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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.

We analyzed the long-term outcome of 4865 patients treated in Studies 82, 87, 88, 91 and 95 for childhood acute lymphoblastic leukemia (ALL) of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Treatment was characterized by progressive intensification of systemic therapy and reduction of cranial radiotherapy. A progressive improvement of results with reduction of isolated central nervous system relapse rate was obtained. Ten-year event-free survival increased from 53% in Study 82 to 72% in Study 95, whereas survival improved from 64 to 82%. Since 1991, all patients were treated according to Berlin-Frankfurt-Muenster (BFM) ALL treatment strategy. In Study 91, reduced treatment intensity (25%) yielded inferior results, but intensification of maintenance with high-dose (HD)-L-asparaginase (randomized) allowed to compensate for this disadvantage; in high-risk patients (HR, 15%), substitution of intensive polychemotherapy blocks for conventional BFM backbone failed to improve results. A marked improvement of results was obtained in HR patients when conventional BFM therapy was intensified with three polychemotherapy blocks and double delayed intensification (Study 95). The introduction of minimal residual disease monitoring and evaluation of common randomized questions by AIEOP and BFM groups in the protocol AIEOP-BFM-ALL 2000 are expected to further ameliorate treatment of children with ALL.

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.

Acute promyelocytic leukaemia (APL) is a rare subtype ofchildhood acute myeloid leukaemia (AML), accounting for5–12% of all AML cases. Treatment with all-trans-retinoicacid (ATRA) and anthracyclines yields complete remission(CR) rates >90% and 10-year event-free survival (EFS) ratesaround 80%.1–3The recent front-line arsenic trioxide(ATO)-based regimens have further improved the APL out-come by reducing toxicity and preventing relapse.4–6Relapsed APL patients are a rare and heterogeneous group,whose prognosis depends on front-line treatment and timeelapsing between diagnosis and recurrence. Currently, ATOis the treatment of choice for relapsed APL. Due to the rarityof relapsed childhood APL, 17–27% in ATRA- andchemotherapy-1,3,7–9and 4% in ATO-containing regimens,10it will be difficult, in the future, to design future prospectivecomparative trials for these patients. In an attempt to designtherapeutic guidelines, recommendations on management ofrelapsed/refractory paediatric APL have been publishedrecently

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.

Purpose Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with relevant toxicity. Therefore, standard-risk patients of trial AIEOP-BFM ALL 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With ALL) were investigated with the specific aim to reduce treatment intensity. Patients and Methods Between July 2000 and July 2006, 1,164 patients (1 to 17 years of age) with standard-risk ALL (defined as the absence of high-risk cytogenetics and undetectable minimal residual disease on days 33 and 78) were randomly assigned to either experimental reduced-intensity DI (protocol III; P-III) or standard DI (protocol II; P-II). Cumulative drug doses of P-III were reduced by 30% for dexamethasone and 50% for vincristine, doxorubicin, and cyclophosphamide, which shortened the treatment duration from 49 to 29 days. The study aimed at noninferiority of reduced-intensity P-III; analyses were performed according to treatment given. Results For P-III and P-II, respectively, the 8-year rate of disease-free survival (± SE) was 89.2 ± 1.3% and 92.3 ± 1.2% ( P = .04); cumulative incidence of relapse, 8.7 ± 1.2% and 6.4 ± 1.1% ( P = .09); and overall survival, 96.1 ± 0.8% and 98.0 ± 0.6% ( P = .06). Patients with ETV6-RUNX1–positive ALL and patients 1 to 6 years of age performed equally well in both arms. The incidence of death during remission was comparable, which indicates equivalent toxicity. The 8-year cumulative incidence rate of secondary malignancies was 1.3 ± 0.5% and 0.6 ± 0.4% for P-III and P-II, respectively ( P = .37). Conclusion Although the criteria used for the standard-risk definition in this trial identified patients with exceptionally good prognosis, reduction of chemotherapy was not successful mainly because of an increased rate of relapse. The data suggest that treatment reduction is feasible in specific subgroups, which underlines the biologic heterogeneity of this cohort selected according to treatment response.

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.

