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Some people infected with SARS-CoV-2 report persisting symptoms following acute infection. If these persist for over three months, they are classified as post-COVID-19 syndrome (PCS). Although PCS is frequently reported, detailed longitudinal neuropsychological characterization remains scarce. We aimed to describe the trajectory of cognitive and neuropsychiatric PCS symptoms. 42 individuals with persisting cognitive deficits after asymptomatic to mild/moderate acute COVID-19 at study inclusion received neuropsychological assessment at baseline (BL) and follow-up (FU; six months after BL). Assessments included comprehensive testing of five neurocognitive domains, two cognitive screening tests, and questionnaires on depression, anxiety, sleep, fatigue, and health-related quality of life. Results showed high rates of subjective cognitive complaints at BL and FU (95.2% versus 88.1%) without significant change over time. However, objectively measured neurocognitive disorder (NCD) decreased (61.9% versus 42.9%). All cognitive domains were affected, yet most deficits were found in learning and memory, followed by executive functions, complex attention, language, and perceptual motor functions. In individuals with NCD, the first three domains mentioned improved significantly over time, while the last two domains remained unchanged. Cognitive screening tests did not prove valuable in detecting impairment. Neuropsychiatric symptoms remained constant except for quality of life, which improved. This study emphasizes the importance of comprehensive neuropsychological assessment in longitudinal research and provides valuable insights into the trajectory of long-term neuropsychological impairments in PCS. While cognitive performance significantly improved in many domains, neuropsychiatric symptoms remained unchanged.
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BACKGROUND: In addition to treatment response, cytogenetic and molecular aberrations are the most important prognostic factors in children with de novo acute myeloid leukemia (AML). However, little is known about cytogenetics at the time of relapse. METHODS: This international study analyzed the prognostic value of cytogenetic profiles and karyotypic changes in pediatric relapsed AML in relation to the probability of event-free (pEFS) and overall survival (pOS). For this purpose, cytogenetic reports from all patients registered on the Relapsed AML 2001/01 Study were reviewed and classified. RESULTS: Cytogenetic information at relapse was available for 403 (71%) of 569 registered patients. Frequently detected aberrations at relapse were t(8;21)(q22;q22) (n = 60) and inv(16)(p13.1q22)/t(16;16)(p13.1;q22) (n = 24), both associated with relatively good outcome (4-year pOS 59% and 71%, respectively). Monosomy 7/7q-, t(9;11)(p22;q23), t(10;11)(p12;q23), and complex karyotypes were associated with poor outcomes (4-year pOS 17%, 19%, 22%, and 22%, respectively). Of 261 (65%) patients for whom cytogenetic data were reliable at both diagnosis and relapse, pEFS was inferior for patients with karyotypic instability (n = 128, 49%), but pOS was similar. Unstable karyotypes with both gain and loss of aberrations were associated with inferior outcome. Early treatment response, time to relapse, and cytogenetic profile at time of relapse were the most important prognostic factors, both outweighing karytoypic instability per se. CONCLUSION: The cytogenetic subgroup at relapse is an independent risk factor for (event-free) survival. Cytogenetic assessment at the time of relapse is of high importance and may contribute to improved risk-adapted treatment for children with relapsed AML.
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Aberraciones Cromosómicas , Leucemia Mieloide Aguda , Niño , Estudios de Cohortes , Humanos , Leucemia Mieloide Aguda/genética , Pronóstico , Recurrencia , Estudios RetrospectivosRESUMEN
We consider so called 2-stage stochastic integer programs (IPs) and their generalized form, so called multi-stage stochastic IPs. A 2-stage stochastic IP is an integer program of the form max { c T x ⣠A x = b , l ≤ x ≤ u , x ∈ Z s + n t } where the constraint matrix A ∈ Z r n × s + n t consists roughly of n repetitions of a matrix A ∈ Z r × s on the vertical line and n repetitions of a matrix B ∈ Z r × t on the diagonal. In this paper we improve upon an algorithmic result by Hemmecke and Schultz from 2003 [Hemmecke and Schultz, Math. Prog. 2003] to solve 2-stage stochastic IPs. The algorithm is based on the Graver augmentation framework where our main contribution is to give an explicit doubly exponential bound on the size of the augmenting steps. The previous bound for the size of the augmenting steps relied on non-constructive finiteness arguments from commutative algebra and therefore only an implicit bound was known that depends on parameters r, s, t and Δ , where Δ is the largest entry of the constraint matrix. Our new improved bound however is obtained by a novel theorem which argues about intersections of paths in a vector space. As a result of our new bound we obtain an algorithm to solve 2-stage stochastic IPs in time f ( r , s , Δ ) · poly ( n , t ) , where f is a doubly exponential function. To complement our result, we also prove a doubly exponential lower bound for the size of the augmenting steps.
