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Active landslide risk assessment and management are primarily based on the availability of dedicated studies and monitoring activities. The establishment of decision support for the efficient management of active landslides threatening urban areas is a worthwhile contribution. Nowadays, consistent information about major landslide hazards is obtained through an interdisciplinary approach, consisting of field survey data and long-time monitoring, with the creation of a high populated dataset. Nevertheless, the large number and variety of acquired data can generate some criticalities in their management. Data fragmentation and a missing standard format of the data should represent a serious hitch in landslide hazard management. A good organization in a standard format can be a good operative solution. Based on standardized approaches such as the ICAO (International Civil Aviation Organization), we developed a standard document called operative monography. This document summarizes all available information by organizing monitoring data and identifying possible lacks. We tested this approach in the Aosta Valley Region (NW Italy) on five different slow moving landslides monitored for twenty years. The critical analysis of the available dataset modifies a simple sequence of information in a more complex document, adoptable by local and national authorities for a more effective management of active landslides.

Purpose Obesity and excessive weight gain during pregnancy is a growing problem, conferring severe health risks for both mother and fetus. Exercise can help combat this epidemic. However, many pregnant women are not meeting the American Congress of Obstetricians and Gynecologists’ (ACOG’s) 2015 guidelines for exercise during pregnancy. The objective of this study was to evaluate obstetricians’ beliefs and recommendations regarding exercise during pregnancy compared to ACOG’s 2015 recommendations. Method Obstetricians were recruited via three different forums to complete a twenty-question survey: at a regional conference for Alabama and Mississippi ACOG members, at the University of Alabama at Birmingham’s Obstetrics and Gynecology Department’s Grand Rounds, and via telephone. Univariate statistical analysis was conducted with RedCap. Results Seventy-one surveys were completed: 33 from the ACOG conference, 27 from Grand Rounds, and 11 from those recruited by telephone. Eighty-eight percent (n=60) of respondents correctly identified ACOG’s recommendation of unrestricted exercise for women with uncomplicated pregnancies. One-fourth (24%; n=16) regularly discuss exercise with most (76%-100%) pregnant patients. Most (57%; n=59) do not consistently (“never,” “rarely,” or “sometimes”) recommend sedentary patients begin exercising during pregnancy. Nearly all (97%; n=66) advise first-trimester patients to perform aerobic exercise two to five days per week, but the recommended duration varies. One-fourth (24%; n=16) do not recommend strength-training exercise during the first trimester. Twenty-five percent (n=17) and 32% (n=22) recommend decreased aerobic or strength-training exercise, respectively, in the third trimester. More than half (54%; n=37) recommend pregnant patients limit exercise by heart rate, most commonly 121-140 bpm (25%; n=17) or 141-160 bpm (24%; n=16). Sixty-eight percent (n=46) feel “comfortable” or “very comfortable” providing advice on exercise during pregnancy. Conclusion Despite believing exercise benefits pregnant women, knowing ACOG’s 2015 guidelines endorse unrestricted exercise for women with uncomplicated pregnancies, and feeling comfortable discussing this topic with patients, obstetricians are not consistently counseling their pregnant patients on exercise. Notably, physicians are not instructing their sedentary pregnant patients to exercise. While most physicians provide appropriate advice on aerobic exercise, their advice on resistance training, maximum heart rate during exercise and third-trimester exercise are often discordant with ACOG’s guidelines.

Allogeneic hematopoietic cell transplantation (allo-HCT) is an adoptive immunotherapy strategy whose effectiveness relies on graft-versus-tumor (GVT) effect. We explored the feasibility of enhancing GVT after allo-HCT by peptide vaccination. Two myeloma patients were transplanted with a fludarabine-total body irradiation conditioning regimen and vaccinated with an HLA-A*0201-restricted modified survivin nonapeptide, plus montanide as adjuvant. At time of first vaccination, one patient had just attained serological remission despite documented relapse after transplant, while the other patient was in stable disease. Both patients had an immune response to vaccination: the frequency of survivin-specific CD8+ T cells increased between second and sixth vaccination and accounted for 0.5–0.8% of CD8+ cells; CD8+ cells were functional in ELISPOT assay. The first patient persists in complete remission with a follow-up of >5 years, while the second patient did not have a clinical response and vaccination was halted. We analyzed the T-cell receptor (TCR) repertoire of the first patient by spectratyping and found that vaccination did not affect the diversity of TCR profile, indicating that survivin clonotypes were probably spread in multiple TCR families. We generated a limited number (n = 4) of survivin-specific T cell clones: three were reactive only against the modified peptide, whereas one clone recognized also the naive peptide. Peptide vaccination is safe and applicable after allo-HCT and elicits an efficient antigen-specific T cell response without causing graft-versus-host disease.

