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OBJECTIVE: We aimed to evaluate epidemiology, seizure type, EEG, and etiology of neonatal seizures (NS) in a tertiary neonatal intensive care unit. METHODS: Data on infants with a neurophysiological confirmation of NS were collected between 2009 and 2022. Seizure types and epileptic syndromes were classified by the ILAE classification and EEG by the Italian Neonatal Seizure Collaborative Network (INNESCO) score. RESULTS: Out of 91,253 neonates, 145 presented with NS; 69.7 % were born at term and 30.3 % were preterm infants. The incidence of NS in neonates born at our center was 1.2 per 1,000 live newborns (96/80697 neonates) while in the entire neonatal population admitted to our center it was 1.6 per 1,000 live births, increasing with lower preterm age. Compared to previous studies, we found a lower proportion of hypoxic-ischemic encephalopathy (HIE) (23.4 %) and a higher rate of genetic contribution (26.2 %). The infection rate was higher in preterm (31.8 %) than in full term (9.9 %) infants. Electrographic seizures were associated with acute provoked seizures (35.9 %), preterm age (52.3 %), and HIE (52.9 %). Vascular etiology was associated with focal clonic seizures (56.8 %). Non-structural neonatal genetic epilepsy was associated with sequential seizures (68.2 %), particularly KCNQ2 and SCN2A epilepsy. Background EEG was abnormal in all HIE, infections (85.7 %) and metabolic NS (83.3 %). In genetic epilepsy, background EEG depended on the epileptic syndrome: normal in 80 % of self-limited neonatal epilepsy and abnormal in 77.8 % of developmental and epileptic encephalopathy. Electroclinical seizures were associated with focal onset, while electrographic seizures correlated with a multifocal onset. CONCLUSIONS: A low incidence of HIE and a high incidence of genetic etiology were observed in our cohort of NS. Seizure type and EEG features are fundamental to address etiology.
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Retinopathy of prematurity (ROP) is a vasoproliferative retinal disease in preterm infants. Oxidative stress plays a key role in the pathogenesis of ROP. Due to its antioxidant effects, bilirubin has been proposed to be protective against ROP. This study explored the association between hyperbilirubinemia and ROP. We analyzed a 10-year cohort from a neonatal intensive care unit in Milan, Italy, including 1606 infants born under 32 weeks and/or < 1500 g. Data from 1606 infants meeting specific inclusion criteria were reviewed. Eighty infants were excluded due to lack of data, 1526 were deemed eligible for analysis, and 1269 had hyperbilirubinemia requiring phototherapy. There was a higher incidence of ROP among infants with hyperbilirubinemia (13.8%) versus those without (7.8%, p<0.01). Infants with any ROP, non-severe or severe ROP, were exposed to hyperbilirubinemia for a significantly higher number of days compared with those without ROP. Each additional day of exposure increases the risk of developing any ROP by 5%, non-severe ROP by 4%, and severe ROP by 6%. However, this correlation was not observed in infants with gestational age less than 27 weeks and/or body weight less than 1000 g. Conclusion: Our data show that hyperbilirubinemia requiring phototherapy is associated with an increased risk of developing ROP. However, severe hyperbilirubinemia and ROP share many of their risk factors. Therefore, rather than being a risk factor itself, hyperbilirubinemia may be a surrogate for other risk factors for ROP. Clinical Trial Registration: NCT05806684. What is Known: ⢠The development of retinopathy of prematurity (ROP) is influenced by several critical risk factors, including low gestational age, low birth weight, supplemental oxygen use, and increased oxidative stress. ⢠In vitro, unconjugated bilirubin is an effective scavenger of harmful oxygen species and a reducing agent, highlighting its potential protective role against oxidative stress. What is New: ⢠Hyperbilirubinemia requiring phototherapy was associated with an increased risk of developing ROP, but this association was not observed in the most vulnerable population of extremely preterm infants. ⢠Every additional day of phototherapy for hyperbilirubinemia increases the risk of ROP by 5% for any ROP, 4% for non-severe ROP, and 6% for severe ROP.
