Publications by authors named "Andrea Biondi"

358 Publications

ALL blasts drive primary mesenchymal stromal cells to increase asparagine availability during Asparaginase treatment.

Blood Adv 2021 Oct 6. Epub 2021 Oct 6.

University of Parma, Parma, Italy.

Mechanisms underlying the resistance of Acute Lymphoblastic Leukemia (ALL) blasts to L-asparaginase are still incompletely known. Here we demonstrate that human primary bone marrow mesenchymal stromal cells (MSCs) successfully adapt to L-asparaginase and markedly protect leukemic blasts from the enzyme-dependent cytotoxicity through an amino acid trade-off. ALL blasts synthesize and secrete glutamine, thus increasing extracellular glutamine availability for stromal cells. In turn, MSCs use glutamine, either synthesized through Glutamine Synthetase (GS) or imported, to produce asparagine, which is then extruded to sustain asparagine-auxotroph leukemic cells. GS inhibition prevents mesenchymal cells adaptation to L-asparaginase, lowers glutamine secretion by ALL blasts, and markedly hinders the protection exerted by MSCs on leukemic cells. The pro-survival amino acid exchange is hindered by the inhibition or silencing of the asparagine efflux transporter SNAT5, which is induced in mesenchymal cells by ALL blasts. Consistently, primary MSCs from ALL patients express higher levels of SNAT5 (p < 0.05), secrete more asparagine (p < 0.05), and protect leukemic blasts (p < 0.05) better than MSCs isolated from healthy donors. In conclusion, ALL blasts arrange a pro-leukemic amino acid trade-off with bone marrow mesenchymal cells, which depends on GS and SNAT5 and promotes leukemic cell survival during L-asparaginase treatment.
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http://dx.doi.org/10.1182/bloodadvances.2020004041DOI Listing
October 2021

Evidence of Treatment Benefits in Patients with Mucopolysaccharidosis Type I-Hurler in Long-term Follow-up Using a New Magnetic Resonance Imaging Scoring System.

J Pediatr 2021 Sep 20. Epub 2021 Sep 20.

Pediatric Department, Fondazione MBBM, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milano, Italy. Electronic address:

We developed a brain and spine magnetic resonance scoring system based on a magnetic resonance assessment of 9 patients with mucopolysaccharidosis type I-Hurler who underwent hematopoietic stem-cell transplantation. The score is reliable and correlates with long-term clinical and cognitive outcome in patients with mucopolysaccharidosis type I-Hurler.
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http://dx.doi.org/10.1016/j.jpeds.2021.09.020DOI Listing
September 2021

Serum anti-Müllerian hormone as a marker of ovarian reserve after cancer treatment and/or hematopoietic stem cell transplantation in childhood: proposal for a systematic approach to gonadal assessment.

Eur J Endocrinol 2021 Oct 11;185(5):717-728. Epub 2021 Oct 11.

Department of Pediatrics, Università degli Studi di Milano-Bicocca, Fondazione MBBM, Ospedale San Gerardo, Monza, Italy.

Objective: Female patients treated with alkylating agents in childhood are at risk for ovarian impairment. We aimed at describing the pattern of residual ovarian function in a cohort of survivors of hematological malignancies and/or hematopoietic stem cell transplantation (HSCT) and assessing the relationship between cyclophosphamide equivalent dose (CED) and anti-Müllerian hormone (AMH).

Design And Methods: Gonadal health was clinically and biochemically assessed in 124 post-menarchal survivors who underwent treatment for pediatric hematological malignancies and/or HSCT between 1992 and 2019.

Results: Overt 'premature ovarian insufficiency' (POI) was detected in 72.1 and 3.7% of transplanted and non-transplanted patients, respectively; milder 'diminished ovarian reserve' (DOR) in 16.3 and 22.2%. In non-transplanted patients, increasing CED values were associated with lower AMH-SDS (P = 0.04), with the threshold of 7200 g/m2 being the best discriminator between DOR/POI and normal ovarian function (AUC: 0.75 on ROC analysis) and with an observed decrease of 0.14 AMH-SDS for each CED increase of 1 g/m2. In addition, age at diagnosis ≥10 years played a detrimental role on ovarian reserve (P = 0.003). In the HSCT group, irradiation was associated with a statistically significant reduction in AMH-SDS (P = 0.04).

Conclusions: In non-transplanted patients, CED ≥ 7200 mg/m2 was associated with a DOR, while younger age at diagnosis played a protective role on ovarian reserve. As a result of the data collected, we propose a systematic algorithm to assess iatrogenic gonadal impairment in young female patients exposed to chemo-radiotherapy in childhood for hematological disorders.
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http://dx.doi.org/10.1530/EJE-21-0351DOI Listing
October 2021

Wearable devices for seizure detection: Practical experiences and recommendations from the Wearables for Epilepsy And Research (WEAR) International Study Group.

Epilepsia 2021 Oct 22;62(10):2307-2321. Epub 2021 Aug 22.

Department of Neurology and Biomedical Engineering, Mayo Foundation, Rochester, Minnesota, USA.

The Wearables for Epilepsy And Research (WEAR) International Study Group identified a set of methodology standards to guide research on wearable devices for seizure detection. We formed an international consortium of experts from clinical research, engineering, computer science, and data analytics at the beginning of 2020. The study protocols and practical experience acquired during the development of wearable research studies were discussed and analyzed during bi-weekly virtual meetings to highlight commonalities, strengths, and weaknesses, and to formulate recommendations. Seven major essential components of the experimental design were identified, and recommendations were formulated about: (1) description of study aims, (2) policies and agreements, (3) study population, (4) data collection and technical infrastructure, (5) devices, (6) reporting results, and (7) data sharing. Introducing a framework of methodology standards promotes optimal, accurate, and consistent data collection. It also guarantees that studies are generalizable and comparable, and that results can be replicated, validated, and shared.
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http://dx.doi.org/10.1111/epi.17044DOI Listing
October 2021

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19.