Human dihydroorotate dehydrogenase ( hDHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. hDHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of hDHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[1,5- a]pyridine, that has been designed starting from brequinar, one of the most potent hDHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound 4, which shows brequinar-like hDHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound 4 also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This Article reports the design, synthesis, SAR, X-ray crystallography, biological assays, and physicochemical characterization of the new class of hDHODH inhibitors.

El presente trabajo busca analizar diversos indicadores vinculados a la práctica evaluativa docente en las diferentes asignaturas que integran el primer semestre del programa de la carrera Medicina Veterinaria de la Facultad de Ciencias Veterinarias de la Universidad Nacional del Litoral, y visibilizar las percepciones que los estudiantes tienen en relación con dicha práctica. Se indagó acerca de las pautas que utilizan los docentes al momento de evaluar y del material de estudio utilizado por los estudiantes para la preparación de exámenes. Los resultados obtenidos permiten reafirmar que la evaluación es un proceso complejo. Este estudio reveló que los estudiantes perciben una falta de consenso en los criterios evaluativos docentes, así como una escasa retroalimentación del proceso realizado. En general, el proceso de aprendizaje estudiantil se complementa con la utilización de estrategias metacognitivas. Con respecto al material de estudio, la mayoría de los estudiantes utilizan apuntes de elaboración propia o confeccionados por las cátedras. El aporte de esta investigación manifiesta la necesidad de construir espacios de debate en torno a las concepciones que los docentes poseen a la hora de evaluar, generando otras miradas que podrían enriquecer los procesos de enseñanza, de aprendizaje y en particular, de las prácticas evaluativas.

Non-infectious soft tissue lesions of the foot and ankle are relatively rare clinically. These include benign and malignant neoplasms, as well as non-neoplastic or pseudotumoral lesions such as ganglionic, synovial and epidermoid cysts, intermetatarsal and adventitious bursitis, inflammatory lesions like gouty tophi and rheumatoid nodules, Morton's neuroma, and granuloma annulare. A 48-year-old male with a history of medically treated tophaceous gout presented with left foot neuropathic pain and paresthesia, in the setting of a well-circumscribed soft tissue lesion of the second intermetatarsal space, suspected to be a Morton's neuroma. Magnetic resonance imaging (MRI) showed a 4.1 x 2.7 x 2.6 cm heterogeneous soft tissue mass containing multiple cystic areas. Excisional biopsy was performed and histologic examination revealed well-circumscribed nodules of amorphous material containing needle-shaped clefts, rimmed by histiocytes, and multinucleated giant cells consistent with a gouty tophus. This is the first case reported in the literature of an intermetatarsal gouty tophus causing neuropathic pain and paresthesia. While Morton's neuroma is the most common cause of this presentation, this case illustrates that other pseudotumoral lesions, such as a gouty tophus, may present similarly, and should be considered in the differential diagnosis. While most cases of tophaceous gout can be adequately treated with urate-lowering therapy, surgery may be indicated for tophi that do not resolve with medical treatment based upon symptom severity, compression of nearby structures, and functional impairment.

