro-organisms were isolated in an unusually high proportion of catheter-related infections (48%). The overall mortality rate from any cause within 30 days from the first positive blood culture was 11%, and was higher among patients who were neutropenic at the onset of the infection than among those who were not neutropenic (15 versus 4%, P = 0.03). In addition, the mortality was significantly higher in recipients of bone marrow transplantation than in patients with acute leukaemia or solid tumour (21, 11 and 6%, respectively) and was also higher in fungaemias and poly-microbial infections (22 and 30%) than in single gram-positive and gram-negative bacteraemias (11 and 6%).

Prophylaxis of Pneumocystis jiroveci pneumonia (PJP) with trimethoprim/sulfamethoxazole is a standard of care for children with hematologic malignancies, while its use in solid tumor patients is still debated. A retrospective study focusing on the use of PJP prophylaxis in patients with solid tumors was performed among 16 AIEOP centers: 1046/2863 patients did not receive prophylaxis and no cases of PJP were reported.

Background: To date, no data on the adherence to specific guidelines for children with chronic myeloid leukemia (CML) in chronic phase (CP) have been reported. Methods: Since 2001, guidelines for treatment with imatinib mesylate (IM) and monitoring in patients younger than 18 years with CP-CML have been shared with 9 pediatric referral centers (P centers) and 4 reference centers for adults and children/adolescents (AP centers) in Italy. In this study, the adherence to these guidelines was analyzed. Results: Thirty-four patients with a median age of 11.4 years and 23 patients with a median age of 11.0 years were managed at 9 P and at 4 AP centers, respectively. Evaluations of bone marrow (BM) and/or peripheral blood (PB) were available for more than 90% of evaluable patients. Cytogenetics and molecular monitoring of PB were more consistently performed in AP centers, whereas molecular analysis of BM was carried out more frequently in P centers. Before 2009, some patients who responded to IM underwent a transplantation, contrary to the guidelines’ recommendations. Conclusions: Our experience shows that having specific guidelines is an important tool for an optimal management of childhood CP-CML, together with exchange of knowledge and proactive discussions within the network.

The outcome of high-risk (HR) Acute Lymphoblastic Leukemia (ALL) patients enrolled in AIEOP-BFM ALL 2000 study (NCT00613457) in Italy is described. Overall, 1999 Philadelphia negative ALL patients entered the study. HR criteria were: minimal residual disease (MRD) levels ≥10-3 at day 78 (HR-MRD), no complete remission (no-CR) at day 33, t(4;11) translocation, Prednisone Poor Response (PPR). Treatment (2 years) included protocol I, 3 polychemotherapy blocks, delayed intensification (protocol IIx2 or IIIx3), cranial radiotherapy, maintenance. 312 HR patients (15.6% of the total) had 5-year event-free survival (EFS) and overall survival (OS) of 58.9%(SE 2.8) and 68.9%(2.6). In hierarchical order, EFS was 45.9%(4.4) in 132 HR-MRD patients, 41.2%(11.9) in 17 patients no-CR at day 33, 36.4%(14.5) in 11 patients with t(4;11), 74.0%(3.6) in 152 HR patients only for PPR. No statistically significant difference was found for disease-free survival (DFS) in patients with very high risk features (HR-MRD, no-CR at day 33, t(4;11) translocation), given HSCT (n=66) or chemotherapy only (n=88), after adjusting for waiting time to hematopoietic stem cell transplantation (HSCT) (5.7 months). Patients at HR only for PPR have favorable outcome. High risk MRD is associated with poor outcome despite intensive treatment and/or HSCT and may qualify for innovative therapies. The study is registered at the US National Institutes of Health website http://clinicaltrials.gov as "Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With Acute Lymphoblastic Leukaemia" with the protocol identification number NCT00613457.

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

Sotos syndrome is included among the overgrowth disorders, most of which have an increased risk of neoplasms. Sotos syndrome does not appear to be related to a specific tumor type, but rather to the development of solid tumors of ectodermal or mesodermal origin in general. We report on two Sotos syndrome patients who developed a non-Hodgkin lymphoma and an acute lymphoblastic leukaemia, respectively. Our experience suggests that there may exist a high frequency of lymphoproliferative disorders in Sotos syndrome, and points out the importance of a long-term follow-up of Sotos syndrome patients, to detect a possible neoplastic evolution. ©1996 Wiley-Liss, Inc.

Primary tumors of the heart are rare, with an incidence between 0.001% and 0.33% in autopsy findings, and with fibromas representing about 4% of benign cardiac tumors. We report the case of a cardiac fibroma in a 5-year-old child affected by Sotos syndrome. The mean sign was a ventricular tachycardia.

