Presentazione lavori,

Si discute del termine "identità", del suo significato per i Greci, di quali termini abbiano usato i Greci per indicare il concetto, come Erodoto elabori una sua concezione di identità probabilmente poi condivisa a partire dal V sec. a. C

Medulloblastoma as a secondary malignancy after radiotherapy-free treatment for acute lymphoblastic leukemia

Malignant brain tumors have been reported to occur in survivors of childhood acute lymphoblastic leukemia (ALL) more frequently than in the noncancer control population. The strongest risk factor seems to be cranial radiotherapy, used as central nervous system (CNS) prophylaxis. We report the case of a 9-year-old girl affected with metastatic medulloblastoma that developed 6 years after a diagnosis of acute lymphoblastic leukemia. CNS prophylaxis for ALL consisted of intrathecal methotrexate plus cytarabine (20 administrations) and 4 courses of high-dose methotrexate (5g/m(2)). No prophylactic cranial radiotherapy was administered. The child, in first complete remission, was well until the occurrence of a second tumor. She was treated for medulloblastoma with craniospinal radiotherapy and chemotherapy. At present, she is alive but with disease. As the unusual association of these 2 malignancies in this patient, the p53 status was investigated using FISH analysis by specific DNA probe; no p53 mutation was detected

EFFICACY OF INDOMETHACIN AS SALVAGE THERAPY IN CHILDREN AND ADULTS WITH LANGERHANS CELL HISTIOCYTOSIS WITH BONE INVOLVEMENT

Purpose: The aim of this study was to analyze the results of treatment with indomethacin in children and adults with recurrent Langerhans cell histiocytosis (LCH) with bone involvement. Methods: Between 1992 and 2014, 17 patients (median age 37 years, range 1-53) with recurrent LCH and active bone lesions were treated with indomethacin 2 mg/Kg/day (maximum dose 150 mg/day) for a minimum of 3 months. Indomethacin was given alone or in combination with surgery/chemotherapy in 10 (59%) and 7 patients (41%), respectively. BRAF mutation analysis was available in 5 patients. Median follow-up was 24 months. Results: All patients were evaluable for response. Median duration of treatment was 6 month. Fourteen of 17 (82.5%) patients obtained a response, that was complete (CR) in 12 (70.5%) and intermediate (IR) in 2 (17.5%) patients. Concerning the disease status at the time of treatment with indomethacin, a CR was obtained in 4/6 (66.6%), 3/4 (75%) and in 5/7 (71%) patients in first, second and in ≥ 3 recurrences, respectively; an IR was achieved in 1 patient in first and 1 patient in ≥ 3 recurrence. Three patients (1 in first and 2 in ≥ 3 recurrences) had a poor response. Five of 14 responding patients (36%) had a disease recurrence after a median time of 4 months from treatment suspension. Two of 17 patients presented a BRAF mutation; they were treated with indomethacin as a single agent at the third recurrence obtaining a CR, but all of them had a disease recurrence. No side effects were observed. All patients are alive. Conclusions: In our experience indomethacin is effective as salvatage regimen in recurrent LCH, also in patients with multiple recurrences. Prospective studies are needed to identify patients with advanced LCH and bone involvement who can optimally benefit from treatment with indomethacin

INDOMETHACIN AS FIRST LINE TREATMENT OF LANGERHANS CELL HISTIOCYTOSIS (LCH). A 20-YEAR EXPERIENCE OF A SINGLE CENTRE.

Purpose: The aim of this study was to analyse the results of treatment with indomethacin as first line treatment in children and adults with Langerhans cell histiocytosis (LCH). Methods: Between 1999 and 2018, 47 patients with a diagnosis of LCH (CD1a+, S100+, CD207+) with a median age of 29 years (range 1-66) were treated with indomethacin 2 mg/Kg/day (maximum dose 150 mg/day) as first line (21 in combination with surgery and/or chemotherapy). Twentyseven patients (57.5%) had single system diseases (SS-LCH), 20 unifocal (74%) and 7 multifocal, and 20 (42.5%) presented multi-system involvement (MS-LCH). BRAF mutation analysis was available in 8/47 patients. Results: Thirty-eight of the 47 patients (81%) were evaluable for response. Two patients (4%) discontinued indomethacin due to toxicity. Considering patients evaluable for response, the median treatment duration was 3 months. All patients obtained a response, that was complete (CR) in 23 (60%) and intermediate (IR) in 15 (40%). Considering the disease status, 16/24 (66.6%) SS-LCH and 7/14 (50%)MS-LCH patients achieved a CR, while an IR was recorded in 8/24 (33.4%) SSLCH and in 7/14 (50%) MS-LCH patients. The CR rate was higher in patients treated with indomethacin as a single agent regimen (14/2, 66.6%) than in those who received a combination regimen (9/17, 53%). Disease reactivation occurred in 2/38 (5%) patients after 3 and 17 months, respectively, from treatment suspension. Three of 8 tested patients (37.5%) were BRAF mutated; all of them obtained a durable CR without recurrence. The most common toxicity was hypertension, recorded in 5/38 (13%) patients. All patients are alive. Conclusion: Our experience shows that indomethacin, used as single agent or in combination, is an effective first-line treatment, for SS-LCH and MS-LCH with bone involvement