La collana pubblica gli atti del convegno annuale di Linguistica Computazionale (CLiC-it), che ha lo scopo di costituire un luogo di discussione di riferimento nel campo delle ricerce sulla linguistica computazionale. Gli atti includono interventi sul trattamento automatico della lingua, comprendenti le riflessioni teoriche e metodologiche sul tema, e forniscono un contributo importante per questo campo di ricerca. Le altre tematiche principali sono: la linguistica computazionale, la linguistica, le scienze cognitive, l'apprendimento automatico, l'informatica, la rappresentazione della conoscenza, l'information retrieval e l'umanistica digitale. L'organizzazione del convegno è il risultato dello sforzo dell'Associazione Italiana di Linguistica Computazionale (AILC http://www.ai-lc.it/), rappresentata ogni anno da alcuni dei membri organizzatori, che sono affiliati anche ad altre organizzazioni che operano nell'ambito della linguistica computazionale. This book presents the proceedings of the annual Conference of Computational Linguistics (CLiC-it), which aims to provide a forum for discussion in the field of computational linguistics. The proceedings include interventions on the automatic treatment of language, with theoretical and methodological reflections on the subject, and provide an important contribution to this field of research. The other main topics are: computational linguistics, linguistics, cognitive sciences, automatic learning, computer science, knowledge representation, information retrieval and digital humanities. The organization of the conference is the result of the effort of the Italian Association of Computational Linguistics (AILC http://www.ai-lc.it/), represented every year by some of the organizing members, who are also affiliated to other organizations operating in the field of computational linguistics.

State-of-the-art Part-of-Speech taggers have been thoroughly evaluated on standard Italian. To understand how Part-of-Speech taggers that have been pretrained on standard Italian fare with a wide array of language anomalies, we evaluate five Part-of-Speech taggers on a corpus of student essays written throughout the largest Italian-speaking area outside of Italy. Our preliminary results show that there is a significant gap between their performance on non-standard Italian and on standard Italian, and that the performance loss mainly comes from relatively subtle tagging errors within morphological categories as opposed to coarse errors across categories. Gli strumenti di Part-of-Speech tagging più rappresentativi dello stato dell’arte sono stati analizzati a fondo con l’italiano standard. Per capire come strumenti pre-addestrati sull’italiano standard si comportano in presenza di un’ampia gamma di anomalie linguistiche, analizziamo le prestazioni di cinque strumenti su di un corpus di elaborati redatti da studenti della scuola dell’obbligo nella Svizzera Italiana. I nostri risultati preliminari mostrano che esiste un notevole divario tra le prestazioni sull’italiano nonstandard e quelle sull’italiano standard, e che la perdita di prestazioni deriva principalmente da errori di tagging relativamente sottili all’interno delle categorie grammaticali.

The article presents the study TIscrivo (Today Written Composition, between Spoken Language and Computer Mediated Communication. Theoretical aspects, diagnosis and teaching methods, Swiss National Science Foundation funding Dore 13DPD3_136603), based on the largest corpus of texts written at school ever collected in Canton Ticino. Section 1 describes the context and the project's main goals. We will then outline some first results from corpus analysis, in particular about the use of punctuation in learners' writing, focusing firstly on primary school (section 2) and then on junior high school (section 3). Afterwards, the article investigates some uses and constructions difficult to teach and to learn properly, and examines them in a sample of schoolbooks (section 4). Finally, specific attention is given to some "stylistic uses" of punctuation (section 5), i.e. to the advanced and conscious insertion of expressive punctuation marks conflicting with the standard rules. We will argue that when this kind of punctuation is introduced in young students' texts, usually it has to be interpreted not as a stylistic, voluntary choice, but as the outcome of a still unsure management of the system.

International audience; The present study investigated the cortical areas engaged in the perception of graviceptive information embedded in biological motion (BM). To this end, functional magnetic resonance imaging was used to assess the cortical areas active during the observation of human movements performed under normogravity and microgravity (parabolic flight). Movements were defined by motion cues alone using point-light displays. We found that gravity modulated the activation of a restricted set of regions of the network subtending BM perception, including form-from-motion areas of the visual system (kinetic occipital region, lingual gyrus, cuneus) and motor-related areas (primary motor and somatosensory cortices). These findings suggest that compliance of observed movements with normal gravity was carried out by mapping them onto the observer's motor system and by extracting their overall form from local motion of the moving light points. We propose that judgment on graviceptive information embedded in BM can be established based on motor resonance and visual familiarity mechanisms and not necessarily by accessing the internal model of gravitational motion stored in the vestibular cortex.