Sci Immunol 2021 08;6(62)

Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran.

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such variants ( = 3.5 × 10). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (=2, 5 and 38 years), or moderate (=1, 5 years), severe (=1, 27 years), or critical (=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious variants in the male general population is < 6.5x10 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.
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http://dx.doi.org/10.1126/sciimmunol.abl4348DOI Listing
August 2021

Autoantibodies neutralizing type I IFNs are present in 4% of uninfected individuals over 70 years old and account for 20% of COVID-19 deaths.

Sci Immunol 2021 08;6(62)

Joint Research Unit, Hospices Civils de Lyon-bio Mérieux, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre-Bénite, France; International Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France.

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.
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http://dx.doi.org/10.1126/sciimmunol.abl4340DOI Listing
August 2021

"Growth patterns in children with mucopolysaccharidosis type I-Hurler after hematopoietic stem cell transplantation: Comparison with untreated patients".

Mol Genet Metab Rep 2021 Sep 9;28:100787. Epub 2021 Aug 9.

Department of Pediatrics, Università degli Studi di Milano Bicocca, Fondazione Monza e Brianza per il Bambino e la sua Mamma, Azienda Ospedaliera San Gerardo, Monza, (MB), Italy.

The impact of hematopoietic stem cell transplantation (HSCT) on growth in patients diagnosed with mucopolysaccharidosis I Hurler (MPS-IH) has been historically regarded as unsatisfactory. Nevertheless, the growth patterns recorded in transplanted patients have always been compared to those of healthy children. The objective of this study was to verify the impact of HSCT on MPS-IH long term growth achievements. The auxological data of 15 patients were assessed longitudinally and compared both to the WHO growth centiles for healthy individuals and to recently published curves of untreated MPS-IH children. Despite a progressive decrease after HSCT when estimated with reference to the WHO growth charts, median height SDS showed a progressive and statistically significant increase when comparing the stature recorded at each timepoint in our population to the curves of untreated MPS-IH individuals (from -0.39 SDS at t to +1.35 SDS 5 years after HSCT,   and to +3.67 SDS at the age of 9 years,  ). In conclusion, though not efficient enough to restore a normal growth pattern in MPS-IH patients, we hereby demonstrate that HSCT positively affects growth and provides transplanted patients with a remarkable height gain compared to untreated gender- and age- matched individuals.
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http://dx.doi.org/10.1016/j.ymgmr.2021.100787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361197PMC
September 2021

Maturation signatures of conventional dendritic cell subtypes in COVID-19 suggest direct viral sensing.

Eur J Immunol 2021 Aug 1. Epub 2021 Aug 1.

Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.

Growing evidence suggests that conventional dendritic cells (cDCs) undergo aberrant maturation in COVID-19, which negatively affects T-cell activation. The presence of effector T cells in patients with mild disease and dysfunctional T cells in severely ill patients suggests that adequate T-cell responses limit disease severity. Understanding how cDCs cope with SARS-CoV-2 can help elucidate how protective immune responses are generated. Here, we report that cDC2 subtypes exhibit similar infection-induced gene signatures, with the upregulation of IFN-stimulated genes and IL-6 signaling pathways. Furthermore, comparison of cDCs between patients with severe and mild disease showed severely ill patients to exhibit profound downregulation of genes encoding molecules involved in antigen presentation, such as MHCII, TAP, and costimulatory proteins, whereas we observed the opposite for proinflammatory molecules, such as complement and coagulation factors. Thus, as disease severity increases, cDC2s exhibit enhanced inflammatory properties and lose antigen presentation capacity. Moreover, DC3s showed upregulation of anti-apoptotic genes and accumulated during infection. Direct exposure of cDC2s to the virus in vitro recapitulated the activation profile observed in vivo. Our findings suggest that SARS-CoV-2 interacts directly with cDC2s and implements an efficient immune escape mechanism that correlates with disease severity by downregulating crucial molecules required for T-cell activation.
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http://dx.doi.org/10.1002/eji.202149298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420462PMC
August 2021

Neutralizing type-I interferon autoantibodies are associated with delayed viral clearance and intensive care unit admission in patients with COVID-19.

Immunol Cell Biol 2021 10 8;99(9):917-921. Epub 2021 Aug 8.

Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Type-I interferons (IFNs) mediate antiviral activity and have emerged as important immune mediators during coronavirus disease 19 (COVID-19). Several lines of evidence suggest that impaired type-I IFN signaling may predispose to severe COVID-19. However, the pathophysiologic mechanisms that contribute to illness severity remain unclear. In this study, our goal was to gain insight into how type-I IFNs influence outcomes in patients with COVID-19. To achieve this goal, we compared clinical outcomes between 26 patients with neutralizing type-I IFN autoantibodies (AAbs) and 192 patients without AAbs who were hospitalized for COVID-19 at three Italian hospitals. The presence of circulating AAbs to type-I IFNs was associated with an increased risk of admission to the intensive care unit and a delayed time to viral clearance. However, survival was not adversely affected by the presence of type-I IFN AAbs. Our findings provide further support for the role of type-I IFN AAbs in impairing host antiviral defense and promoting the development of critical COVID-19 pneumonia in severe acute respiratory syndrome coronavirus 2-infected individuals.
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http://dx.doi.org/10.1111/imcb.12495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444766PMC
October 2021

Catch me if you can: how AML and its niche escape immunotherapy.

Leukemia 2021 Jul 23. Epub 2021 Jul 23.

Tettamanti Research Center, Department of Pediatrics, University of Milano-Bicocca/Fondazione MBBM, Monza, Italy.

