Management of patients with concomitant acute lymphoblastic leukemia (ALL) and COVID-19 infection is challenging. We describe the clinical history of a 40-year-old male with relapsed B-common ALL who developed Sars-CoV2 prior to treatment initiation with inotuzumab. Since the patient was asymptomatic for COVID-19, the first dose of inotuzumab was administered, followed by remdesivir as prophylaxis. However, a worsening in respiratory findings led to a delay in administering the following doses of inotuzumab. Interestingly, even if the patient did not receive the full inotuzumab cycle, he achieved a complete hematologic remission: furthermore, he spontaneously developed anti-sars-COV2 antibodies. COVID-19 treatment also included convalescent plasma, leading to negativization of the viral load. The patient, after COVID-19 recovery, received a second full cycle of inotuzumab, underwent allogeneic transplantation, and is currently in complete hematologic and molecular remission, in good clinical conditions, five months from allograft. Keywords: acute lymphoblastic leukemia, COVID-19, inotuzumab, remdesevir, convalescent plasma

<p>Urban and sub-urban systems are increasingly exposed to high vulnerability to climate risks with a long-term cascading impact on communities, the physical environment and ecosystems.Cities represent the areas where the world's population is most concentrated (UN World Urbanization Prospects,2018) with major impacts on land use change and reduction of permeable surfaces. This condition increases the level of climate risk for urban areas as it increases the exposure of assets and individuals but also affects the ability of urban systems to respond to extreme weather phenomena.</p> <p>In this framework, Urban Green Infrastructure (UGI) is recognised by international literature and policy as a strategic factor in reducing the vulnerability of urban systems to climate change impacts such as heat island, heat canyon, flooding, runoff. I.G.U., in fact, produce ecosystem services capable of mitigating climate stress phenomena in cities by cooling (shading and evapotranspiration) and controlling runoff.<br />The scientific literature shows that interest in the U.G.I. project has shifted from a predominantly empirical and qualitative approach to an approach that sees the analytical implementation of information as an indispensable support of the project in terms of simulation, monitoring and control of the climate efficiency of infrastructures.</p> <p>In particular, the analytical approach is functional to the "site-specific" and "hazard-specific" condition that characterises the U.G.Is. project. Among the main objects of investigation, the scientific community has long identified ecosystem services as a discriminating factor in assessing the climate efficiency of urban green areas. Recent studies have also made explicit the need to develop methods for the analytical measurement of ecosystem services in order to guide design towards appropriate climate performance thresholds.Starting from the assumption that information is the opposite of uncertainty (Ciribini, 1984), the U.G.I. design process must necessarily take advantage of new knowledge methods aimed at reducing the risk of failure and error, according to a predictive logic that aims to identify the most appropriate solution for a given urban context.</p> <p>Remote sensing is an essential source of information on ecosystems and the state of natural capital for large-scale applications, but in the last two decades, the availability and advent of optical remote sensing and Earth observation data with various spectral, radiometric, spatial and temporal resolutions have increased significantly and constitute a very useful source of data even at the urban and site scale.</p> <p>The paper presents a methodology for using remote sensing in the context of the U.G.I. project and in particular for mapping ecosystem services at the urban district scale.The methodology is tested on a case study chosen in the context of the metropolitan city of Naples and specifically in the eastern area, characterised by a peri-urban condition with strong environmental criticality.</p> <p> </p> <p> </p>