Background and aim Feedforward and online controls are two facets of predictive motor control from internal models, which is suspected to be impaired in learning disorders. We examined whether the feedforward component is affected in children (8–12 years) with developmental dyslexia (DD) and/or with developmental coordination disorder (DCD) compared to typically developing (TD) children. Methods Children underwent a bimanual unloading paradigm during which a load supported to one arm, the postural arm, was either unexpectedly unloaded by a computer or voluntary unloaded by the subject with the other arm. Results All children showed a better stabilization (lower flexion) of the postural arm and an earlier inhibition of the arm flexors during voluntary unloading, indicating anticipation of unloading. Between-group comparisons of kinematics and electromyographic activity of the postural arm revealed that the difference during voluntary unloading was between DD-DCD children and the other groups, with the former showing a delayed inhibition of the flexor muscles. Conclusion Deficit of the feedforward component of motor control may particularly apply to comorbid subtypes, here the DD-DCD subtype. The development of a comprehensive framework for motor performance deficits in children with learning disorders will be achieved only by dissociating key components of motor prediction and focusing on subtypes and comorbidities.

International audience; Alzheimer’s and Parkinson’s diseases are age-related progressive neurodegenerative diseases of increasing prevalence worldwide. In the absence of curative therapy, current research is interested in prevention, by identifying subtle signs of early-stage neurodegeneration. Today, the field of behavioral neuroscience has emerged as one of the most promising areas of research on this topic. Recently, it has been shown that the exacerbation of gait disorders under dual-task conditions (i.e., simultaneous performance of cognitive and motor tasks) could be a characteristic feature of Alzheimer’s and Parkinson’s diseases. The cognitive-motor dual-task paradigm during walking allows to assess whether (i) executive attention is abnormally impaired in prodromal Alzheimer’s disease or (ii) compensation strategies are used in order to preserve gait function when the basal ganglia system is altered in prodromal Parkinson’s disease. This review aims at (i) identifying patterns of dual-task-related gait changes that are specific to Alzheimer’s and Parkinson’s diseases, respectively, (ii) demonstrating that these changes could potentially be used as prediagnostic markers for disease onset, (iii) reviewing pros and cons of existing dual-task studies, and (iv) proposing future directions for clinical research.

Deep-seated Gravitational Slope Deformations (DsGSDs) are widespread phenomena in mountain regions. In the Valle d’Aosta alpine region of northern Italy, DsGSDs occupy 13.5% of the entire regional territory. A total of 280 phenomena have been inventoried in the IFFI (Italian Landslide Inventory) project. These large slope instabilities often affect urbanized areas and strategic infrastructure and may involve entire valley flanks. The presence of settlements on DsGSDs has led the regional Geological Survey to assess the possible effects of these phenomena on human activities. This study is aimed at implementing a methodology that is based on interpreting Synthetic Aperture Radar (SAR) data for recognizing the most active sectors of these phenomena. Starting from the available RADARSAT−1 dataset, we attempt to propose a methodology for the identification of the main morpho-structural domains that characterize these huge phenomena and the definition of different sectors that make up the DsGSDs, which are characterized by different levels of activity. This subdivision is important for linking the different kinematic domains within DsGSDs with the level of attention that should be given to them in the studies that support the request for authorization of new infrastructure. We apply this method to three case studies that represent significant phenomena involving urban areas within the Valle d’Aosta region. In particular, we analyze study areas containing the Cime Bianche DsGSD, the Valtourenenche DsGSD, and the Quart DsGSD. These phenomena have different levels of evolution that are controlled by the interaction of diverse factors, and involve buildings and other infrastructure. This setting has been useful for testing the development of the methodology, which takes advantage of remote-sensing investigations, together with the local geological, geomorphological and structural setting of each case study that we analyzed. This method aims to produce a useful method for delineating guidelines for the building of new infrastructure, in support of the Regional Agency.