In spite of the remarkable progress in basic and preclinical studies of acute myeloid leukemia (AML), the five-year survival rate of AML patients remains poor, highlighting the urgent need for novel and synergistic therapies. Over the past decade, increased attention has been focused on identifying suitable immunotherapeutic strategies for AML, and in particular on targeting leukemic cells and their progenitors. However, recent studies have also underlined the important contribution of the leukemic microenvironment in facilitating tumor escape mechanisms leading to disease recurrence. Here, we describe the immunological features of the AML niche, with particular attention to the crosstalk between the AML blasts and the cellular components of the altered tumor microenvironment (TME) and the mechanisms of immune escape that hamper the therapeutic effects of the most advanced treatments. Considering the AML complexity, immunotherapy approaches may benefit from a rational combination of complementary strategies aimed at preventing escape mechanisms without increasing toxicity.
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http://dx.doi.org/10.1038/s41375-021-01350-xDOI Listing
July 2021

Remission, treatment failure, and relapse in pediatric ALL: An international consensus of the Ponte-di-Legno Consortium.

Blood 2021 Jun 30. Epub 2021 Jun 30.

Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, United States.

Comparison of treatment strategies in de novo pediatric acute lymphoblastic leukemia (ALL) requires standardized measures of efficacy. Key parameters that define disease-related events, including 'complete remission' (CR), 'treatment failure' (TF; not achieving CR), and 'relapse' (loss of CR) require an updated consensus incorporating modern diagnostics. We collected the definitions of CR, TF and relapse from recent and current pediatric clinical trials for the treatment of ALL, including the key components of response evaluation (timing, anatomic sites, detection methods, and thresholds), and found significant heterogeneity, most notably in the definition of TF. Representatives of the major international ALL clinical trial groups convened to establish consensus definitions. CR should be defined at a time point no earlier than at the end of induction (EOI), and should include the reduction of blasts below a specific threshold in bone marrow and extramedullary sites, incorporating minimal residual disease (MRD) techniques for marrow evaluations. TF should be defined as failure to achieve CR by a pre-specified time point in therapy. Relapse can only be defined in patients who have achieved CR, and must include a specific threshold of leukemic cells in the bone marrow confirmed by MRD, the detection of central nervous system leukemia, or documentation of extramedullary disease. Definitions of TF and relapse should harmonize with eligibility criteria for clinical trials in relapsed/refractory ALL. These consensus definitions will enhance the ability to compare outcomes across pediatric ALL trials, and facilitate development of future international collaborative trials.
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http://dx.doi.org/10.1182/blood.2021012328DOI Listing
June 2021

COVID-19 in Immunosuppressed Children.

Front Pediatr 2021 29;9:629240. Epub 2021 Apr 29.

Pediatric Hepatology, Gastroenterology and Transplantation Unit, Hospital Papa Giovanni XXIII, Bergamo, Italy.

Following the spread of the SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) to a global pandemic, concerns have arisen for the disease impact in at-risk populations, especially in immunocompromised hosts. On the other hand, clinical studies have clarified that the COVID-19 clinical burden is mostly due to over-inflammation and immune-mediated multiorgan injury. This has led to downsizing the role of immunosuppression as a determinant of outcome, and early reports confirm the hypothesis that patients undergoing immunosuppressive treatments do not have an increased risk of severe COVID-19 with respect to the general population. Intriguingly, SARS-CoV-2 natural reservoirs, such as bats and mice, have evolved mechanisms of tolerance involving selection of genes optimizing viral clearance through interferon type I and III responses and also dampening inflammasome response and cytokine expression. Children exhibit resistance to COVID-19 severe manifestations, and age-related features in innate and adaptive response possibly explaining this difference are discussed. A competent recognition by the innate immune system and controlled pro-inflammatory signaling seem to be the pillars of an effective response and the premise for pathogen clearance in SARS-CoV-2 infection. Immunosuppression-if not associated with other elements of fragility-do not represent an obstacle to this competent/tolerant phenotype in children. Several reports confirm that children receiving immunosuppressive medications have similar clinical involvement and outcomes as the pediatric general population, indicating that maintenance treatments should not be interrupted in suspect or confirmed SARS-CoV-2 infection.
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http://dx.doi.org/10.3389/fped.2021.629240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116542PMC
April 2021

Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis.

Front Immunol 2021 16;12:673487. Epub 2021 Apr 16.

Pediatric Hematology Outpatient Clinic, Department of Pediatrics, Fondazione MBBM, Monza, Italy.

DOCK8 deficiency is a combined immunodeficiency due to biallelic variants in dedicator of cytokinesis 8 () gene. The disease has a wide clinical spectrum encompassing recurrent infections (candidiasis, viral and bacterial infections), virally driven malignancies and immune dysregulatory features, including autoimmune (cytopenia and vasculitis) as well as allergic disorders (eczema, asthma, and food allergy). Hypomorphic function and somatic reversion of has been reported to result in incomplete phenotype without IgE overproduction. Here we describe a case of DOCK8 deficiency in a 8-year-old Caucasian girl. The patient's disease was initially classified as autoimmune thrombocytopenia, which then evolved toward a combined immunodeficiency phenotype with recurrent infections, persistent EBV infection and lymphoproliferation. Two novel variants (one deletion and one premature stop codon) were characterized, resulting in markedly reduced, but not absent, DOCK8 expression. Somatic reversion of the deletion was identified in T cells. Hypomorphic function and somatic reversion were associated with restricted T cell repertoire, decreased STAT5 phosphorylation and impaired immune synapse functioning in T cells. Although the patient presented with incomplete phenotype (absence of markedly increase IgE and eosinophil count), sclerosing cholangitis was incidentally detected, thus indicating that hypomorphic function and somatic reversion of may delay disease progression but do not necessarily prevent from severe complications.
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http://dx.doi.org/10.3389/fimmu.2021.673487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085392PMC
October 2021

Childhood cancer in Italy: background, goals, and achievements of the Italian Paediatric Hematology Oncology Association (AIEOP).

Tumori 2021 Oct 20;107(5):370-375. Epub 2021 Apr 20.

Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Azienda Ospedaliera-Universitaria Città della Salute e della Scienza, University of Torino, Piemonte, Italy.