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Retinopatia da Prematuridade , Humanos , Retinopatia da Prematuridade/epidemiologia , Retinopatia da Prematuridade/etiologia , Retinopatia da Prematuridade/sangue , Recém-Nascido , Estudos Retrospectivos , Masculino , Feminino , Itália/epidemiologia , Fatores de Risco , Recém-Nascido Prematuro , Fototerapia/métodos , Incidência , Hiperbilirrubinemia Neonatal/terapia , Hiperbilirrubinemia Neonatal/etiologia , Hiperbilirrubinemia Neonatal/epidemiologia , Idade Gestacional , Unidades de Terapia Intensiva NeonatalRESUMO
BACKGROUND: The prognostic relevance of fetal/early postnatal magnetic resonance (MR) imaging (MRI) isolated "minor" lesions in congenital cytomegalovirus (CMV) infection is still unclear, because of the heterogeneity of previously reported case series. The aim of this study was to report the imaging and long-term clinical follow-up data on a relatively large cohort of infected fetuses. METHODS: Among 140 CMV-infected fetuses from a single-center 12-year-long fetal MRI database, cases that showed isolated "minor" lesions at MRI, mainly represented by polar temporal lesions, were selected. MRI features were described, and clinical follow-up information was collected through consultation of medical records and telephone interview to establish the auditory and neurological outcome of each patient. RESULTS: Thirty-six cases were included in the study. The frequency of "minor" lesions increased progressively with ongoing gestational age in cases who underwent serial MR examination; 31% of cases were symptomatic at birth for unilateral altered auditory brainstem response. At long-term clinical follow-up, performed in 35 patients at a mean age of 64.5 months (range: 25 to 138), 43% of patients were asymptomatic and 57% presented with mild/moderate disability including hearing loss (34%), unilateral in all cases but one (therefore classified as severe), and/or minor cognitive and behavioral disorders (49%). CONCLUSIONS: Descriptive analysis of the type and modality of occurrence of "minor" lesions suggests performing serial fetal/postnatal MR examinations not to miss later-onset lesions. Follow-up data from the present cohort, combined with maternal/fetal factors and serologic-laboratory parameters may contribute to improve prenatal and neonatal period counselling skills.
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Infecções por Citomegalovirus , Imageamento por Ressonância Magnética , Humanos , Infecções por Citomegalovirus/diagnóstico por imagem , Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/complicações , Feminino , Gravidez , Masculino , Lactente , Pré-Escolar , Seguimentos , Recém-Nascido , Criança , Encéfalo/diagnóstico por imagem , Diagnóstico Pré-NatalRESUMO
BACKGROUND: Non-polio enteroviruses (EV) and human parechoviruses (HPeV) are known etiological agents of meningoencephalitis in neonates. However, reports of neuroradiological findings and neurodevelopmental outcomes in this population are scarce. OBJECTIVES: to describe clinical characteristics, neuroradiological findings and, in a subset of patients, neurodevelopmental outcomes in a cohort of infants with EV or HPeV meningoencephalitis within 60 days of life. STUDY DESIGN: clinical/laboratory data, neuroradiological findings (cranial ultrasound, cUS, brain magnetic resonance imaging, MRI), and neurodevelopmental outcomes assessed by Ages and Stages Questionnaires - third edition were prospectively collected. RESULTS: overall, 32 infants with EV (21, 67.8 %) or HPeV (11, 28.2 %) meningoencephalitis were enrolled. Infants with HPeV (73 %: type 3 HPeV) presented more frequently with seizures (18.2 % vs. 0, p value=0.03), lymphopenia (1120 vs. 2170 cells/mm3, p = 0.02), focal anomalies at electroencephalography (EEG) (63.6 vs. 23.8 %, p = 0.03), and pathological findings at MRI (72.7 % vs. 15.8 %, p value=0.004) compared to those affected by EV. cUS was not significantly altered in any of the enrolled infants. All infants with EV meningoencephalitis evaluated at 12-24 months and at 30-48 months were normal. Two out of the 7 infants with HPeV meningoencephalitis showed some concerns in gross motor (1/7, 14.3 %) or in problem solving (1/7, 14.3 %) function at 30-48 months of age. CONCLUSIONS: In our cohort, neonates infected by HPeV had more severe clinical manifestations, more alterations at brain MRI, and some signs of long-term neurodevelopmental delay. Our data highlight the heterogeneity of manifestations in infants with EV or HPeV meningoencephalitis, and the need for long-term follow-up of those infected by HPeV in the neonatal period.