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Limited data are available on the incidence and impact of TP53 alterations and TP53 pathway deregulation in paediatric acute myeloid leukaemia (AML). We analysed TP53 alterations in bone marrow samples of 229 patients with de novo paediatric AML, and detected heterozygous missense exon mutations in two patients (1%) and 17p deletions of the TP53 gene in four patients (2%). These patients more frequently had complex karyotype (50% vs. 4%, P = 0·002) or adverse cytogenetic abnormalities, including complex karyotype (67% vs. 17%, P = 0·013), compared to TP53 wild-type. Differential expression of TP53 pathway genes was associated with poor survival, indicating a role for TP53 regulators and effector genes.
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Deleción Cromosómica , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda , Mutación , Transducción de Señal , Síndrome de Smith-Magenis , Proteína p53 Supresora de Tumor , Adolescente , Niño , Preescolar , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 17/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/metabolismo , Síndrome de Smith-Magenis/mortalidad , Tasa de Supervivencia , Proteína p53 Supresora de Tumor/biosíntesis , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: With the current more effective treatment regimens for pediatric acute myeloid leukemia (AML), research on early death (ED), treatment-related mortality (TRM), and toxicity becomes increasingly important. The aim of this study was to give an overview of the frequency, clinical features, and risk factors associated with ED and TRM in first complete remission (CR1) during the last three consecutive treatment protocols of the Dutch Childhood Oncology Group (DCOG) between 1998 and 2014. METHODS: Incidence and risk factors associated with ED and TRM in CR1 were retrospectively studied in 245 patients treated according to the Dutch ANLL-97/AML-12 (n = 118), AML-15 (n = 60), or DB AML-01 (n = 67) protocols. RESULTS: The incidence of ED was, respectively, 5.1%, 6.7%, and 3.0% excluding deaths before treatment (P = NS), and 7.4%, 11.1%, and 4.4% including deaths before the onset of treatment. Severe underweight at initial diagnosis was significantly associated with more frequent ED. When relapse was included as a competing risk, cumulative incidence of death in CR1 were 5.9%, 5.0%, and 4.6% for ANLL97, AML15, and DB01, respectively (P = NS). The most important cause of TRM included infectious and SCT-related complications. CONCLUSION: We report relatively stable rates of ED and TRM in CR1 in the latest completed DCOG protocols for newly diagnosed AML patients. The most important causes of TRM were SCT- or infection-related, warranting further evaluation and awareness.
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Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
Prevention of infections is of obvious relevance in paediatric patients with acute myeloid leukaemia (AML). However, recommendations are often non-specific and supported by low-quality evidence, resulting in divergent infection preventive regimens. Using a web-based survey, we investigated the infection prophylaxis guidelines of 22 paediatric AML study groups affiliated to the international Berlin-Frankfürt-Münster study group. In order to evaluate differences in daily practice among hospitals, representatives (n = 27) from the Nordic Society for Paediatric Haematology and Oncology-Dutch-Belgium-Hong Kong - AML study group participated in a slightly modified survey. Seven study groups (32%) advise gram-negative antibiotic prophylaxis, mainly with fluoroquinolones (n = 6). Gram-positive prophylaxis is prescribed by eight groups (36%). Over 60% of the study groups prescribe food and social restrictions, but the specific topics and strictness differ widely. According to the hospital-based survey, sites roughly comply with common study group guidelines. However, the use of any gram-negative antibiotic prophylaxis, the specific prophylactic antifungal agent and the strictness of the food and social restrictions differ substantially between the hospitals. Despite a long history of close collaboration, many differences are still present between the affiliated groups. The results of this survey provide an appropriate baseline measure to study the emergence and impact of future guidelines on infection prophylaxis in paediatric AML.