This article reviews the primary goals and achievements of the Italian Association for Pediatric Hematology-Oncology (Associazione Italiana Ematologia Oncologia Pediatrica [AIEOP]), a national cooperative group that has been working for children and adolescents with cancer in Italy since 1975.
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http://dx.doi.org/10.1177/03008916211007934DOI Listing
October 2021

Beating vs Arrested Heart Isolated Tricuspid Valve Surgery: Long-term Outcomes.

Ann Thorac Surg 2021 Apr 5. Epub 2021 Apr 5.

Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria.

Background: Isolated tricuspid valve (TV) surgery is a rare procedure generally considered at high risk of perioperative mortality and poor long-term outcomes. Surgical treatment can be performed with either an arrested heart (AH) or beating heart (BH) technique. Aim of this study is to compare the outcomes of isolated tricuspid surgery with two different approaches.

Methods: The SUR-TRI study is a multicenter international retrospective study enrolling adult patients who underwent isolated tricuspid valve procedures (n=406, 56±16 years; 56% female) at 13 international sites. AH and BH strategies were performed in 253 and 153 cases, respectively. Propensity score-matched analysis was used to compare groups.

Results: After matching, 129 pairs were obtained and analyzed. The 30-day mortality rate was 6.2 vs 5.0% in the AH and BH groups, respectively (p=0.9). The rates of acute renal failure requiring replacement therapy (3 vs 10%, p=0.02) and stroke (0 vs 1.8%, p=0.08) were numerically higher in the AH group. The 6-year survival rate was 67±6 vs 78±5% in the AH and BH groups, respectively (p=0.18), while freedom from cardiac death was 75±5 vs 84±4% (p=0.21). The six-year composite cardiac endpoint of cardiac death and reoperation rate was 60±9 vs 86±5% (p=0.024) comparing AH-TV replacement and BH-TV repair groups.

Conclusions: Isolated tricuspid valve surgery performed with a beating heart strategy is a safe option and resulted in a trend of increased long-term survival and freedom from reoperation when compared with the standard arrested heart technique. Patients undergoing beating heart valve repair had the best long-term outcome.
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http://dx.doi.org/10.1016/j.athoracsur.2021.03.070DOI Listing
April 2021

Digital semiology and time-evolution pattern of bio-signals in focal onset motor seizures.

Seizure 2021 Apr 17;87:114-120. Epub 2021 Mar 17.

www.radar-cns.org.

Purpose: Focal seizures constitute the most common seizure type and are associated with poor control. One of the major difficulties in detecting focal onset with wearable devices seizures is related to their phenomenological complexity. We aimed at capturing focal onset seizures with motor manifestations with a multimodal wearable device to identify the digital semiology and the evolution pattern of ictal manifestations.

Methods: Participants were asked to wear a multimodal wearable device (IMEC) aimed at seizure detection while admitted to an epilepsy monitoring unit. Seizures were labelled by a neurologist and start and offset time were noted. The signals captured by the device during the seizure window were plotted and a visual inspection was performed for focal motor seizures with impaired awareness and for focal motor aware seizures.

Results: Fifty-three seizures from twelve patients with focal seizures with motor manifestations recorded with the device were visually inspected. Overall, a common pattern presented across focal motor seizures with impaired awareness and it was characterized by early cardiac manifestations followed by motor phenomena and final EDA response. Motor seizures with retained awareness appeared to be characterized by brief motor events not associated with major autonomic manifestations Conclusion: an overall common digital phenotype and time-evolution pattern was demonstrated for focal motor seizures with impaired awareness. The identification of the evolution pattern could more precisely inform the development of highly preforming algorithms opening the possibility to a more precise, and potentially customizable way to optimize focal seizure detection.
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http://dx.doi.org/10.1016/j.seizure.2021.03.013DOI Listing
April 2021

Remote and Long-Term Self-Monitoring of Electroencephalographic and Noninvasive Measurable Variables at Home in Patients With Epilepsy ([email protected]): Protocol for an Observational Study.

JMIR Res Protoc 2021 Mar 19;10(3):e25309. Epub 2021 Mar 19.

Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.

Background: Epileptic seizures are spontaneous events that severely affect the lives of patients due to their recurrence and unpredictability. The integration of new wearable and mobile technologies to collect electroencephalographic (EEG) and extracerebral signals in a portable system might be the solution to prospectively identify times of seizure occurrence or propensity. The performances of several seizure detection devices have been assessed by validated studies, and patient perspectives on wearables have been explored to better match their needs. Despite this, there is a major gap in the literature on long-term, real-life acceptability and performance of mobile technology essential to managing chronic disorders such as epilepsy.

Objective: [email protected] is an observational, nonrandomized, noninterventional study that aims to develop a new feasible procedure that allows people with epilepsy to independently, continuously, and safely acquire noninvasive variables at home. The data collected will be analyzed to develop a general model to predict periods of increased seizure risk.

Methods: A total of 12 adults with a diagnosis of pharmaco-resistant epilepsy and at least 20 seizures per year will be recruited at King's College Hospital, London. Participants will be asked to self-apply an easy and portable EEG recording system (ANT Neuro) to record scalp EEG at home twice daily. From each serial EEG recording, brain network ictogenicity (BNI), a new biomarker of the propensity of the brain to develop seizures, will be extracted. A noninvasive wrist-worn device (Fitbit Charge 3; Fitbit Inc) will be used to collect non-EEG biosignals (heart rate, sleep quality index, and steps), and a smartphone app (Seer app; Seer Medical) will be used to collect data related to seizure occurrence, medication taken, sleep quality, stress, and mood. All data will be collected continuously for 6 months. Standardized questionnaires (the Post-Study System Usability Questionnaire and System Usability Scale) will be completed to assess the acceptability and feasibility of the procedure. BNI, continuous wrist-worn sensor biosignals, and electronic survey data will be correlated with seizure occurrence as reported in the diary to investigate their potential values as biomarkers of seizure risk.

Results: The [email protected] project received funding from Epilepsy Research UK in 2018 and was approved by the Bromley Research Ethics Committee in March 2020. The first participants were enrolled in October 2020, and we expect to publish the first results by the end of 2022.