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Infecções por Enterovirus , Enterovirus , Unidades de Terapia Intensiva Neonatal , Imageamento por Ressonância Magnética , Meningoencefalite , Parechovirus , Infecções por Picornaviridae , Humanos , Meningoencefalite/virologia , Meningoencefalite/diagnóstico por imagem , Estudos Prospectivos , Infecções por Picornaviridae/patologia , Infecções por Picornaviridae/virologia , Infecções por Enterovirus/virologia , Infecções por Enterovirus/patologia , Masculino , Recém-Nascido , Enterovirus/isolamento & purificação , Feminino , Lactente , Eletroencefalografia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/virologiaRESUMO
A retrospective survey was conducted in hematologic centres of the Rete Ematologica Lombarda (REL) on 529 older AML patients seen between 2020-2022. Compared to 2008-2016, the use of intensive chemotherapy (ICT) decreased from 40% to 18.1% and of hypomethylating agents (HMAs) from 19.5% to 13%, whereas the combination of Venetoclax/HMA, initially not available, increased from 0% to 36.7%. Objective treatment-specific fitness criteria proposed by SIE/SIES/GITMO in 2013 allow an appropriate choice between ICT and HMAs by balancing their efficacy and toxicity. Venetoclax/HMA, registered for patients unfit to ICT, has a unique toxicity profile because of prolonged granulocytopenia and increased infectious risk. Aiming at defining specific fitness criteria for the safe use of Venetoclax/HMA, a preliminary investigation was conducted among expert REL hematologists, asking for modifications of SIE/SIES/GITMO criteria they used to select candidates for Venetoclax/HMA. While opinions among experts varied, a general consensus emerged on restricting SIE/SIES/GITMO criteria for ICT-unfit patients to an age limit of 80-85, cardiac function > 40%, and absence of recurrent lung infections, bronchiectasis, or exacerbating COPD. Also, the presence of an adequate caregiver was considered mandatory. Such expert opinions may be clinically useful and may be considered when treatment-specific fitness criteria are updated to include Venetoclax/HMA.
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BACKGROUND: The SafeBoosC project aims to test the clinical value of non-invasive cerebral oximetry by near-infrared spectroscopy in newborn infants. The purpose is to establish whether cerebral oximetry can be used to save newborn infants' lives and brains or not. Newborns contribute heavily to total childhood mortality and neonatal brain damage is the cause of a large part of handicaps such as cerebral palsy. The objective of the SafeBoosC-IIIv trial is to evaluate the benefits and harms of cerebral oximetry added to usual care versus usual care in mechanically ventilated newborns. METHODS/DESIGN: SafeBoosC-IIIv is an investigator-initiated, multinational, randomised, pragmatic phase-III clinical trial. The inclusion criteria will be newborns with a gestational age more than 28 + 0 weeks, postnatal age less than 28 days, predicted to require mechanical ventilation for at least 24 h, and prior informed consent from the parents or deferred consent or absence of opt-out. The exclusion criteria will be no available cerebral oximeter, suspicion of or confirmed brain injury or disorder, or congenital heart disease likely to require surgery. A total of 3000 participants will be randomised in 60 neonatal intensive care units from 16 countries, in a 1:1 allocation ratio to cerebral oximetry versus usual care. Participants in the cerebral oximetry group will undergo cerebral oximetry monitoring during mechanical ventilation in the neonatal intensive care unit for as long as deemed useful by the treating physician or until 28 days of life. The participants in the cerebral oximetry group will be treated according to the SafeBoosC treatment guideline. Participants in the usual care group will not receive cerebral oximetry and will receive usual care. We use two co-primary outcomes: (1) a composite of death from any cause or moderate to severe neurodevelopmental disability at 2 years of corrected age and (2) the non-verbal cognitive score of the Parent Report of Children's Abilities-Revised (PARCA-R) at 2 years of corrected age. DISCUSSION: There is need for a randomised clinical trial to evaluate cerebral oximetry added to usual care versus usual care in mechanically ventilated newborns. TRIAL REGISTRATION: The protocol is registered at www. CLINICALTRIALS: gov (NCT05907317; registered 18 June 2023).