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Control de Infecciones/métodos , Infecciones/etiología , Leucemia Mieloide Aguda/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Profilaxis Antibiótica/métodos , Antifúngicos/uso terapéutico , Niño , Femenino , Inocuidad de los Alimentos , Infecciones por Bacterias Gramnegativas/prevención & control , Infecciones por Bacterias Grampositivas/prevención & control , Humanos , Leucemia Mieloide Aguda/complicaciones , Masculino , Premedicación/métodos , Conducta Social , Encuestas y CuestionariosRESUMEN
BACKGROUND: The cytogenetic aberrations inv(16)(p13.1q22)/t(16;16)(p13.1;q22), frequently detected in acute myelomonocytic leukemia with eosinophilia (FAB type M4eo), are generally considered a prognostically favorable subgroup. M4eo comprises a distinct morphology compared to M4 without eosinophilia (M4eo-) and therefore may be indicative for a different pathogenesis. PROCEDURES: Morphology and cytogenetic/molecular analyses of a Dutch cohort of pediatric acute myelomonocytic leukemia (AML-M4) patients were performed and studied in order to analyze the association between the presence of eosinophilia morphology (M4eo+), inv(16)/t(16;16) (inv(16)+), clinical features, and outcome. RESULTS: Of the 119 included patients with available combined morphological and cytogenetic results, 60% had M4eo- without inv(16) (inv(16)-), 10% had M4eo-/inv(16)+, 13% had M4eo+/inv(16)-, and 17% had M4eo+/inv(16)+. M4eo+ was significantly associated with the presence of inv(16)/t(16;16) (P < 0.001). Patients with M4eo+ had no significantly superior outcome compared with patients with M4eo-, whereas patients with inv(16)+ had significantly superior probabilities of event-free survival and probabilities of overall survival compared with patients without inv(16)-. Patients with M4eo+/inv(16)+ had no significantly better outcome than those with M4eo-/inv(16)+. CONCLUSION: The prognostically favorable impact of distinct morphology with eosinophilia probably relies on its association with inv(16)/t(16;16). Simultaneous presence of both eosinophilia and inv(16) was not associated with superior outcome in our study. These results may be relevant for risk-group classification and risk-group adapted treatment and underline the importance of accurate cytogenetic analysis.
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Aberraciones Cromosómicas , Cromosomas Humanos Par 16/genética , Eosinofilia , Leucemia Mieloide Aguda , Sistema de Registros , Adolescente , Niño , Preescolar , Supervivencia sin Enfermedad , Eosinofilia/genética , Eosinofilia/mortalidad , Femenino , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Países Bajos/epidemiología , Tasa de SupervivenciaRESUMEN
We evaluated the in vitro glucocorticoid (GC) responsiveness of 117 pediatric acute myeloid leukemia cells by considering GC resistance, GC-induced proliferation, and GC-induced differentiation. None of the samples was highly GC sensitive, and only 15% were intermediately sensitive. GC-induced differentiation was not observed, while GC-induced proliferation was observed in 27% of the samples. Samples with French-American-British classification (FAB) type M5 or activating Fms-like tyrosine kinase 3 (FLT3) mutations were significantly more prone to this phenomenon. Although we could not confirm this in our study, if induced proliferation in vitro is paralleled in vivo, GCs during consolidation may have adverse effects on minimal residual leukemic cells, which might increase relapse risk.