Conclusions: With the [email protected] study, we aim to take advantage of new advances in remote monitoring technology, including self-applied EEG, to investigate the feasibility of long-term disease self-monitoring. Further, we hope our study will bring new insights into noninvasively collected personalized risk factors of seizure occurrence and seizure propensity that may help to mitigate one of the most difficult aspects of refractory epilepsy: the unpredictability of seizure occurrence.

International Registered Report Identifier (irrid): PRR1-10.2196/25309.
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http://dx.doi.org/10.2196/25309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088854PMC
March 2021

Acute Rheumatic Fever: Where Do We Stand? An Epidemiological Study in Northern Italy.

Front Med (Lausanne) 2021 24;8:621668. Epub 2021 Feb 24.

Department of Pediatrics, Desio Hospital, Azienda Socio Sanitaria Territoriale Monza, Monza, Italy.

Acute rheumatic fever (ARF) is a non-septic complication of group A β-hemolytic streptococcal (GAS) throat infection. Since 1944, ARF diagnosis relies on the Jones criteria, which were periodically revised. The 2015 revision of Jones criteria underlines the importance of knowing the epidemiological status of its own region with updated data. This study aims to describe ARF features in a retrospective cohort retrieved over a 10-year timespan (2009-2018) and to report the annual incidence of ARF among children in the Province of Monza-Brianza, Lombardy, Italy during the same period. This is a multicentric cross-sectional/retrospective study; 70 patients (39 boys) were diagnosed with ARF. The median age at diagnosis was 8.5 years (range, 4-14.2 years). Overall, carditis represented the most reported major Jones criteria followed by arthritis and chorea (40, 27, and 20 cases, respectively). In order to calculate the annual incidence of ARF, only children resident in the Province of Monza-Brianza were included in this part of the analysis. Therefore, 47 patients aged between 5 and 14 years were identified. The median incidence during the study time was 5.7/100,000 (range, 2.8-8.3/100,000). In the Province of Monza-Brianza, we found an incidence rate of ARF among children aged 5-14 years constantly above the threshold of low-risk area as defined in the 2015 revision of Jones criteria. Therefore, the diagnosis of ARF should be based on the moderate-high-risk set of Jones criteria. However, given the burden of secondary prophylaxis, expert opinion is advisable when the diagnosis of ARF is uncertain.
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http://dx.doi.org/10.3389/fmed.2021.621668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943448PMC
February 2021

Monocyte-macrophage polarization and recruitment pathways in the tumour microenvironment of B-cell acute lymphoblastic leukaemia.

Br J Haematol 2021 06 13;193(6):1157-1171. Epub 2021 Mar 13.

Centro Ricerca Tettamanti, Pediatric Dep, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy.

B-cell acute lymphoblastic leukaemia (B-ALL) reprograms the surrounding bone marrow (BM) stroma to create a leukaemia-supportive niche. To elucidate the contribution of immune cells to the leukaemic microenvironment, we investigated the involvement of monocyte/macrophage compartments, as well as several recruitment pathways in B-ALL development. Immunohistochemistry analyses showed that CD68-expressing macrophages were increased in leukaemic BM biopsies, compared to controls and predominantly expressed the M2-like markers CD163 and CD206. Furthermore, the "non-classical" CD14 CD16 monocyte subset, expressing high CX3CR1 levels, was significantly increased in B-ALL patients' peripheral blood. CX3CL1 was shown to be significantly upregulated in leukaemic BM plasma, thus providing an altered migratory pathway possibly guiding NC monocyte recruitment into the BM. Additionally, the monocyte/macrophage chemoattractant chemokine ligand 2 (CCL2) strongly increased in leukaemic BM plasma, possibly because of the interaction of leukaemic cells with mesenchymal stromal cells and vascular cells and due to a stimulatory effect of leukaemia-related inflammatory mediators. C5a, a macrophage chemoattractant and M2-polarizing factor, further appeared to be upregulated in the leukaemic BM, possibly as an effect of PTX3 decrease, that could unleash complement cascade activation. Overall, deregulated monocyte/macrophage compartments are part of the extensive BM microenvironment remodelling at B-ALL diagnosis and could represent valuable targets for novel treatments to be coupled with classical chemotherapy.
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http://dx.doi.org/10.1111/bjh.17330DOI Listing
June 2021

Droplet Digital PCR Improves IG-/TR-based MRD Risk Definition in Childhood B-cell Precursor Acute Lymphoblastic Leukemia.

Hemasphere 2021 Mar 24;5(3):e543. Epub 2021 Feb 24.

Tettamanti Research Centre, Pediatrics, University of Milano-Bicocca, Monza, Italy.

Minimal residual disease (MRD) is the most powerful prognostic factor in pediatric acute lymphoblastic leukemia (ALL). Real-time quantitative polymerase chain reaction (RQ-PCR) represents the gold standard for molecular MRD assessment and risk-based stratification of front-line treatment. In the protocols of the Italian Association of Pediatric Hematology and Oncology (AIEOP) and the Berlin-Frankfurth-Munschen (BFM) group AIEOP-BFM ALL2009 and ALL2017, B-lineage ALL patients with high RQ-PCR-MRD at day+33 and positive at day+78 are defined slow early responders (SERs). Based on results of the AIEOP-BFM ALL2000 study, these patients are treated as high-risk also when positive MRD signal at day +78 is below the lower limit of quantification of RQ-PCR ("positive not-quantifiable," POS-NQ). To assess whether droplet digital polymerase chain reaction (ddPCR) could improve patients' risk definition, we analyzed MRD in 209 pediatric B-lineage ALL cases classified by RQ-PCR as POS-NQ and/or negative (NEG) at days +33 and/or +78 in the AIEOP-BFM ALL2000 trial. ddPCR MRD analysis was performed on 45 samples collected at day +78 from SER patients, who had RQ-PCR MRD ≥ 5.0 × 10 at day+33 and POS-NQ at day+78 and were treated as medium risk (MR). The analysis identified 13 of 45 positive quantifiable cases. Most relapses occurred in this patients' subgroup, while ddPCR NEG or ddPCR-POS-NQ patients had a significantly better outcome ( < 0.001). Overall, in 112 MR cases and 52 standard-risk patients, MRD negativity and POS-NQ were confirmed by the ddPCR analysis except for a minority of cases, for whom no differences in outcome were registered. These data indicate that ddPCR is more accurate than RQ-PCR in the measurement of MRD, particularly in late follow-up time points, and may thus allow improving patients' stratification in ALL protocols.
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http://dx.doi.org/10.1097/HS9.0000000000000543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909459PMC
March 2021

Helmet CPAP to treat hypoxic pneumonia outside the ICU: an observational study during the COVID-19 outbreak.