// Chiara Palmi 1 , Angela M. Savino 1 , Daniela Silvestri 2, 3 , Ilaria Bronzini 4 , Gunnar Cario 5 , Maddalena Paganin 4 , Barbara Buldini 4 , Marta Galbiati 1 , Martina U. Muckenthaler 6 , Cristina Bugarin 1 , Pamela Della Mina 7 , Stefan Nagel 8 , Elena Barisone 9 , Fiorina Casale 10 , Franco Locatelli 11 , Luca Lo Nigro 12 , Concetta Micalizzi 13 , Rosanna Parasole 14 , Andrea Pession 15 , Maria C. Putti 4 , Nicola Santoro 16 , Anna M. Testi 17 , Ottavio Ziino 18 , Andreas E. Kulozik 6 , Martin Zimmermann 19 , Martin Schrappe 5 , Antonello Villa 7 , Giuseppe Gaipa 1 , Giuseppe Basso 4 , Andrea Biondi 3 , Maria G. Valsecchi 2 , Martin Stanulla 19 , Valentino Conter 3 , Geertruy te Kronnie 4 , Giovanni Cazzaniga 1 1 Centro Ricerca M. Tettamanti, Clinica Pediatrica, Universita di Milano Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy 2 Center of Biostatistics for Clinical Epidemiology, Department of Health Sciences, University of Milano-Bicocca, Milan, Italy 3 Clinica Pediatrica, Universita di Milano Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy 4 Laboratory of Onco-Hematology, Department SDB, Universita di Padova, Padova, Italy 5 Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany 6 Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and EMBL/Medical Faculty Molecular Medicine Partnership Unit, Heidelberg, Germany 7 Microscopy and Image Analysis Consortium, Universita di Milano-Bicocca, Monza, Italy 8 Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany 9 Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children’s Hospital, Turin, Italy 10 Pediatric Oncology Service, Pediatric Department of 2nd University of Naples, Naples, Italy 11 Department of Pediatric Hematology/Oncology, IRCCS Ospedale Bambino Gesu, Rome - University of Pavia, Pavia, Italy 12 Center of Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria “Policlinico Vittorio Emanuele”, Catania, Italy 13 Hematology/Oncology Unit, G. Gaslini Children’s Hospital, Genoa, Italy 14 Department of Pediatric Hemato-Oncology, Ospedale Pausilipon, Napoli, Italy 15 Department of Pediatrics, “Lalla Seragnoli” Hematology-Oncology Unit, University of Bologna, Bologna, Italy 16 Department of Pediatrics, Division of Pediatric Hematology-Oncology, University “A. Moro” of Bari, Bari, Italy 17 Division of Hematology, Department of Biotechnologies and Hematology, “Sapienza” University of Rome, Rome, Italy 18 Pediatric Hematology and Oncology Unit, A.R.N.A.S. Civico, Di Cristina and Benfratelli Hospital, Palermo, Italy 19 Department of Paediatric Haematology and Oncology, Hannover Medical School, Hannover, Germany Correspondence to: Giovanni Cazzaniga, email: gianni.cazzaniga@hsgerardo.org Andrea Biondi, email: abiondi.unimib@gmail.com Keywords: CRLF2, pediatric leukemia, T acute lymphoblastic leukemia, prognostic marker, high risk Received: May 20, 2016 Accepted: July 01, 2016 Published: July 15, 2016 ABSTRACT Pediatric T-ALL patients have a worse outcome compared to BCP-ALL patients and they could benefit from new prognostic marker identification. Alteration of CRLF2 gene, a hallmark correlated with poor outcome in BCP-ALL, has not been reported in T-ALL. We analyzed CRLF2 expression in 212 T-ALL pediatric patients enrolled in AIEOP-BFM ALL2000 study in Italian and German centers. Seventeen out of 120 (14.2%) Italian patients presented CRLF2 mRNA expression 5 times higher than the median ( CRLF2-high ); they had a significantly inferior event-free survival (41.2%±11.9 vs. 68.9%±4.6, p=0.006) and overall survival (47.1%±12.1 vs. 73.8%±4.3, p=0.009) and an increased cumulative incidence of relapse/resistance (52.9%±12.1 vs. 26.2%±4.3, p=0.007) compared to CRLF2-low patients. The prognostic value of CRLF2 over-expression was validated in the German cohort. Of note, CRLF2 over-expression was associated with poor prognosis in the high risk (HR) subgroup where CRLF2-high patients were more frequently allocated. Interestingly, although in T-ALL CRLF2 protein was localized mainly in the cytoplasm, in CRLF2-high blasts we found a trend towards a stronger TSLP-induced pSTAT5 response, sensitive to the JAK inhibitor Ruxolitinib. In conclusion, CRLF2 over-expression is a poor prognostic marker identifying a subset of HR T-ALL patients that could benefit from alternative therapy, potentially targeting the CRLF2 pathway.