Efficacy of ibrutinib as salvage treatment in a secondary central nervous system lymphoma (SCNSL) progressed after chemorefractory Primary Mediastinal B Cell Lymphoma (PMBCL)

In the last few years, promising data have been published about frontline treatment in Primary Mediastinal BCell Lymphoma (PMBCL), both in adults and children; adapting different rituximab-based regimens, relapse free survival (RFS) rates range from 78% to 93% and overall survival (OS) from 88% to 97% in distinct cohorts [1–3]. However, few data are available for relapsed/refractory (R/R) patients, globally showing a poor prognosis. Patients with chemo-sensitive relapse usually undergo to a salvage treatment followed by autologous stem cell transplant (ASCT) but only 25%–40% of these patients receive ASCT and 60–70% of them show durable remission [4]. Patients with chemo-resistant disease have historically a dismal outcome demonstrating lack of therapeutic strategies in this subset. Central nervous system (CNS) relapse is a rare event in PMBCL accounting for approximately 5% of Diffuse Large B cell Lymphomas (DLBCL) in adult series [5]. Data regarding treatment and prognosis in these patients are still lacking. Therefore, treatments of PMBCL CNS involvement often refer to those employed in the more frequent diffuse large B-cell lymphoma (DLBCL)

Terapia con Idrossiurea in bambini e adolescenti affetti da anemia falciforme nel “real life setting

Il termine anemia falciforme comprende un gruppo di disordini congeniti del globulo rosso caratterizzati da un’anomala struttura dell’emoglobina (Hb), trasmessa come carattere autosomico recessivo. Può manifestarsi in omozigosi per l’HbS (HbSS), la drepanocitosi classica, o in eterozigosi in combinazione con le mutazioni della ß-thalassemia (HbS/ß0 e HbS/ß+ ), nota come microdrepanocitosi. Le linee guida attuali hanno come obiettivo la prevenzione delle infezioni e dello stroke, ed il trattamento ottimale delle crisi vaso-occlusive e dell’emolisi cronica. Studi clinici hanno dimostrato l’efficacia dell’oncocarbide (HU) nel ridurre la morbidità e la mortalità di adulti e bambini (inclusi gli infants) con anemia falciforme, con un meccanismo d’azione diretto alla riduzione dell’HbS e un incremento dell’emoglobina fetale (HbF). Abbiamo voluto valutare la terapia con HU in termini di tolleranza, riduzione della frequenza delle crisi dolorose (comprendenti le crisi vasculo-occlusive e la sindrome toracica acuta con una VAS >5 che hanno richiesto trattamento con antidolorifici), del numero degli accessi ospedalieri e delle trasfusioni nei pazienti affetti da drepanocitosi o microdrepanocitosi, seguiti presso la nostra struttura. Dei 13 pazienti (10 con drepanocitosi e 3 con microdrepanocitosi) che sono aderenti ai controlli, 7 (6 con drepanocitosi e 1 con microdrepanocitosi) hanno iniziato il trattamento con HU. L’età mediana alla diagnosi dei 7 pazienti (4 femmine e 3 maschi) è di 2 anni (range: 2 mesi -13 anni), mentre l’età all’inizio dell’HU è di 12 anni (range: 2- 27 anni). Il follow-up minimo pre-terapia è di due anni e quello post-terapia di 1 anno. In 7 pazienti sono stati valutati la tolleranza e il valore dell’emoglobina prima e dopo l’inizio della terapia, mentre 6 pazienti sono risultati valutabili per la riduzione della frequenza delle ospedalizzazioni, delle trasfusioni e delle crisi dolorose. Il valore mediano di Hb era di 7,6g/dL (range: 5.9-8.9 g/dL) alla diagnosi e di 8,4 g/dL (range: 7.1-9.9g/dL) al momento dell’inizio dell’HU. La dose di HU è stata variabile fra 10mg/Kg/die e 15 mg/Kg/die. La terapia è stata ben tollerata. Una paziente ha sviluppato un’ulcera malleolare in corso di trattamento. Tre pazienti sono risultati non aderenti alla terapia. Nei 7 pazienti, il valore mediano di Hb valutato dopo un anno dall’inizio dell’HU è risultato pari a 9.9 g/dL (range: 7.6- 11.1g/dL). Nei 6 pazienti valutabili, la frequenza mediana annua di crisi dolorose si è ridotta da 2.2 riscontrata nei due anni precedenti l’inizio dell’HU a 0.5 nell’anno successivo, così come la frequenza mediana di ospedalizzazione annua da 1.2 a 0.5. La frequenza mediana annua di trasfusione di emazie è passata da 3 nei due anni precedenti l’inizio dell’HU a 1 nell’anno successivo. Nonostante la scarsa numerosità dei pazienti, l’ HU si è dimostrato un farmaco ben tollerato anche nei bambini più piccoli ed è stato in grado di modificare positivamente il decorso clinico dei pazienti trattati, compresi quelli con scarsa compliance alla terapia

