Integrated Genomic, Functional, and Prognostic Characterization of Atypical Chronic Myeloid Leukemia

Atypical chronic myeloid leukemia (aCML) is a BCR-ABL1-negative clonal disorder, which belongs to the myelodysplastic/myeloproliferative group. This disease is characterized by recurrent somatic mutations in SETBP1, ASXL1 and ETNK1 genes, as well as high genetic heterogeneity, thus posing a great therapeutic challenge. To provide a comprehensive genomic characterization of aCML we applied a high-throughput sequencing strategy to 43 aCML samples, including both whole-exome and RNA-sequencing data. Our dataset identifies ASXL1, SETBP1, and ETNK1 as the most frequently mutated genes with a total of 43.2%, 29.7 and 16.2%, respectively. We characterized the clonal architecture of 7 aCML patients by means of colony assays and targeted resequencing. The results indicate that ETNK1 variants occur early in the clonal evolution history of aCML, while SETBP1 mutations often represent a late event. The presence of actionable mutations conferred both ex vivo and in vivo sensitivity to specific inhibitors with evidence of strong in vitro synergism in case of multiple targeting. In one patient, a clinical response was obtained. Stratification based on RNA-sequencing identified two different populations in terms of overall survival, and differential gene expression analysis identified 38 significantly overexpressed genes in the worse outcome group. Three genes correctly classified patients for overall survival

Post-Transplant Lymphoproliferative Disease (PTLD) after Allogeneic Hematopoietic Stem Cell Transplantation: Biology and Treatment Options

Post-transplant lymphoproliferative disease (PTLD) is a serious complication occurring as a consequence of immunosuppression in the setting of allogeneic hematopoietic stem cell transplantation (alloHSCT) or solid organ transplantation (SOT). The majority of PTLD arises from B-cells, and Epstein–Barr virus (EBV) infection is present in 60–80% of the cases, revealing the central role played by the latent infection in the pathogenesis of the disease. Therefore, EBV serological status is considered the most important risk factor associated with PTLDs, together with the depth of T-cell immunosuppression pre- and post-transplant. However, despite the advances in pathogenesis understanding and the introduction of novel treatment options, PTLD arising after alloHSCT remains a particularly challenging disease, and there is a need for consensus on how to treat rituximab-refractory cases. This review aims to explore the pathogenesis, risk factors, and treatment options of PTLD in the alloHSCT setting, finally focusing on adoptive immunotherapy options, namely EBV-specific cytotoxic T-lymphocytes (EBV-CTL) and chimeric antigen receptor T-cells (CAR T)

IRON CHELATION THERAPY WITH DEFERASIROX IN THE MANAGEMENT OF IRON OVERLOAD IN PRIMARY MYELOFIBROSIS

Deferasirox (DSX) is the principal option currently available for iron-chelation-therapy (ICT), principally in the management of myelodysplastic syndromes (MDS), while in primary myelofibrosis (PMF) the expertise is limited. We analyzed our experience in 10 PMF with transfusion-dependent anemia, treated with DSX from September 2010 to December 2013. The median dose tolerated of DSX was 750 mg/day (10 mg/kg/day), with 3 transient interruption of treatment for drug-related adverse events (AEs) and 3 definitive discontinuation for grade 3/4 AEs. According to IWG 2006 criteria, erythroid responses with DSX were observed in 4/10 patients (40%), 2 of them (20%) obtaining transfusion independence. Absolute changes in median serum ferritin levels (Delta ferritin) were greater in hematologic responder (HR) compared with non-responder (NR)  patients, already at 6 months of ICT respect to baseline. Our preliminary data open new insights regarding the benefit of ICT not only in MDS, but also in PMF with the possibility to obtain an erythroid response, overall in 40 % of patients. HR patients receiving DSX seem to have a better survival and a lower incidence of leukemic transformation (PMF-BP). Delta ferritin evaluation at 6 months could represent a significant predictor for a different survival and PMF-BP.  However, the tolerability of the drug seems to be lower compared to MDS, both in terms of lower median tolerated dose and for higher frequency of discontinuation for AEs. The biological mechanism of action of DSX in chronic myeloproliferative setting through an independent NF-κB inhibition could be involved, but further investigations are required