The shallow landslides occurrence is strongly correlated with climatic conditions and environmental settings. In the Liguria region (northwestern Italy), the landscape presents an ancient human intervention represented by terraces and, in the last century, by a general overbuilding, both in the few flat areas and in the steep slope hinterland. From the twentieth century, the progressive abandonment of agriculture generated a lack of maintenance of terraced areas, which associated to the urban and the road net development, supported the slope susceptibility to instability. This makes the assessment of the predisposing factors for shallow landslides a multidisciplinary task, combining natural and man-made issues. In this work, we try to define all the main predisposing factors of the Rupinaro catchment (southeast Liguria). We operate starting from a high-resolution Digital Terrain Model (DTM) supplied by an airborne LiDAR survey carried out after the autumn 2014 rainfall events. From this DTM, we mapped a total amount of 96 landslides in the study area. Then, we implemented a classification methodology based on a simple parametric score. In GIS environment we overlaid several layers: i) lithological and hydrogeological map, ii) slope iii) aspect, iv) the land use information, available by the CORINE land cover, and iv) the presence of terraces. Each spatial data was than reclassified according a numerical code. The sum, by raster math, of these factors provided an overall score raster for the entire basin. This method allows the characterization of the entire watershed, gathering all the predisposing factors for the shallow landslides activation. A categorization of the landslides area mapped from the DTM and stored in a vector layer has been made. In particular, we estimated the most frequent code within each landslide polygon, obtaining a representative data of the most influential factors that triggered shallow landslides. The results showed the prevalent occurrence of shallow landslides in correspondence of terraced areas, cultivated by olive grove, with an impervious bedrock, and presenting gently slope and variable exposure from east/west to south. Our approach focuses on the interaction of landslides susceptibility and the land use modifications over time, with more attention over maintenance level of terraces. This methodology represents a starting point for the correct assessment of shallow landslides occurrence factors, capable to generate a susceptibility map of the entire basin, taking in account of the characteristic features of this extremely man-made territory. In order to assess the spatial connectivity of the basin and in addition to highlight the road network and the terraces role in the shallow landslides occurrence, a future comparison of the obtained data with hydrological indexes is planned.

Febrile neutropenia (FN) represents a life-threatening complication in hematological malignancies. Its etiology is most often due to infections even though FN of other origins, such as tumor-related fever and non-infectious inflammation, should rapidly be ruled out. Initially, C-reactive protein and, more recently, procalcitonin (PCT) have been proposed as useful biomarkers for differential diagnosis. PCT was shown to be a good biomarker of bacterial infections and their clinical outcomes. Definition of standard cut-offs and design of PCT-guided treatment protocols remain however to be defined. Areas covered: In this review, highlights on the current clinical use of PCT and its potential role as a diagnostic tool have been discussed by a panel of physicians from different areas of expertise. We provide current clinical evidence that PCT has been shown to be a reliable biomarker to differentiate fever of bacterial origin from other causes. Moreover, the Authors convened to a round-table to discuss their 'real-life experience' and offer their recommendations by a Delphi survey. Expert commentary: PCT has an important clinical role in FN. Issues such as the validation of a specific decision algorithm that includes PCT to monitor antibiotic choice and treatment duration will be addressed in prospective studies.

In eosinophilic granulomatosis with polyangiitis (EGPA) clonally expanded T cells might concur in granuloma formation and vascular injury. The TCR β-variable (BV) chain repertoire and third complementarity determining region (CDR3) of peripheral CD4+ and CD8+ cells in EGPA patients and age-matched controls and the expression of cytokines and chemokine receptors were investigated. The CD8+ lymphocytes of EGPA patients showed an increased frequency of BV expansions with a skewed profile of BV CDR3 lengths, increased CCR5 and CXCR3 expression and increased INFγ and TNFα production. In two patients, the TCR CDR3 cDNA sequences of the expanded BV family were identified. The CD4+ lymphocytes of EGPA patients revealed a higher expression of CRTH2 and increased production of IL-5. In conclusion, CD4+ T cells display a Th2 profile and CD8+ T cells are clonally expanded in EGPA and have a proinflammatory phenotype, suggesting their pathogenic role in vasculitic damage.