Crit Care 2021 02 24;25(1):80. Epub 2021 Feb 24.

ASST Monza, San Gerardo Hospital, Monza, Italy.

Background: Respiratory failure due to COVID-19 pneumonia is associated with high mortality and may overwhelm health care systems, due to the surge of patients requiring advanced respiratory support. Shortage of intensive care unit (ICU) beds required many patients to be treated outside the ICU despite severe gas exchange impairment. Helmet is an effective interface to provide continuous positive airway pressure (CPAP) noninvasively. We report data about the usefulness of helmet CPAP during pandemic, either as treatment, a bridge to intubation or a rescue therapy for patients with care limitations (DNI).

Methods: In this observational study we collected data regarding patients failing standard oxygen therapy (i.e., non-rebreathing mask) due to COVID-19 pneumonia treated with a free flow helmet CPAP system. Patients' data were recorded before, at initiation of CPAP treatment and once a day, thereafter. CPAP failure was defined as a composite outcome of intubation or death.

Results: A total of 306 patients were included; 42% were deemed as DNI. Helmet CPAP treatment was successful in 69% of the full treatment and 28% of the DNI patients (P < 0.001). With helmet CPAP, PaO/FiO ratio doubled from about 100 to 200 mmHg (P < 0.001); respiratory rate decreased from 28 [22-32] to 24 [20-29] breaths per minute, P < 0.001). C-reactive protein, time to oxygen mask failure, age, PaO/FiO during CPAP, number of comorbidities were independently associated with CPAP failure. Helmet CPAP was maintained for 6 [3-9] days, almost continuously during the first two days. None of the full treatment patients died before intubation in the wards.

Conclusions: Helmet CPAP treatment is feasible for several days outside the ICU, despite persistent impairment in gas exchange. It was used, without escalating to intubation, in the majority of full treatment patients after standard oxygen therapy failed. DNI patients could benefit from helmet CPAP as rescue therapy to improve survival.

Trial Registration: NCT04424992.
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http://dx.doi.org/10.1186/s13054-021-03502-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903369PMC
February 2021

Therapeutic afucosylated monoclonal antibody and bispecific T-cell engagers for T-cell acute lymphoblastic leukemia.

J Immunother Cancer 2021 02;9(2)

Department of Medical and Surgical Sciences, Pediatric Unit, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a poor cure rate for relapsed/resistant patients. Due to the lack of T-cell restricted targetable antigens, effective immune-therapeutics are not presently available and the treatment of chemo-refractory T-ALL is still an unmet clinical need. To develop novel immune-therapy for T-ALL, we generated an afucosylated monoclonal antibody (mAb) (ahuUMG1) and two different bispecific T-cell engagers (BTCEs) against UMG1, a unique CD43-epitope highly and selectively expressed by T-ALL cells from pediatric and adult patients.

Methods: UMG1 expression was assessed by immunohistochemistry (IHC) on a wide panel of normal tissue microarrays (TMAs), and by flow cytometry on healthy peripheral blood/bone marrow-derived cells, on 10 different T-ALL cell lines, and on 110 T-ALL primary patient-derived cells. CD43-UMG1 binding site was defined through a peptide microarray scanning. ahuUMG1 was generated by Genetic Glyco-Engineering technology from a novel humanized mAb directed against UMG1 (huUMG1). BTCEs were generated as IgG1-(scFv) constructs with bivalent (2+2) or monovalent (2+1) CD3ε arms. Antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP) and redirected T-cell cytotoxicity assays were analysed by flow cytometry. In vivo antitumor activity of ahUMG1 and UMG1-BTCEs was investigated in NSG mice against subcutaneous and orthotopic xenografts of human T-ALL.

Results: Among 110 T-ALL patient-derived samples, 53 (48.1%) stained positive (24% of TI/TII, 82% of TIII and 42.8% of TIV). Importantly, no expression of UMG1-epitope was found in normal tissues/cells, excluding cortical thymocytes and a minority (<5%) of peripheral blood T lymphocytes. ahUMG1 induced strong ADCC and ADCP on T-ALL cells in vitro, which translated in antitumor activity in vivo and significantly extended survival of treated mice. Both UMG1-BTCEs demonstrated highly effective killing activity against T-ALL cells in vitro. We demonstrated that this effect was specifically exerted by engaged activated T cells. Moreover, UMG1-BTCEs effectively antagonized tumor growth at concentrations >2 log lower as compared with ahuUMG1, with significant mice survival advantage in different T-ALL models in vivo.

Conclusion: Altogether our findings, including the safe UMG1-epitope expression profile, provide a framework for the clinical development of these innovative immune-therapeutics for this still orphan disease.
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http://dx.doi.org/10.1136/jitc-2020-002026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893666PMC
February 2021

Prenatal Origin of Pediatric Leukemia: Lessons From Hematopoietic Development.

Front Cell Dev Biol 2020 12;8:618164. Epub 2021 Jan 12.

School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.