Advances and Hurdles in CAR T Cell Immune Therapy for Solid Tumors

Chimeric antigen receptor (CAR) T cells in solid tumors have so far yielded limited results, in terms of therapeutic effects, as compared to the dramatic results observed for hematological malignancies. Many factors involve both the tumor cells and the microenvironment. The lack of specific target antigens and severe, potentially fatal, toxicities caused by on-target off-tumor toxicities constitute major hurdles. Furthermore, the tumor microenvironment is usually characterized by chronic inflammation, the presence of immunosuppressive molecules, and immune cells that can reduce CAR T cell efficacy and facilitate antigen escape. Nonetheless, solid tumors are under investigation as possible targets despite their complexity, which represents a significant challenge. In preclinical mouse models, CAR T cells are able to efficiently recognize and kill several tumor xenografts. Overall, in the next few years, there will be intensive research into optimizing novel cell therapies to improve their effector functions and keep untoward effects in check. In this review, we provide an update on the state-of-the-art CAR T cell therapies in solid tumors, focusing on the preclinical studies and preliminary clinical findings aimed at developing optimal strategies to reduce toxicity and improve efficacy

Introduzione

Il saggio introduce la nuova traduzione dell'ultima edizione del manuale di W.A. Corsaro SOCIOLOGY OF CHILDHOOD. nella prima parte inquadra l'A. e i suoi studi dagli anni 60 ad oggi, nell'alveo della sociologia americana di stampo interazionista, e ne sottolinea l'attualit\ue0 di vedute, Presenta la teoria della riproduzione interpretativa quale nuova sociologia dell'infanzia. I principali concetti contenuti nel volume (routines, conflitti e condivisione, ruolo attivo dei bambini nel costruire le regole delle interazioni). La seconda parte mette in collegamento le idee dell'A. con lo stato dell'arte della sociologia dell'infanzia in Italia e espone in sintesi le principali difficolt\ue0 dei minori italiani. La terza parte riprende il concetto di riproduzione interpretativa, in relazione alla presenza attiva dei piccoli nell'universo dei media. La quarta parte sottolinea luci e ombre dell'approccio di Corsaro alla luce dell'agency infantile

Sociologia dell'infanzia

Quando l\u2019infanzia ha smesso di essere una condizione temporanea della vita, che prelude ad altre fasi e ai ruoli sociali adulti, e ha cominciato a costituire una categoria sociale a s\ue9 stante? Solo negli ultimi decenni del Novecento, i bambini sono arrivati ad essere considerati attori sociali dotati di un proprio punto di vista, quindi capaci di vivere entro la \u2018cultura dei pari\u2019. Il sociologo statunitense W.A. Corsaro pubblica in lingua italiana la quinta edizione del manuale di Sociologia dell\u2019infanzia, che contiene gli elementi teorici, metodologici e i risultati empirici di quarant\u2019anni di indagine con bambini e ragazzi di diversi Paesi. Il volume riporta le sue pi\uf9 note argomentazioni sulla \u2018riproduzione interpretativa\u2019, concetto che ribalta il punto di vista sulla socializzazione e sull\u2019infanzia in modo da includere la prospettiva dei bambini stessi. Fornisce ampia letteratura sia americana sia europea sulle strategie di ricerca sociale per interpretare correttamente la condizione infantile. Applica l\u2019analisi alle pratiche culturali dei bambini e per i bambini: dall\u2019uso dei media al linguaggio delle fiabe; dai giochi spontanei al marketing dei giocattoli. L\u2019opera di Corsaro si rivolge a educatori, maestri e studiosi dell\u2019infanzia che vogliano abbracciare uno sguardo critico sul mutare della vita dei bambini in famiglia, nei contesti urbani e nei servizi per l\u2019infanzia, ma soprattutto che siano disponibili a \u2018guardare il mondo con gli occhi dei bambini\u2019

Transfusion of blood products derived from {SARS}-{CoV}-2mathplusmathplus donors to patients with hematological malignancies

SARS-CoV-2 infection incidence related to blood transfusio