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Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Dexametasona/uso terapéutico , Glucocorticoides/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Prednisolona/uso terapéutico , Resultado del Tratamiento , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
The growing use of silver nanoparticles (Ag-NP) triggered an increasing interest in their environmental fate and possible ecotoxicological impacts. To investigate the potential risk of Ag-NP to soil organisms, the springtail Folsomia candida was exposed to Ag-NP (reported diameter size 3-8 nm) and AgNO3 in Lufa 2.2 natural soil for 28 days to determine effects on survival and reproduction. Also, the kinetics of uptake and elimination of Ag were studied for F. candida exposed in Lufa 2.2 soil to Ag-NP (at 168 mg Ag/kg dry soil) and AgNO3 (at 30 and 60 mg Ag/kg dry soil). AgNO3 was toxic with an LC50 was 284 mg Ag/kg dry soil for effects on survival and EC10 and EC50 values of 47.6 and 99.5 mg Ag/kg dry soil, respectively for the effect on reproduction. These values did correspond with porewater concentrations of 0.801, 0.042 and 0.082 mg Ag/l, respectively. No effects on survival and reproduction of Ag-NP were observed up to 673 mg Ag/kg dry soil, although porewater concentration was similar to the EC50 for AgNO3. Exposure to both Ag forms caused a fast uptake of Ag, but the Ag elimination rate was significantly higher for Ag-NP than for AgNO3. Bioaccumulation factor was higher for AgNO3 (on average 5.64) than for Ag-NP (1.12). These findings indicate that silver ions are more toxic than Ag-NP and have a higher potential to accumulate in F. candida.
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Artrópodos/efectos de los fármacos , Nanopartículas del Metal/toxicidad , Nitrato de Plata/toxicidad , Contaminantes del Suelo/toxicidad , Animales , Monitoreo del Ambiente , Iones/toxicidad , Reproducción/efectos de los fármacos , Plata/farmacocinética , Plata/toxicidad , Contaminantes del Suelo/farmacocinética , Pruebas de ToxicidadRESUMEN
ABSTRACT: A comprehensive international consensus on the cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1256 children with KMT2A-r AML aims to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs) and to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared with our previous study, 3 additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, and 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8%-76.2%; P < .01). ACAs occurred in 46.8% of 1200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P < .01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British-type M5 with favorable outcomes was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate 5 adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine the risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcomes and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.
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N-Metiltransferasa de Histona-Lisina , Leucemia Mieloide Aguda , Proteína de la Leucemia Mieloide-Linfoide , Humanos , Proteína de la Leucemia Mieloide-Linfoide/genética , Niño , N-Metiltransferasa de Histona-Lisina/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Femenino , Preescolar , Adolescente , Lactante , Pronóstico , Aberraciones Cromosómicas , Reordenamiento Génico , Estudios RetrospectivosRESUMEN
PURPOSE: The Pediatric Oncology in Developing Countries (PODC) committee of the International Society of Pediatric Oncology (SIOP) published a pediatric acute myeloid leukemia (AML)-specific adapted treatment guideline for low- and middle-income countries. We evaluated the outcomes of children with AML at a large Kenyan academic hospital before (period 1) and after (period 2) implementing this guideline. PATIENTS AND METHODS: Records of children (≤17 years) newly diagnosed with AML between 2010 and 2021 were retrospectively studied. In period 1, induction therapy comprised two courses with doxorubicin and cytarabine, and consolidation comprised two courses with etoposide and cytarabine. In period 2, a prephase with intravenous low-dose etoposide was administered prior to induction therapy, induction course I was intensified, and consolidation was adapted to two high-dose cytarabine courses. Probabilities of event-free survival (pEFS) and overall survival (pOS) were estimated using the Kaplan-Meier method. RESULTS: One-hundred twenty-two children with AML were included - 83 in period 1 and 39 in period 2. Overall, 95 patients received chemotherapy. The abandonment rate was 19% (16/83) in period 1 and 3% (1/39) in period 2. The early death, treatment-related mortality, complete remission, and relapse rates in periods 1 and 2 were 46% (29/63) versus 44% (14/32), 36% (12/33) versus 47% (8/17), 33% (21/63) versus 38% (12/32), and 57% (12/21) versus 17% (2/12), respectively. The 2-year pEFS and pOS in periods 1 and 2 were 5% versus 15% (p = .53), and 8% versus 16% (p = .93), respectively. CONCLUSION: The implementation of the SIOP PODC guideline did not result in improved outcomes of Kenyan children with AML. Survival of these children remains dismal, mainly attributable to early mortality.