Several lines of evidence suggest that childhood leukemia, the most common cancer in young age, originates during development. However, our knowledge of the cellular origin of this large and heterogeneous group of malignancies is still incomplete. The identification and characterization of their cell of origin is of crucial importance in order to define the processes that initiate and sustain disease progression, to refine faithful animal models and to identify novel therapeutic approaches. During embryogenesis, hematopoiesis takes place at different anatomical sites in sequential waves, and occurs in both a hematopoietic stem cell (HSC)-dependent and a HSC-independent fashion. Despite the recently described relevance and complexity of HSC-independent hematopoiesis, few studies have so far investigated its potential involvement in leukemogenesis. Here, we review the current knowledge on prenatal origin of leukemias in the context of recent insights in developmental hematopoiesis.
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http://dx.doi.org/10.3389/fcell.2020.618164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835397PMC
January 2021

More than an 'atypical' phenotype: dual molecular diagnosis of autoimmune lymphoproliferative syndrome and Becker muscular dystrophy.

Br J Haematol 2020 10 19;191(2):291-294. Epub 2020 Jul 19.

Pediatric Hematology Department, Fondazione MBBM, University of Milano Bicocca, Monza, Italy.

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http://dx.doi.org/10.1111/bjh.16967DOI Listing
October 2020

Clinical Implications of Minimal Residual Disease Detection in Infants With -Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol.

J Clin Oncol 2021 02 6;39(6):652-662. Epub 2021 Jan 6.

Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

Purpose: Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with -rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide).

Materials And Methods: MRD was measured in 249 infants by DNA-based polymerase chain reaction of rearranged , immunoglobulin, and/or T-cell receptor genes, at the end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate (< 5 × 10), and high (≥ 5 × 10).

Results: EOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively ( = .0039). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2% (95% CI, 55.2 to 78.1), 40.1% (95% CI, 28.1 to 51.9), and 11.9% (95% CI, 2.6 to 29.1) for infants with negative, intermediate, and high EOC MRD levels, respectively ( < .0001). Analysis of EOI MRD according to the type of consolidation treatment showed that infants treated with lymphoid-style consolidation had 6-year DFS of 78.2% (95% CI, 51.4 to 91.3), 47.2% (95% CI, 33.0 to 60.1), and 23.2% (95% CI, 12.1 to 36.4) for negative, intermediate, and high MRD levels, respectively ( < .0001), while for myeloid-style-treated patients the corresponding figures were 45.0% (95% CI, 23.9 to 64.1), 41.3% (95% CI, 23.2 to 58.5), and 45.9% (95% CI, 29.4 to 60.9).

Conclusion: This study provides support for the idea that induction therapy selects patients for subsequent therapy; infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9% 23.2%), whereas patients with low EOI MRD may benefit from ALL-like consolidation (DFS 78.2% 45.0%). Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol.
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http://dx.doi.org/10.1200/JCO.20.02333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196086PMC
February 2021

Dexamethasone Stimulation Test in the Diagnostic Work-Up of Growth Hormone Deficiency in Childhood: Clinical Value and Comparison With Insulin-Induced Hypoglycemia.

Front Endocrinol (Lausanne) 2020 9;11:599302. Epub 2020 Dec 9.

Department of Pediatrics, Università degli studi di Milano-Bicocca, Fondazione MBBM, San Gerardo Hospital, Monza, Italy.

Context: dexamethasone has been demonstrated to elicit GH secretion in adults, but few data are available about its effectiveness as a provocative in the diagnostic work-up of GH deficiency (GHD) in childhood.

Objective: to assess the clinical value of dexamethasone stimulation test (DST) as a diagnostic tool for pediatric GHD.

Design And Setting: retrospective single-center analysis. The study population included 166 patients with a pathological response to arginine stimulation test (AST, first-line test) and subsequently tested with either insulin tolerance test (ITT) or DST as a second-line investigation between 2008 and 2019.

Main Outcome Measures: comparison between GH peaks and secretory curves induced by ITT and DST; degree of agreement between DST and AST ITT and AST.

Results: the pathological response to AST (GH peak < 8 ng/mL) was confirmed by an ITT in 80.2% (89/111) of patients and by a DST in 76.4% (42/55), with no statistical difference between the two groups ( value 0.69). Mean GH peaks achieved after ITT and DST were entirely comparable (6.59 ± 3.59 6.50 ± 4.09 ng/ml, respectively, 0.97) and statistically higher than those elicited by arginine ( < 0.01 for both), irrespectively of the average GH peaks recorded for each patient (Bland-Altman method). Dexamethasone elicited a longer lasting and later secretory response than AST and ITT. No side effects were recorded after DST.

Conclusions: DST and ITT confirmed GHD in a superimposable percentage of patients with a pathological first-line test. DST and ITT share a similar secretagogue potency, overall greater than AST.
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http://dx.doi.org/10.3389/fendo.2020.599302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757782PMC
June 2021

Outcomes of paediatric patients with B-cell acute lymphocytic leukaemia with ABL-class fusion in the pre-tyrosine-kinase inhibitor era: a multicentre, retrospective, cohort study.

Lancet Haematol 2021 Jan 22;8(1):e55-e66. Epub 2020 Dec 22.

Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands. Electronic address:

Background: ABL-class fusion genes other than BCR-ABL1 have been identified in approximately 3% of children with newly diagnosed acute lymphocytic leukaemia, and studies suggest that leukaemic cells carrying ABL-class fusions can be targeted successfully by tyrosine-kinase inhibitors. We aimed to establish the baseline characteristics and outcomes of paediatric patients with ABL-class fusion B-cell acute lymphocytic leukaemia in the pre-tyrosine-kinase inhibitor era.