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Oximetria , Respiração Artificial , Lactente , Criança , Recém-Nascido , Humanos , Oximetria/métodos , Respiração Artificial/efeitos adversos , Circulação Cerebrovascular , Encéfalo , Unidades de Terapia Intensiva Neonatal , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Significance: Critically ill newborns are at risk of brain damage from cerebrovascular disturbances. A cerebral hemodynamic monitoring system would have the potential role to guide targeted intervention. Aim: To obtain, in a population of newborn infants, simultaneous near-infrared spectroscopy (NIRS)-based estimates of cerebral tissue oxygen saturation (StO2) and blood flow during variations of carbon dioxide tension (pCO2) levels within physiologic values up to moderate permissive hypercapnia, and to examine if the derived estimate of metabolic rate of oxygen would stay constant, during the same variations. Approach: We enrolled clinically stable mechanically ventilated newborns at postnatal age >24 h without brain abnormalities at ultrasound. StO2 and blood flow index were measured using a non-invasive device (BabyLux), which combine time-resolved NIRS and diffuse-correlation spectroscopy. The effect of changes in transcutaneous pCO2 on StO2, cerebral blood flow (CBF), and cerebral metabolic rate of oxygen index (tCMRO2i) were estimated. Results: Ten babies were enrolled and three were excluded. Median GA at enrollment was 39 weeks and median weight 2720 g. StO2 increased 0.58% (95% CI 0.55; 0.61, p<0.001), CBF 2% (1.9; 2.3, p<0.001), and tCMRO2 0.3% (0.05; 0.46, p=0.017) per mmHg increase in pCO2. Conclusions: BabyLux device detected pCO2-induced changes in cerebral StO2 and CBF, as expected. The small statistically significant positive relationship between pCO2 and tCMRO2i variation is not considered clinically relevant and we are inclined to consider it as an artifact.
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BACKGROUND: In the SafeBoosC-III trial, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth did not reduce the incidence of death or severe brain injury in extremely preterm infants at 36 weeks' postmenstrual age, as compared with usual care. Despite an association between severe brain injury diagnosed in the neonatal period and later neurodevelopmental disability, this relationship is not always strong. The objective of the SafeBoosC-III follow-up study is to assess mortality, neurodevelopmental disability, or any harm in trial participants at 2 years of corrected age. One important challenge is the lack of funding for local costs for a trial-specific assessment. METHODS: Of the 1601 infants randomised in the SafeBoosC-III trial, 1276 infants were alive at 36 weeks' postmenstrual age and will potentially be available for the 2-year follow-up. Inclusion criteria will be enrollment in a neonatal intensive care unit taking part in the follow-up study and parental consent if required by local regulations. We aim to collect data from routine follow-up programmes between the ages of 18 and 30 months of corrected age. If no routine follow-up has been conducted, we will collect informal assessments from other health care records from the age of at least 12 months. A local co-investigator blinded to group allocation will classify outcomes based on these records. We will supplement this with parental questionnaires including the Parent Report of Children's Abilities-Revised. There will be two co-primary outcomes: the composite of death or moderate or severe neurodevelopmental disability and mean Bayley-III/IV cognitive score. We will use a 3-tier model for prioritisation, based on the quality of data. This approach has been chosen to minimise loss to follow-up assuming that little data is better than no data at all. DISCUSSION: Follow-up at the age of 2 years is important for intervention trials in the newborn period as only time can show real benefits and harms later in childhood. To decrease the risk of generalisation and data-driven biased conclusions, we present a detailed description of the methodology for the SafeBoosC-III follow-up study. As funding is limited, a pragmatic approach is necessary. TRIAL REGISTRATION: ClinicalTrials.gov NCT05134116 . Registered on 24 November 2021.