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Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Niño , Humanos , Kenia/epidemiología , Etopósido , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del Tratamiento , Citarabina/uso terapéutico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológicoRESUMEN
The complex cytoarchitecture of neurons poses significant challenges for the maturation of synaptic membrane proteins. It is currently unclear whether locally secreted synaptic proteins bypass the Golgi or whether they traffic through Golgi satellites (GSs). Here, we create a transgenic GS reporter mouse line and show that GSs are widely distributed along dendrites and are capable of mature glycosylation, in particular sialylation. We find that polysialylation of locally secreted NCAM takes place at GSs. Accordingly, in mice lacking a component of trans-Golgi network-to-plasma membrane trafficking, we find fewer GSs and significantly reduced PSA-NCAM levels in distal dendrites of CA1 neurons that receive input from the temporoammonic pathway. Induction of long-term potentiation at those, but not more proximal, synapses is severely impaired. We conclude that GSs serve the need for local mature glycosylation of synaptic membrane proteins in distal dendrites and thereby contribute to rapid changes in synaptic strength.
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Potenciación a Largo Plazo , Sinapsis , Ratones , Animales , Potenciación a Largo Plazo/fisiología , Sinapsis/metabolismo , Neuronas/metabolismo , Dendritas/metabolismo , Moléculas de Adhesión de Célula Nerviosa/metabolismoRESUMEN
Although survival in pediatric acute myeloid leukemia (AML) has increased considerably over the past decades, refractory disease and relapse rates remain high. Refractory and relapsed disease are difficult to treat, with overall survival rates less than 40-50%. Preventing relapse should, therefore, be one of the highest priorities. Current conventional chemotherapy regimens are hard to intensify due to associated toxic complications, hence more effective therapies that do not increase toxicity are needed. A promising targeted agent is the CD33-directed antibody-drug conjugate gemtuzumab ozogamicin (GO). Because CD33 is highly expressed on leukemic cells in the majority of AML patients, GO can be useful for a broad range of patients. Better relapse-free survival (RFS) after therapy including GO has been reported in several pediatric clinical trials; however, ambiguity about the clinical value of GO in newly diagnosed children remains. Treatment with GO in de novo AML patients aged ≥1 month, in combination with standard chemotherapy is approved in the United States, whereas in Europe, GO is only approved for newly diagnosed patients aged ≥15 years. In this review, we aimed to clarify the clinical value of GO for treatment of newly diagnosed pediatric AML patients. Based on current literature, GO seems to have additional value, in terms of RFS, and acceptable toxicity when used in addition to chemotherapy during initial treatment. Moreover, in KMT2A-rearranged patients, the clinical value of GO was even more evident. Also, we addressed predictors of response, being CD33 expression and SNPs, PgP-1 and Annexin A5. The near finalized intent-to-file clinical trial in the MyeChild consortium investigates whether fractionated dosing has additional value for pediatric AML, which may pave the way for a broader application of GO in pediatric AML.
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BACKGROUND: A fraction of patients with asymptomatic to mild/moderate acute COVID-19 disease report cognitive deficits as part of the post-COVID-19 syndrome. This study aimed to assess the neuropsychological profile of these patients. METHODS: Assessment at baseline (three months or more following acute COVID-19) of a monocentric prospective cohort of patients with post-COVID-19 syndrome. Multidomain neuropsychological tests were performed, and questionnaires on depression, anxiety, fatigue, sleep, and general health status were administered. RESULTS: Of the 58 patients screened, six were excluded due to possible alternative causes of cognitive impairment (major depression, neurodegenerative disease). Of the remaining 52 individuals, only one had a below-threshold screening result on Mini-Mental State Examination, and 13 scored below the cut-off on Montreal Cognitive Assessment. Extended neuropsychological testing revealed a neurocognitive disorder (NCD) in 31 (59.6%) participants with minor NCD in the majority of cases (n = 26). In patients with NCD, the cognitive domains learning/memory and executive functions were impaired in 60.7%, complex attention in 51.6%, language in 35.5%, and perceptual-motor function in 29.0%. Cognitive profiles were associated with daytime sleepiness but not with depression, anxiety, sleep quality, total general health status, or fatigue. CONCLUSION: Neurocognitive impairment can be confirmed in around 60% of individuals with self-reported deficits as part of post-COVID-19 syndrome following a mild acute COVID-19 disease course. Notably, screening tests cannot reliably detect this dysfunction. Standard psychiatric assessments showed no association with cognitive profiles. Longitudinal studies are needed to further evaluate the course of neurocognitive deficits and clarify pathophysiology.