Le controle anticipe et le controle en ligne sont les deux facettes du controle predictif, bases sur les modeles internes, qui sont suspectes d’etre impactes dans les troubles des apprentissages. Nous avons examine le controle anticipe dans une tâche bimanuelle de delestage, qui teste la coordination entre la posture du bras qui soutient le poids et le bras manipulateur qui realise le delestage, chez des enfants dyslexiques (DD) et/ou dyspraxiques (DCD), compares a des enfants au developpement typique (TD). Il ressort de cette etude une meilleure stabilisation du bras postural, basee sur une inhibition plus precoce des muscles flechisseurs au cours du delestage volontaire, traduisant ainsi l’anticipation de l’effet destabilisateur du delestage, pour l’ensemble des sujets. En revanche, seul le groupe avec une comorbidite DD/DCD, presente une anticipation des muscles flechisseurs moins precoce que les autres groupes (Cignetti et al., 2018). Ainsi cette tâche permet de reveler que sans contrainte temporelle, tous les enfants sont capables de construire une representation interne de leur action, y compris les enfants DCD. Par ailleurs, lorsque les contraintes temporelles sont tres elevees, comme dans le cas d’un apprentissage moteur en 60 essais, les enfants DCD et DD/DCD presentent des performances moins elevees. La question de la comorbidite, qui est de plus en plus renseignee dans la litterature, permet de nuancer certains resultats anterieurs et devient une veritable question en matiere d’etiologie et de remediation.

Introduction De nombreuses etudes rapportent que la scoliose idiopathique de l’adolescent (SIA) s’accompagne d’un defaut d’integration centrale des informations sensorielles [1] , [2] , [3] , [4] . Methode Afin de mieux comprendre si les processus d’integration proprioceptive sont impactes chez les sujets atteints de SIA, nous avons explore les bases neurales de l’integration proprioceptive en IRMf de stimulation, par vibration tendineuse, chez les enfants et les adolescents au developpement typiques [5] , [6] ainsi que chez 13 adolescents atteints de SIA (Assaiante et al., en preparation). La question principale etait de savoir si les reseaux responsables de l’integration proprioceptive presentent un dysfonctionnement ou un retard de maturation dans le cas de la scoliose. Resultats Il ressort de nos etudes neurodeveloppementales que les cartes d’activation cerebrales consecutives aux vibrations tendineuses rapportent des activations similaires chez les adolescents SIA, les enfants typiques et adolescents typiques, suggerant ainsi que les principaux reseaux impliques dans la construction de la representation du corps sont actifs et preserves. Neanmoins, les adolescents SIA presentent un pattern de connectivite fonctionnelle frontostriatale et frontoparietale plus diffus que les adolescents typiques ainsi qu’une epaisseur corticale des cortex frontaux et parietaux plus importante, rappelant ainsi les caracteristiques des sujets plus jeunes. Discussion/conclusion Plutot qu’un dysfonctionnement, ces resultats semblent etre plus en faveur d’un retard de maturation des reseaux qui contribuent a construire et a reactualiser la representation du corps en action.