The knowledge of Langerhans Cell Histiocytosis (LCH) is based on pediatric studies. Adults with LCH are usually treated with pediatric protocols. In 2001, guidelines for adults with LCH (GIMEMA LCH 2001) were proposed, in order to standardize the diagnostic and therapeutic approaches for this category of patients. The aims of this retrospective study are: a) to evaluate the role of a multidisciplinary assessment in adults with LCH, according to the GIMEMA LCH 2001 guidelines, and b) to analyze the results obtained with the GIMEMA LCH 2001 guidelines and those obtained with pediatric protocols. Pts aged >18 years with a diagnosis of LCH (S-100+, CD1a+, CD207+) managed at our Institution since 1985 to 2018 were considered. As diagnostic and treatment approaches, two different strategies were used over time: the GIMEMA LCH 2001 guidelines and the pediatric protocols. The GIMEMA LCH 2001 guidelines included a multidisciplinary diagnostic work-up with complete odontostomatologic, pulmonary and endocrinologic assessments; treatment strategy consisted of: wait and see or local therapy in unifocal single system (SS), indomethacin in bone multifocal SS and vinblastine combined with low-dose prednisone (PDN) in multi-system (MS), PDN in pulmonary honey-combing disease (PHCD) and cladribine in central nervous system involvement. DAL-HX 83 and 90, LCH-I and LCH II were the pediatric protocols utilized over time. Response to treatment was defined as complete (CR) or intermediate (IR). Persistence of the symptoms and/or appearance of new lesions were defined no response (NR). Progression was considered the appearance of symptoms and/or new lesions after initial response. One-hundred-thirty-one LCH pts (females 72, males 59) with a median age at diagnosis of 36 years (range 18 - 71) were considered. Median follow up was 43 months (range 12 - 330). One-hundred-seven patients were managed according to the GIMEMA LCH 2001 guidelines, 16 of them previously treated with a pediatric protocol. Pulmonary and/or oral involvements were identified in 31/107 (29%) and 12/107 (11%) patients, respectively, 5/16 (31%) and 3/16 (19%), respectively, of previously treated asymptomatic patients. Ninety-one newly diagnosed patients (median age at diagnosis: 36 years) were treated according to the GIMEMA LCH 2001 guidelines and 40 (median age at diagnosis: 33 years) were managed with pediatric protocols. All patients treated with the GIMEMA LCH 2001 were evaluable for response. In particular, all patients with SS-LCH achieved a response (100%), that was complete in 20/26 (76.9%) unifocal-SS and in 10/14 (71.4%) multifocal-SS. All but one patient with MS-LCH reached a response that was complete in 22/45 (48.9%). Of 6 pts with PHCD, 5 had a IR and one a CR. No pt presented CNS involvement at initial diagnosis. Thirty-nine of 40 pts managed with pediatric protocols were evaluable for response. All 13 pts with SS-LCH had a response that was complete in 6 (46.1%). Among 26 patients with MS-LCH, 3 of them with organ risk involvement achieved a response, that was complete in 1, while among 23 patients without organ risk, 12 (52.2%), 8 (34.8%) and 3 (13%) had a CR, IR and NR, respectively. Overall, 12 patients were lost to follow-up. Disease progression was recorded in 47/95 pts (49.5%) after a median time of 19 months (range: 6-147 months). The progression-free survival at 43 months was significantly better for patients treated according to the GIMEMA LCH 2001 guidelines compared to those managed with pediatric protocols, 67% (IC95% 53.14 - 80.86%) vs 48% (IC95% 31.37 - 64.63%), respectively (p 0.005). Overall, 7 deaths were recorded, 5 in patients treated with the pediatric protocols. The overall survival at 43 months, was similar in patients managed with the GIMEMA LCH 2001 guidelines and in those treated with pediatric protocols (97.9%, CI 95%: 93.75% - 100% and 97.3%, (IC95% 91.96% - 100%). BRAF V600E mutation was found in 13/35 (37%) evaluable cases. No differences in response and outcome between BRAFV600E-mutated patients and those not-mutated were found. Our experience in a large cohort of LCH adults shows that a multidisciplinary approach is useful in identifying organ involvement in adults, including those asymptomatic. This is critical for an adequate treatment. Moreover, guidelines specific for adults with LCH proved efficacy in improving the outcome in this category of patients. Disclosures No relevant conflicts of interest to declare.