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COVID-19 , Disfunción Cognitiva , Enfermedades Neurodegenerativas , Humanos , Síndrome Post Agudo de COVID-19 , Estudios Prospectivos , COVID-19/complicaciones , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Pruebas Neuropsicológicas , Fatiga/diagnóstico , Fatiga/etiologíaRESUMEN
PURPOSE: A previous study by the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG) on childhood KMT2A-rearranged (KMT2A-r) AML demonstrated the prognostic value of the fusion partner. This I-BFM-SG study investigated the value of flow cytometry-based measurable residual disease (flow-MRD) and evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission (CR1) in this disease. METHODS: A total of 1,130 children with KMT2A-r AML, diagnosed between January 2005 and December 2016, were assigned to high-risk (n = 402; 35.6%) or non-high-risk (n = 728; 64.4%) fusion partner-based groups. Flow-MRD levels at both end of induction 1 (EOI1) and 2 (EOI2) were available for 456 patients and were considered negative (<0.1%) or positive (≥0.1%). End points were 5-year event-free survival (EFS), cumulative incidence of relapse (CIR), and overall survival (OS). RESULTS: The high-risk group had inferior EFS (30.3% high risk v 54.0% non-high risk; P < .0001), CIR (59.7% v 35.2%; P < .0001), and OS (49.2% v 70.5%; P < .0001). EOI2 MRD negativity was associated with superior EFS (n = 413; 47.6% MRD negativity v n = 43; 16.3% MRD positivity; P < .0001) and OS (n = 413; 66.0% v n = 43; 27.9%; P < .0001), and showed a trend toward lower CIR (n = 392; 46.1% v n = 26; 65.4%; P = .016). Similar results were obtained for patients with EOI2 MRD negativity within both risk groups, except that within the non-high-risk group, CIR was comparable with that of patients with EOI2 MRD positivity. Allo-SCT in CR1 only reduced CIR (hazard ratio, 0.5 [95% CI, 0.4 to 0.8]; P = .00096) within the high-risk group but did not improve OS. In multivariable analyses, EOI2 MRD positivity and high-risk group were independently associated with inferior EFS, CIR, and OS. CONCLUSION: EOI2 flow-MRD is an independent prognostic factor and should be included as risk stratification factor in childhood KMT2A-r AML. Treatment approaches other than allo-SCT in CR1 are needed to improve prognosis.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Trastornos Mieloproliferativos , Niño , Humanos , Trasplante Homólogo , Trasplante de Células Madre Hematopoyéticas/métodos , Pronóstico , Recurrencia , Neoplasia Residual/etiología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapiaRESUMEN
Knowledge about the resistance of wood-polymer composites (WPCs) to biological attack is of high importance for purpose-oriented use in outdoor applications. To gain this knowledge, uniform test methods are essential. EN 15534-1 (2018) provides a general framework, including the recommendation of applying a pre-weathering procedure before the biological laboratory tests. However, the procedure's manner is not specified, and its necessity assumes that a durability test without such pre-weathering will not produce the structural changes that occur during outdoor use. To verify this assumption, this study examined the influence of natural, ground-level pre-weathering on the material properties of different WPC variants, which were tested at intervals of six months in four durability tests under laboratory conditions in accordance with EN 15534-1 (2018). Weathering factors were calculated from determined characteristic values such as mass loss, and loss in moduli of elasticity (MOE) and rupture (MOR). The weathering factors based on mechanical properties tended to decrease with increasing weathering duration. The expected negative influence of pre-weathering on these material properties was thus not confirmed. The weathering factors based on mass loss were subject to high variation. No significant effect of pre-weathering on mass loss due to fungal attack became evident. Overall, the necessity of a pre-weathering step in biological durability tests shall be questioned based on the presented results.