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Lesões Encefálicas , Lactente Extremamente Prematuro , Lactente , Criança , Recém-Nascido , Humanos , Pré-Escolar , Adolescente , Adulto Jovem , Adulto , Oximetria/métodos , Seguimentos , Circulação Cerebrovascular , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Objective: To examine the effect of twin birth on long-term neurodevelopmental outcomes in a cohort of Italian preterm infants with very low birth weight. Study design: We performed a retrospective cohort study on children born in a tertiary care centre. We included children born between 1 January 2007 and 31 December 2013 with a gestational age (GA) of ≤32 weeks and birth weight of <1,500â g. The infants born from twin pregnancies complicated by twin-to-twin transfusion syndrome and from higher-order multiple pregnancies were excluded. The children were evaluated both at 2 years corrected age and 5 years chronological age with Griffiths mental development scales revised (GMDS-R). The linear mixed effects models were used to study the effect of being a twin vs. being a singleton on GMDS-R scores, adjusting for GA, being born small for gestational age, sex, length of NICU stay, socio-economic status, and comorbidity score (CS) calculated as the sum of the weights associated with each of the major morbidities of the infants. Results: A total of 301 children were included in the study, of which 189 (62.8%) were singletons and 112 (37.2%) were twins; 23 out of 112 twins were monochorionic (MC). No statistically significant differences were observed between twins and singletons in terms of mean general quotient and subscales at both 2 and 5 years. No effect of chorionicity was found when comparing scores of MC and dichorionic twins vs. singletons; however, after adjusting for the CS, the MC twins showed lower scores in the hearing and language and performance subscales at 5 years. Conclusion: Overall, in our cohort of children born very preterm, twin infants were not at higher risk of neurodevelopmental impairment compared with singletons at pre-school age.
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Background and Objectives: Very low birth weight infants (VLBW) are at risk for adverse growth and neurodevelopmental outcomes. We aimed to evaluate the association between growth during Neonatal Intensive Care Unit (NICU) stay and long-term neurodevelopmental outcomes in a cohort of preterm VLBW newborns. Methods: We conducted a longitudinal observational study in the Follow-up Service of our Clinic from January 2014 to April 2017. All preterm VLBW infants born at our hospital and enrolled in our follow-up program were considered eligible for the study. The neurodevelopmental assessment was performed using the Griffiths Mental Development Scales at 12 and 24 months corrected age. Results: Study population included 172 subjects (47.1% males) with a mean gestational age of 29 weeks and a mean birth weight of 1,117â g. A unitarian Δz-score increase in head circumference from birth to discharge was associated with a 1.6-point increase in General Quotient at 24 months corrected age. An association with subscales C and D was also found. Likewise, an increase in length Δz-score was associated with better 24-month subscale C scores although not reaching statistical significance. No relationship with the outcome at 24 months was found for weight gain. Conclusions: Growth during NICU stay appears to be related to a more favorable neurodevelopmental outcome at 24 months corrected age, especially in the hearing and language domain (subscale C). The longitudinal evaluation of auxological parameters during hospitalization can contribute to the identification of subjects at risk for adverse neurodevelopmental outcomes in the first years of life.
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BACKGROUND: The use of cerebral oximetry monitoring in the care of extremely preterm infants is increasing. However, evidence that its use improves clinical outcomes is lacking. METHODS: In this randomized, phase 3 trial conducted at 70 sites in 17 countries, we assigned extremely preterm infants (gestational age, <28 weeks), within 6 hours after birth, to receive treatment guided by cerebral oximetry monitoring for the first 72 hours after birth or to receive usual care. The primary outcome was a composite of death or severe brain injury on cerebral ultrasonography at 36 weeks' postmenstrual age. Serious adverse events that were assessed were death, severe brain injury, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and late-onset sepsis. RESULTS: A total of 1601 infants underwent randomization and 1579 (98.6%) were evaluated for the primary outcome. At 36 weeks' postmenstrual age, death or severe brain injury had occurred in 272 of 772 infants (35.2%) in the cerebral oximetry group, as compared with 274 of 807 infants (34.0%) in the usual-care group (relative risk with cerebral oximetry, 1.03; 95% confidence interval, 0.90 to 1.18; P = 0.64). The incidence of serious adverse events did not differ between the two groups. CONCLUSIONS: In extremely preterm infants, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth was not associated with a lower incidence of death or severe brain injury at 36 weeks' postmenstrual age than usual care. (Funded by the Elsass Foundation and others; SafeBoosC-III ClinicalTrials.gov number, NCT03770741.).