Immune thrombocytopenic purpura (ITP) is one of the most common hemorrhagic disorders in childhood, often caused by an acute self-limiting event. However, 30% of these children develop chronic ITP. Identification of the underlying causes in ITP is an important challenge. Inherited thrombocytopenia (IT) is a rare, underdiagnosed disease, included among the chronic platelet disorders. Next-Generation-Sequencing (NGS) could be an efficient way of discovering potential IT-associated mutations in children with chronic ITP. The purpose of this retrospective study was to investigate children with chronic ITP using a targeted NGS, in order to identify IT-associated mutations. Between June 2017 and April 2020, mutational screening by a targeted NGS was performed on 19 children, either with a familial history of IT [4 unrelated patients (pts)], or with chronic ITP (15 pts), after all other causes of thrombocytopenia were excluded. Nineteen relatives were also investigated. This study was carried out in collaboration with the Laboratory of Genetics, IRCCS Burlo Garofolo in Trieste, that developed a targeted NGS method for the simultaneous analysis of 28 IT genes. The cost of the NGS tests were supported by the public healthcare service. We retrospectively divided our cohort of 19 pts, into three subgroups: Group I included 4 unrelated pts with familial IT; Group II consisted of 6 pts with chronic ITP and a clinical history and/or laboratory features associated with familial IT; and, Group III included 9 pts with chronic ITP refractory to several treatments (Table 1). The median age at the initial diagnosis of thrombocytopenia was lower in Group I than in Groups II and III (19/12 years vs 1310/12 years and 9 years, respectively, p=0.33). The median time between the diagnosis of thrombocytopenia, and the time of the study, was shorter in Group I compared to Groups II and III (11.7 months vs 45.3 and 51.7 months, respectively, p=0.16). Median platelet count at the disease onset was lower in Group III than in Groups I and II (21 x 109/L vs 99 x 109/L and 38 x 109/L, respectively, p=0.28). The median MPV values were 12.5 fL, 9.85 fL and 8.8 fL in Groups II, III, and I respectively. Bleeding symptoms requiring treatment were present at diagnosis in 1/6 (16%) and in 5/9 (55%) children of Groups II and III, respectively. Genetic variants, usually detected in IT, were found in heterozygosity in all children in Groups I and II, and in 7/9 (78%) in Group III. Two out of 4, 2/6 and 2/9 children in Groups I, II, and III, respectively, presented ≥2 variants. Among the 4 children of Group I, ANKDR26 variant was found in 2 pts, together with GP1BA and NBEAL2 (pt#1) and TUBB1 (pt#2). ANKDR26 variant was also recorded as a single mutation in their relatives. Two different variants involving GP1BA (c.98T>A and c.515C<T) were detected in the remaining 2 children of Group I and in their relatives. Pt #4 with GP1BA c.515C>T mutation with mild macrothrombocytopenia had relatives with a previous diagnosis of monoallelic Bernard-Souliers syndrome. As shown in table 1, ABCG8, ACTN1, ETV6, GP1BA, MYH9, SLFN14, or WAS variants, found in combination in 2 pts (pt#5, pt#8), were also detected in the children in Group II, as well as, at least one of the relatives (for a total of 7 cases). ABCG5, ABCG8, ETV6, FLNA, GP1BA, NBEAL2, or SLFN14 were found as variants in patients of Group III. The peripheral blood smear evaluation confirmed the diagnosis of grey platelet syndrome with two NBEAL2 mutations in pt #16. SLFN14, as a single variant, was associated with macrothrombocytopenia in one pt (#10). Three pts (#5, #6, #17), with variants of ABCG8 had hypercholesterolemia. In the cohort of pts with chronic ITP, 4 (#12, #13, #14, #15) had relatives with thrombocytopenia, and 2 (#11, #13) had a familial history of hematological malignancies. Segregation analysis in families, and functional studies to evaluate the pathogenic role of the variants reported, are still in progress. The clinical significance of IT-associated mutations in chronic ITP is uncertain, and yet to be clarified. However, our experience has shown that an in-depth clinical history, and accurate peripheral blood smear examinations, are important to better characterize chronic ITP in children. A targeted NGS method for the simultaneous analysis of different IT genes, has demonstrated to be an effective approach to explore in-depth the IT-associated mutations in children with chronic ITP, refractory to treatment. Table 1. Disclosures Giona: Novartis: Research Funding; Takeda: Speakers Bureau; Sanofi Genzyme: Research Funding, Speakers Bureau.

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