Myofibromatosis is an uncommon disorder of infancy, characterized by proliferation of myofibroblasts in solitary or multiple nodules. The clinical characteristics depend on the involved sites: Myofibromatosis may develop as a musculoskeletal form, with non-painful swellings and eventual mass effect symptoms, or as a generalized form with visceral involvement and organ failure. Prognosis and therapy vary between the abovementioned patterns. When there is no visceral involvement, the tumors may regress spontaneously; however, the visceral form may represent a lifethreatening condition with poor outcome and it requires aggressive management. Imaging assessment of disease spread is mandatory to determine diagnosis, prognosis and therapy. Due to the young age of the patients, a radiation-free evaluation is recommended. We herein describe a case of musculoskeletal myofibromatosis diagnosed in a 3-month-old male infant, investigated by serial wholebody magnetic resonance imaging (MRI) examination. The histological analysis and MRI characteristics enabled a correct diagnosis and organ involvement assessment with no radiation exposure. Moreover, whole-body MRI sequences provided a detailed evaluation of the disease within a short time frame, reducing the time of sedation, which is required to perform MRI in very young patients. Therefore, whole-body MRI was found to be accurate and safe in the diagnosis and follow-up of multicentric infantile myofibromatosis. Myofibromatosis is an uncommon disorder of infancy, characterized by proliferation of myofibroblasts in solitary or multiple nodules. The clinical characteristics depend on the involved sites: Myofibromatosis may develop as a musculoskeletal form, with non-painful swellings and eventual mass effect symptoms, or as a generalized form with visceral involvement and organ failure. Prognosis and therapy vary between the abovementioned patterns. When there is no visceral involvement, the tumors may regress spontaneously; however, the visceral form may represent a lifethreatening condition with poor outcome and it requires aggressive management. Imaging assessment of disease spread is mandatory to determine diagnosis, prognosis and therapy. Due to the young age of the patients, a radiation-free evaluation is recommended. We herein describe a case of musculoskeletal myofibromatosis diagnosed in a 3-month-old male infant, investigated by serial wholebody magnetic resonance imaging (MRI) examination. The histological analysis and MRI characteristics enabled a correct diagnosis and organ involvement assessment with no radiation exposure. Moreover, whole-body MRI sequences provided a detailed evaluation of the disease within a short time frame, reducing the time of sedation, which is required to perform MRI in very young patients. Therefore, whole-body MRI was found to be accurate and safe in the diagnosis and follow-up of multicentric infantile myofibromatosis.

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

We analyzed the outcome of 243 children with high-risk (HR) AML in first CR1 enrolled in the AIEOP-2002/01 protocol, who were given either allogeneic (ALLO; n=141) or autologous (AUTO; n=102) hematopoietic SCT (HSCT), depending on the availability of a HLA-compatible sibling. Infants, patients with AML-M7, or complex karyotype or those with FLT3-ITD, were eligible to be transplanted also from alternative donors. All patients received a myeloablative regimen combining busulfan, cyclophosphamide and melphalan; [corrected] AUTO-HSCT patients received BM cells in most cases, while in children given ALLO-HSCT stem cell source was BM in 96, peripheral blood in 19 and cord blood in 26. With a median follow-up of 57 months (range 12-130), the probability of disease-free survival (DFS) was 73% and 63% in patients given either ALLO- or AUTO-HSCT, respectively (P=NS). Although the cumulative incidence (CI) of relapse was lower in ALLO- than in AUTO-HSCT recipients (17% vs 28%, respectively; P=0.043), the CI of TRM was 7% in both groups. Patients transplanted with unrelated donor cord blood had a remarkable 92.3% 8-year DFS probability. Altogether, these data confirm that HSCT is a suitable option for preventing leukemia recurrence in HR children with CR1 AML.

Objective To determine whether a simplified, 1-day/week regimen of trimethoprim/sulfamethoxazole is sufficient to prevent Pneumocystis (jirovecii [carinii]) pneumonia (PCP). Current recommended regimens for prophylaxis against PCP range from daily administration to 3 consecutive days per week dosing. Study design A prospective survey of the regimens adopted for the PCP prophylaxis in all patients treated for childhood cancer at pediatric hematology-oncology centers of the Associazione Italiana Ematologia Oncologia Pediatrica. Results The 20 centers participating in the study reported a total of 2466 patients, including 1093 with solid tumor and 1373 with leukemia/lymphoma (or primary immunodeficiency; n = 2). Of these patients, 1371 (55.6%) received the 3-day/week prophylaxis regimen, 406 (16.5%) received the 2-day/week regimen, and 689 (27.9%), including 439 with leukemia/lymphoma, received the 1-day/week regimen. Overall, only 2 cases of PCP (0.08%) were reported, both in the 2-day/week group. By intention to treat, the cumulative incidence of PCP at 3 years was 0.09% overall (95% CI, 0.00-0.40%) and 0.51% for the 2-day/week group (95% CI, 0.10%-2.00%). Remarkably, both patients who failed had withdrawn from prophylaxis. Conclusion A single-day course of prophylaxis with trimethoprim/sulfamethoxazole may be sufficient to prevent PCP in children with cancer undergoing intensive chemotherapy regimens. This simplified strategy might have implications for the emerging need for PCP prophylaxis in other patients subjected to the increased use of biological and nonbiological agents that induce higher levels of immune suppression, such as those with rheumatic diseases.

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.