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Lactente Extremamente Prematuro , Doenças do Prematuro , Oximetria , Humanos , Lactente , Recém-Nascido , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/etiologia , Displasia Broncopulmonar/etiologia , Circulação Cerebrovascular , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/mortalidade , Doenças do Prematuro/terapia , Oximetria/métodos , Cérebro , Ultrassonografia , Retinopatia da Prematuridade/etiologia , Enterocolite Necrosante/etiologia , Sepse Neonatal/etiologiaRESUMO
PURPOSE: Skin lesions in neonatal population are an emerging problem deserving attention from health care professionals. The purpose of this study is to retrospectively assess the incidence of hospital-acquired skin lesions during a 6-year period and to describe the characteristics of infants who developed them. DESIGN AND METHODS: This was a retrospective observational study conducted in a university-tertiary care center between 2015 and 2020. A descriptive analysis of the observed skin lesions is presented according to 2 time periods: 1) the implementation phase of a quality improvement program (2015-2019) and 2) the postimplementation phase (2020). RESULTS: Our findings showed an apparent increase in the incidence of all reported skin lesions throughout the study period. Pressure injuries were the most frequently reported skin lesions showing an increasing incidence over time which, however, was paralleled by a reduction in their severity. Among pressure injuries, device-related injuries were the most commonly observed (56.6% and 62.5% in the two periods, respectively) with nasal continuous positive airway pressure-related injuries accounting for 71.7% and 56.0% of lesions, respectively, and mainly affecting the nose root. The occipital area was the most frequently involved site in cases of conventional pressure injuries. CONCLUSION: Infants admitted to Neonatal Intensive Care Units may be at high risk of developing skin lesions. The adoption of appropriate preventative as well as treatment interventions could be effective in reducing the severity of pressure injuries. PRACTICE IMPLICATIONS: The implementation of quality improvement strategies may contribute to prevent skin injuries or lead to their early detection.
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Unidades de Terapia Intensiva Neonatal , Úlcera por Pressão , Recém-Nascido , Lactente , Humanos , Estudos Retrospectivos , Úlcera por Pressão/epidemiologia , Úlcera por Pressão/prevenção & controle , Melhoria de Qualidade , HospitaisRESUMO
BACKGROUND: Venetoclax in combination with hypomethylating agents (HMA) is revolutionizing the therapy of acute myeloid leukemia (AML). However, evidence on large sets of patients is lacking, especially in relapsed or refractory leukemia. METHODS: AVALON is a multicentric cohort study that was conducted in Italy on patients with AML who received venetoclax-based therapies from 2015 to 2020. The study was approved by the ethics committee of the participating institution and was conducted in accordance with the Declaration of Helsinki. The effectiveness and toxicity of venetoclax + HMA in 190 (43 newly diagnosed, 68 refractory, and 79 relapsed) patients with AML are reported here. RESULTS: In the newly diagnosed AML, the overall response rate and survival confirmed the brilliant results demonstrated in VIALE-A. In the relapsed or refractory AML, the combination demonstrated a surprisingly complete remission rate (44.1% in refractory and 39.7% in relapsed evaluable patients) and conferred to treated patients a good expectation of survival. Toxicities were overall manageable, and most incidents occurred in the first 60 days of therapy. Infections were confirmed as the most common nonhematologic adverse event. CONCLUSIONS: Real-life data show that the combination of venetoclax and HMA offers an expectation of remission and long-term survival to elderly, newly diagnosed patients, and to relapsed or chemoresistant AML, increasing the chance of cure through a different mechanism of action. The venetoclax + HMA combination is expected to constitute the base for triplet combinations and integration of target therapies. Our data contribute to ameliorate the understanding of venetoclax + HMA effectiveness and toxicities in real life.