Background The Revised- International Prognostic Index (R-IPI), the current standard prognostic tool for patients with diffuse large cell lymphoma (DLBCL), considers only patient and clinical disease characteristics. The role of host immune homeostasis as an independent prognostic indicator in different diseases including DLBCL is evolving. Rambaldi et al 2013, showed that the lymphocyte monocyte ratio (LMR) at diagnosis is a simple prognostic biomarker and independent of the R-IPI. Low level of immunoglobulin at diagnosis, in particular IgG, is associated with inferior survival in Hodgkin and Non Hodgkin lymphoma patients (NHL). In DLBCL patients who underwent autologous transplants, Brown et al 2004 documented 18 months relapse free survival of 44% if IgG levels at time of transplant are below 600 mg/dL and 63% if higher. To our knowledge, the prognostic impact of immunoglobulin levels at diagnosis in patients with aggressive B-NHL has not been investigated. Therefore, we aimed to evaluate the prognostic role of the immunologic profile in terms of the pretreatment levels LMR and of immunoglobulins in patients with aggressive B-NHL. Methods and results: We retrospectively patients diagnosed with aggressive B non-Hodgkin lymphoma (NHL) at both the European Institute of Oncology in Milan and the Mauriziano Hospital in Turin from April 2014 to October 2018. Patients with DLBCL, Burkitt, Mantle cell and follicular G3B lymphomas were eligible. All patients were treated with chemo-immunotherapy according to center guidelines and a written informed consent was obtained from all them. A total of 105 patients were included, with male predominance (60%), median age of 64.5 years (range 20-83) and ECOG score 0-1 in 66%. Stage III-IV disease was seen in 58%, extranodal involvement in 73%, bone marrow infiltration in 26%, bulky disease in 39% and high LDH in 66%. Median IgG level was 1003 (range 436-2236) and the median LMR was 2.4 (range 0.2-44.2). By univariate analysis older age, advanced stage, higher ECOG PS, 2 or more extranodal disease sites, poor R-IPI, higher LDH, low LMR ratio as well as low IgG level at diagnosis was associated with a worse 1-year PFS. LMR inferior or equal to 2.4 had 1-year PFS of 70%, compared to 90% if LMR was higher (p 0.025). Patients with IgG levels less than 1003 had 1-year PFS of 70% compared to 90% in higher IgG levels. The later, didn' t reach statistical significance, due to small number of patients, but remains clinically relevant. Interestingly, there was no correlation between the levels of IgG and the LMR. Therefore, we examined the impact of combining each to R-IPI groups. A low IgG at diagnosis worsen the PFS in patients with good or very good R-IPI with 1 year PFS 83% (95% CI 60-93%) compared 97% (95% CI 79%-100%) if IgG levels are higher. Interestingly, patients in the poor IPI risk group and high IgG levels ad 1-year PFS similar to the good risk group with low IgG levels (PFS 84%, 95% CI 57-94%). The worst PFS is seen in the group of patients with poor IPI score and low IgG, PFS 61%, (95% CI 40%-77%). Similar results were seen in case of LMR. We then examined a novel immunologic prognostic score system that includes the three factors: baselines IGg levels, LMR and the R-IPI Figure 1. Because IgG levels and LMR are independent we put the same weight on each factor as well as the R-IPI score. We gave 1 point to each factor R-IPI poor (1 point) + IgG low (1 point) + LMR low (1 point). The sum of the chosen points correlated with four risk groups: group 1 = 0 points, group =2 = 1 point, group 3= 2 points and group 4= 3 points. The 1 year PFS was 95% (95% CI 68%-99%), 94% (95% CI 77%-98%), 75% (95% CI 54%-87%), 52% (95% CI 27%-73%), respectively. Conclusion: To our knowledge, this study is the first to report the prognostic implications of pretreatment levels of immunoglobulin IgG within the immunologic profile of patients with aggressive B-NHL. Our results suggests that IgG level at diagnosis is a clinically important prognostic factor. With the proposed immunologic score, patients are reclassified into four sub-groups with 3 significantly different 1-year PFS of 95% 75%, 50% in patients with no or one poor risk factor, 2 factors or 3 factors, respectively. This study confirms that the addition of baseline immunologic profile to R-IPI in patients with aggressive B-NHL optimizes their prognostic stratification and better identify patients who are at risk of poor outcome compared to the R-IPI alone. Disclosures Saglio: BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Jansen: Consultancy; Celgene: Consultancy.