Methods: This multicentre, retrospective, cohort study included paediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion (ABL1 fusion-positive, ABL2 fusion-positive, CSF1R fusion-positive, and PDGFRB fusion-positive) B-cell acute lymphocytic leukaemia enrolled in clinical trials of multidrug chemotherapy done between Oct 3, 2000, and Aug 28, 2018, in which tyrosine-kinase inhibitors had not been given as a first-line treatment. Patients from 14 European, North American, and Asia-Pacific study groups of the Ponte di Legno group were included. No patients were excluded, and patients were followed up by individual study groups. Through the Ponte di Legno group, we collected data on the baseline characteristics of patients, including IKZF1, PAX5, and CDKN2A/B deletion status, and whether haematopoietic stem cell transplantation (HSCT) had been done, as well as treatment outcomes, including complete remission, no response, relapse, early death, and treatment-related mortality, response to prednisone, and minimal residual disease (MRD) at end of induction therapy. 5-year event-free survival and 5-year overall survival were estimated by use of Kaplan-Meier methods, and the 5-year cumulative incidence of relapse was calculated by use of a competing risk model.

Findings: We identified 122 paediatric patients with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukaemia (77 from European study groups, 25 from North American study groups, and 20 from Asia-Pacific study groups). 64 (52%) of 122 patients were PDGFRB fusion-positive, 40 (33%) were ABL1 fusion-positive, ten (8%) were CSF1R fusion-positive, and eight (7%) were ABL2 fusion-positive. In all 122 patients, 5-year event-free survival was 59·1% (95% CI 50·5-69·1), 5-year overall survival was 76·1% (68·6-84·5), and the 5-year cumulative incidence of relapse was 31·0% (95% CI 22·4-40·1). MRD at the end of induction therapy was high (≥10 cells) in 61 (66%) of 93 patients, and most prevalent in patients with ABL2 fusions (six [86%] of 7 patients) and PDGFRB fusion-positive B-cell acute lymphocytic leukaemia (43 [88%] of 49 patients). MRD at the end of induction therapy of 10 cells or more was predictive of an unfavourable outcome (hazard ratio of event-free survival in patients with a MRD of ≥10vs those with a MRD of <10 3·33 [95% CI 1·46-7·56], p=0·0039). Of the 36 (30%) of 119 patients who relapsed, 25 (69%) relapsed within 3 years of diagnosis. The 5-year cumulative incidence of relapse in 41 patients who underwent HSCT (17·8% [95% CI 7·7-31·3]) was lower than in the 43 patients who did not undergo HSCT (45·1% [28·4-60·5], p=0·013), but event-free survival and overall survival did not differ between these two groups.

Interpretation: Children with ABL-class fusion B-cell acute lymphocytic leukaemia have poor outcomes when treated with regimens that do not contain a tyrosine-kinase inhibitor, despite the use of high-risk chemotherapy regimens and frequent HSCT upon first remission. Our findings provide a reference for evaluating the potential benefit of first-line tyrosine-kinase inhibitor treatment in patients with ABL-class fusion B-cell acute lymphocytic leukaemia.

Funding: The Oncode Institute, Pediatric Cancer Foundation Rotterdam, Dutch Cancer Society, Kika Foundation, Deutsche Krebshilfe, Blood Cancer UK, Associazione Italiana per la Ricerca sul Cancro, Cancer Australia, National Cancer Institute, National Institute of Health, and St Baldrick's Foundation.
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http://dx.doi.org/10.1016/S2352-3026(20)30353-7DOI Listing
January 2021

Remote Assessment of Disease and Relapse in Epilepsy: Protocol for a Multicenter Prospective Cohort Study.

JMIR Res Protoc 2020 Dec 16;9(12):e21840. Epub 2020 Dec 16.

Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.

Background: In recent years, a growing body of literature has highlighted the role of wearable and mobile remote measurement technology (RMT) applied to seizure detection in hospital settings, whereas more limited evidence has been produced in the community setting. In clinical practice, seizure assessment typically relies on self-report, which is known to be highly unreliable. Moreover, most people with epilepsy self-identify factors that lead to increased seizure likelihood, including mood, behavior, sleep pattern, and cognitive alterations, all of which are amenable to measurement via multiparametric RMT.

Objective: The primary aim of this multicenter prospective cohort study is to assess the usability, feasibility, and acceptability of RMT in the community setting. In addition, this study aims to determine whether multiparametric RMT collected in populations with epilepsy can prospectively estimate variations in seizure occurrence and other outcomes, including seizure frequency, quality of life, and comorbidities.

Methods: People with a diagnosis of pharmacoresistant epilepsy will be recruited in London, United Kingdom, and Freiburg, Germany. Participants will be asked to wear a wrist-worn device and download ad hoc apps developed on their smartphones. The apps will be used to collect data related to sleep, physical activity, stress, mood, social interaction, speech patterns, and cognitive function, both passively from existing smartphone sensors (passive remote measurement technology [pRMT]) and actively via questionnaires, tasks, and assessments (active remote measurement technology [aRMT]). Data will be collected continuously for 6 months and streamed to the Remote Assessment of Disease and Relapse-base (RADAR-base) server.

Results: The RADAR Central Nervous System project received funding in 2015 from the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement No. 115902. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and European Federation of Pharmaceutical Industries and Associations. Ethical approval was obtained in London from the Bromley Research Ethics Committee (research ethics committee reference: 19/LO/1884) in January 2020. The first participant was enrolled on September 30, 2020. Data will be collected until September 30, 2021. The results are expected to be published at the beginning of 2022.

Conclusions: RADAR Epilepsy aims at developing a framework of continuous data collection intended to identify ictal and preictal states through the use of aRMT and pRMT in the real-life environment. The study was specifically designed to evaluate the clinical usefulness of the data collected via new technologies and compliance, technology acceptability, and usability for patients. These are key aspects to successful adoption and implementation of RMT as a new way to measure and manage long-term disorders.

International Registered Report Identifier (irrid): PRR1-10.2196/21840.
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http://dx.doi.org/10.2196/21840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773514PMC
December 2020

An immune-based biomarker signature is associated with mortality in COVID-19 patients.

JCI Insight 2021 01 11;6(1). Epub 2021 Jan 11.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.

Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients' first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.
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http://dx.doi.org/10.1172/jci.insight.144455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821609PMC
January 2021
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