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Leucemia Mieloide Aguda , Humanos , Idoso , Estudos de Coortes , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Sulfonamidas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.This multicenter cohort study reports on the long-term effects of prenatal exposure to maternal cancer and its treatment on cognitive and behavioral outcomes in 9-year-old children. In total, 151 children (mean age, 9.3 years; range, 7.8-10.6 years) were assessed using a neurocognitive test battery and parent-report behavioral questionnaires. During pregnancy, 109 children (72.2%) were exposed to chemotherapy (only or in combination with other treatment modalities), 18 (11.9%) to surgery only, 16 (10.6%) to radiotherapy, one to trastuzumab, and 16 (10.6%) were not exposed to oncologic treatment. Mean cognitive and behavioral outcomes were within normal ranges. Gestational age at birth showed a positive association with Full Scale Intelligence Quotient (FSIQ), with the average FSIQ score increasing by 1.6 points for each week increase in gestational age (95% CI, 0.7 to 2.5; P < .001). No difference in FSIQ was found between treatment types (F[4,140] = 0.45, P = .776). In children prenatally exposed to chemotherapy, no associations were found between FSIQ and chemotherapeutic agent, exposure level, or timing during pregnancy. These results indicate a reassuring follow-up during the critical maturational period of late childhood, when complex functions develop and rely on the integrity of early brain development. However, associations were observed with preterm birth, maternal death, and maternal education.
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Neoplasias , Nascimento Prematuro , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Feminino , Criança , Humanos , Recém-Nascido , Estudos de Coortes , Estudos Prospectivos , Neoplasias/tratamento farmacológico , CogniçãoRESUMO
Doxorubicin (Dox) is one of the most commonly used anthracyclines for the treatment of solid and hematological tumors such as B-/T cell acute lymphoblastic leukemia (ALL). Dox compromises topoisomerase II enzyme functionality, thus inducing structural damages during DNA replication and causes direct damages intercalating into DNA double helix. Eukaryotic cells respond to DNA damages by activating the ATM-CHK2 and/or ATR-CHK1 pathway, whose function is to regulate cell cycle progression, to promote damage repair, and to control apoptosis. We evaluated the efficacy of a new drug schedule combining Dox and specific ATR (VE-821) or CHK1 (prexasertib, PX) inhibitors in the treatment of human B-/T cell precursor ALL cell lines and primary ALL leukemic cells. We found that ALL cell lines respond to Dox activating the G2/M cell cycle checkpoint. Exposure of Dox-pretreated ALL cell lines to VE-821 or PX enhanced Dox cytotoxic effect. This phenomenon was associated with the abrogation of the G2/M cell cycle checkpoint with changes in the expression pCDK1 and cyclin B1, and cell entry in mitosis, followed by the induction of apoptosis. Indeed, the inhibition of the G2/M checkpoint led to a significant increment of normal and aberrant mitotic cells, including those showing tripolar spindles, metaphases with lagging chromosomes, and massive chromosomes fragmentation. In conclusion, we found that the ATR-CHK1 pathway is involved in the response to Dox-induced DNA damages and we demonstrated that our new in vitro drug schedule that combines Dox followed by ATR/CHK1 inhibitors can increase Dox cytotoxicity against ALL cells, while using lower drug doses. ⢠Doxorubicin activates the G2/M cell cycle checkpoint in acute lymphoblastic leukemia (ALL) cells. ⢠ALL cells respond to doxorubicin-induced DNA damages by activating the ATR-CHK1 pathway. ⢠The inhibition of the ATR-CHK1 pathway synergizes with doxorubicin in the induction of cytotoxicity in ALL cells. ⢠The inhibition of ATR-CHK1 pathway induces aberrant chromosome segregation and mitotic spindle defects in doxorubicin-pretreated ALL cells.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteínas Quinases , Humanos , Proteínas Quinases/metabolismo , Quinase 1 do Ponto de Checagem/genética , Quinase 1 do Ponto de Checagem/metabolismo , Doxorrubicina/farmacologia , Dano ao DNA , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismoRESUMO
Infants born preterm are at high risk of presenting neurodevelopmental delay. The Neurofunctional Assessment (NFA) describes infants' neurodevelopment through the evaluation of six different domains. This study aimed to evaluate how, in a cohort of preterm infants, each NFA domain assessed at 3 months of corrected age (CA) was associated with neurodevelopment at 2 years of CA using the Griffiths Mental Developmental Scales Extended Revised (GMDS-ER). In addition, by introducing the NFA complexity score (CS), the study aimed to define a threshold that can help clinicians discriminate infants at higher risk of later neurodevelopmental delay. We conducted an observational, longitudinal study including 211 preterm infants. At 3 months of CA, infants who had normal scores in each domain showed a significantly higher GMDS-ER global quotient (GQ) at 2 years of CA. In addition, linear model results showed a significant negative relationship between the NFA CS and 2-year GMDS-ER GQ (estimate: - 0.27; 95% CI - 0.35, - 0.20; p value < 0.001). Each 10-point increase in the NFA CS was associated with an average 2.7-point decrease in the GMDS GQ. These results highlight how the NFA domains and NFA CS are compelling instruments for the early identification of children at risk for long-term adverse outcomes.