Introduction: In the revised 2017 World Health Organization (WHO) classification of lymphoid neoplasms, high-grade B-cell lymphoma with C-MYC and BCL2 or BCL6 rearrangements is classified as Double-Hit lymphoma (DHL), while the term Triple Hit lymphoma (THL) is employed when the three genes are rearranged (Swerdlow SH, et al 2017). Amplification of C-MYC plus BCL2 and/or BCL6 rearrangement or amplification are defined as "atypical DHL and THL" (Li S., et al 2015). We will here collectively refer to DHL and THL as DHL. Both true and atypical DHL are resistant to conventional chemo-immunotherapy and are associated with poorer outcome. The median survival is shorter than 12 months with standard regimens (Snuderl M, et al 2010). The success of intensified chemo-immunotherapy protocols in Burkitt lymphoma, encouraged many Centres to include these regimens in the treatment armamentarium of DHL. Among these protocols, the B-ALL/NHL 2002 of the GMALL multicenter group is an effective and well tolerated regimen in the treatment of Burkitt's lymphoma (Pollen M, et al 2011). We have adopted the GMALL protocol, as our guideline for the treatment of patients with true or atypical DHL. The preliminary experience with the GMALL protocol in 18 patients is here reported. Methods: We retrospectively evaluated patients with true or atypical DHL treated with the GMALL protocol at the European Institute of Oncology in Milan from 2015 and at the Mauriziano Hospital in Turin from 2012. The diagnosis was confirmed according to 2017 WHO classification and immunohistochemistry analysis and fluorescent in situ hybridization were performed in all patients. Patients were treated following the R-GMALL protocol according to their age group with less intensified doses applied to patients older than 55 years. The program was part of the treatment guidelines developed at each Center for the management of lymphoma patients and a written informed consent was obtained from all patients. Results: Eighteen patients were included in this analysis, 14 were true DH and 3 atypical DH and 1 was Burkitt like lymphoma. Five were transformed lymphomas, 4 after follicular and 1 after marginal zone lymphoma. The median age of the whole group was 64 years (range 43-77years). Eleven patients were male (61%), 15 patients (83%) had Ann-Arbor stage IV and 5 (28%) had bone marrow infiltration. Median lymphoma cells proliferation fraction assessed by Ki-67 IHC was 90% (range 70-100%). Patients received a median of 6 courses (range 2-6) of the GMALL schedule, as inpatient therapy. No patients died of infectious complications during chemotherapy. Twelve patients (67%) were in complete metabolic response (CR) at end of treatment and another patient in complete response by CT scan. Of the 5 refractory patients, four have died (3 for lymphoma progression, one due to infectious complications after salvage splenectomy plus RT), one is still alive, under salvage therapy at 7 months from end of treatment. Among 12 patients who achieved CR, 3 relapsed at 7, 10, 16 months from end of treatment, they are presently alive under salvage treatment. At a median follow up of 21.7 month, the median PFS is 21.4 months while median OS is not reached. The two-year PFS and OS rates are 42% and 66%, respectively (figure 1 A & B). PFS was significantly worse in patients with bone marrow infiltration with median PFS of 7 months while not reached in the rest of patients. The median PFS was approximately 17 months for patients older than 55 years (n=13) and not reached for younger patients, with PFS at 2 years of 75%. There was no correlation with transformation, or Ki-67. Conclusion: This study indicates that intensive treatment with B-ALL/NHL 2002 GMALL protocol is effective and well tolerated in true and atypical DHL patients aged up to 77 years. In this preliminary series, the OS resulted superior to that commonly reported with standard chemo-immunotherapies, with median 17-month OS in older patients while median OS is not reached in younger patients. In fact, the results were particularly promising in patients younger than 55 years probably reflecting the proper dose schedule delivery in younger patients. Based on these preliminary results, we are continuing to use the GMALL protocol as upfront therapy in DH lymphoma patients and we are exploring the possibility of improving the therapeutic efficacy by supplementing the GMALL schedule with one of the novel non-chemotherapeutic drugs. Figure 1 Disclosures Derenzini: TG-THERAPEUTICS: Research Funding. Saglio:Celgene: Consultancy; Jansen: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy.

The analyses carried out using 2 different bioinformatics pipelines (SomaticSniper and MuTect) on the same set of genomic data from 133 acute myeloid leukemia (AML) patients, sequenced inside the Cancer Genome Atlas project, gave discrepant results. We subsequently tested these 2 variant-calling pipelines on 20 leukemia samples from our series (19 primary AMLs and 1 secondary AML). By validating many of the predicted somatic variants (variant allele frequencies ranging from 100% to 5%), we observed significantly different calling efficiencies. In particular, despite relatively high specificity, sensitivity was poor in both pipelines resulting in a high rate of false negatives. Our findings raise the possibility that landscapes of AML genomes might be more complex than previously reported and characterized by the presence of hundreds of genes mutated at low variant allele frequency, suggesting that the application of genome sequencing to the clinic requires a careful and critical evaluation. We think that improvements in technology and workflow standardization, through the generation of clear experimental and bioinformatics guidelines, are fundamental to translate the use of next-generation sequencing from research to the clinic and to transform genomic information into better diagnosis and outcomes for the patient.