WHO 2016 classification in 80 children and adolescents with chronic myeloproliferative neoplasms

Background The first classification of chronic myeloproliferative neoplasms (MPNs) was proposed in 1951 by Dameshek and since then it has been modified several times. The last classification of BCR-ABL1-negative MPNs, defined in 2016 by the World Health Organization (WHO), considers morphologic bone marrow (BM) features and driver mutations (JAK2V617F, JAK2 exon 12, CALR and MPL) as major criteria. Thus, the WHO 2016 criteria better define MPNs as polycythemia vera (PV), essential thrombocythemia (ET), prefibrotic/early primary myelofibrosis (PMF) (pre-PMF) and overt PMF, making the identification of masked PV (mPV) and “true” JAK2-mutated ET easier. Our experience has suggested that MPNs in children and adolescents are characterized by subtypes that differ from those found in adults and require specific diagnostic criteria. Aims The present study was carried out in order to (a) retrospectively review the diagnosis of MPNs in patients aged <20 years based on the WHO 2016 classification and adapted in accordance with our experience in this category of patients, and (b) analyze their clinical and biologic features according to both the initial diagnosis criteria and the adapted WHO 2016 criteria. Methods Out of 93 patients aged <20 years with a diagnosis of MPNs carried out from 1980 to 2015, 80 (median age: 14.6 years) with bone marrow (BM) evaluation and available molecular analysis (JAK2V617F, JAK2 exon 12, CALR, MPL, EPO-R and HIF) were considered. These patients were divided into different subgroups according to the criteria of their initial diagnosis (PVSG 1975, 1986, 1996, WHO 2001 and 2008): ET, PV, PMF. The subgroups were then retrospectively revised according to the WHO 2016 criteria into: ET, mPV, PV, pre-PMF, overt PMF. Patients with HIF mutations and/or criteria of familial erythrocytosis were defined as FE. Patients with MPLS505A mutation were diagnosed as hereditary thrombocytosis (HT). Results As shown in Fig. 1, of the 56 patients with an initial diagnosis of ET, 16 (28.5%) had HT due to a MPLS505A mutation, 3 (5.4%) were classified, according to the WHO 2016 classification, as mPV and 2 (3.6%) as PMF. Two out of 8 patients, with an initial diagnosis of PV, had FE due to a HIF2α mutation. Considering the adapted WHO 2016 classification, JAK2V617F mutation was found in 28.5% and 44% of ET and PV patients, respectively. CALR mutations and MPLW515_P518>KT were found in 26% and 2.7% of ET patients. Of 23 HT patients, 87% showed MPLS505A and 13% MPLV501A. Considering both the classification at initial diagnosis and the adapted WHO 2016 criteria, hemoglobin and hematocrit values were significantly higher in FE and slightly lower in PV patients (p<0.0001) and platelet counts were higher in ET and slightly lower in HT patients (p <0.0001) compared to other subgroups. Regarding the other features at diagnosis, leukocyte counts were significantly higher in PMF and ET patients (p= 0.0032), and the presence of medullary fibrosis (> 2 WHO grading) became significant in PMF patients (p= 0.0052), only according to the adapted WHO classification. Conclusion The WHO 2016 criteria are able to identify mPV, pre-PMF and overt PMF in children and adolescents with MPNs also. On the whole, 43%, 56% and 75% of ET, PV and PMF, respectively, did not show gene driver mutations. Hereditary forms can be observed in a significant proportion (41%) of young patients with MPNs. Taken together, our observations suggest that molecular analysis to identify inherited molecular defects must be performed in children and adolescents with MPNs