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Recém-Nascido Prematuro , Projetos de Pesquisa , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Modelos Lineares , Estudos Longitudinais , Parto , GravidezAssuntos
Antineoplásicos , Doença Hepática Induzida por Substâncias e Drogas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Asparaginase/efeitos adversos , Carnitina/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antineoplásicos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Suplementos Nutricionais/efeitos adversosRESUMO
We present a family case of neonatal-onset KCNQ2-related epilepsy due to a novel intronic mutation. Three members of an Italian family (father and offspring) presented with neonatal-onset asymmetric tonic and clonic seizures with peculiar video-electroencephalography and aEEG features referring to sequential seizures. The father and the first son underwent standard of care treatments in line with current neonatal intensive care unit protocols, with a prolonged hospitalization before reaching full seizure control with carbamazepine. After the experience acquired with her family and the latest advances in the literature, the younger daughter was directly treated with carbamazepine, obtaining rapid seizure control and short hospitalization. They all had normal development. Carbamazepine is rarely administered as a first-line option in neonatal seizures. Recent evidence suggests that neonatal intensive care unit protocols should implement a trial with sodium channel blockers such as carbamazepine as first-option anti-seizure medication and a fast access to genetic testing in neonates with sequential seizures without structural brain injury or acute causes. Moreover, we report and discuss the laboratory studies performed on a novel causative intronic mutation in KCNQ2 (c.1525+5 G>A in IVS13), since pathogenicity may be difficult to prove for intronic variants.
RESUMO
Aberrant activation of the Hh pathway promotes cell proliferation and multi-drug resistance (MDR) in several cancers, including Acute Myeloid Leukemia (AML). Notably, only one Hh inhibitor, glasdegib, has been approved for AML treatment, and most patients eventually relapse, highlighting the urgent need to discover new therapeutic targets. Hh signal is transduced through the membrane of the primary cilium, a structure expressed by non-proliferating mammalian cells, whose stabilization depends on the activity of HDAC6. Here we describe a positive correlation between Hh, HDAC6, and MDR genes in a cohort of adult AML patients, human leukemic cell lines, and a zebrafish model of Hh overexpression. The hyper-activation of Hh or HDAC6 in zebrafish drove the increased proliferation of hematopoietic stem and progenitor cells (HSPCs). Interestingly, this phenotype was rescued by inhibition of HDAC6 but not of Hh. Also, in human leukemic cell lines, a reduction in vitality was obtained through HDAC6, but not Hh inhibition. Our data showed the presence of a cross-talk between Hh and HDAC6 mediated by stabilization of the primary cilium, which we detect for the first time in zebrafish HSPCs. Inhibition of HDAC6 activity alone or in combination therapy with the chemotherapeutic agent cytarabine, efficiently rescued the hematopoietic phenotype. Our results open the possibility to introduce HDAC6 as therapeutic target to reduce proliferation of leukemic blasts in AML patients.