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Bloodstream infections (BSIs), especially those caused by Gram-negative rods (GNR) and viridans group streptococci (VGS), are common and potentially life-threatening complications of pediatric acute myeloid leukemia (AML) treatment. Limited literature is available on prophylactic regimens. We retrospectively evaluated the effect of different antibacterial prophylaxis regimens on the incidence of febrile neutropenic (FN) episodes and bacterial BSIs. Medical records of children (0−18 years) diagnosed with de novo AML and treated at two Dutch centers from May 1998 to March 2021 were studied. Data were analyzed per chemotherapy course and consecutive neutropenic period. A total of 82 patients had 316 evaluable courses: 92 were given with single-agent ciprofloxacin, 138 with penicillin plus ciprofloxacin, and 51 with teicoplanin plus ciprofloxacin. The remaining 35 courses with various other prophylaxis regimens were not statistically compared. During courses with teicoplanin plus ciprofloxacin, significantly fewer FN episodes (43 vs. 90% and 75%; p < 0.0001) and bacterial BSIs (4 vs. 63% and 33%; p < 0.0001) occurred than with single-agent ciprofloxacin and penicillin plus ciprofloxacin, respectively. GNR and VGS BSIs did not occur with teicoplanin plus ciprofloxacin and no bacterial BSI-related pediatric intensive care unit (PICU) admissions were required, whereas, with single-agent ciprofloxacin and penicillin plus ciprofloxacin, GNR BSIs occurred in 8 and 1% (p = 0.004), VGS BSIs in 24 and 14% (p = 0.0005), and BSI-related PICU admissions were required in 8 and 2% of the courses (p = 0.029), respectively. Teicoplanin plus ciprofloxacin as antibacterial prophylaxis is associated with a lower incidence of FN episodes and bacterial BSIs. This may be a good prophylactic regimen for pediatric AML patients during treatment.
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BACKGROUND: Pediatric acute myeloid leukemia (AML) is a challenging disease to treat in low- and middle-income countries (LMICs). Literature suggests that survival in LMICs is poorer compared with survival in high-income countries (HICs). AIMS: This study evaluates the outcomes of Kenyan children with AML and the impact of sociodemographic and clinical characteristics on outcome. METHODS AND RESULTS: A retrospective medical records study was performed at Moi Teaching and Referral Hospital (MTRH) in Eldoret, Kenya, between January 2010 and December 2018. Sociodemographic and clinical characteristics, and treatment outcomes were evaluated. Chemotherapy included two "3 + 7" induction courses with doxorubicin and cytarabine and two "3 + 5" consolidation courses with etoposide and cytarabine. Supportive care included antimicrobial prophylaxis with cotrimoxazole and fluconazole, and blood products, if available. Seventy-three children with AML were included. The median duration of symptoms before admission at MTRH was 1 month. The median time from admission at MTRH to diagnosis was 6 days and to the start of AML treatment 16 days. Out of the 55 children who were started on chemotherapy, 18 (33%) achieved complete remission, of whom 10 (56%) relapsed. The abandonment rate was 22% and the early death rate was 46%. The 2-year probabilities of event-free survival and overall survival were 4% and 7%, respectively. None of the sociodemographic and clinical characteristics were significantly associated with outcome. CONCLUSION: Survival of Kenyan children with AML is dismal and considerably lower compared with survival in HICs. Strategies to improve survival should be put in place including better supportive care, optimization of the treatment protocol, and reduction of the abandonment rate and time lag to diagnosis with sooner start of treatment.
Asunto(s)
Leucemia Mieloide Aguda , Combinación Trimetoprim y Sulfametoxazol , Protocolos de Quimioterapia Combinada Antineoplásica , Niño , Citarabina/farmacología , Citarabina/uso terapéutico , Doxorrubicina/uso terapéutico , Etopósido , Fluconazol/uso terapéutico , Humanos , Kenia/epidemiología , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Estudios Retrospectivos , Combinación Trimetoprim y Sulfametoxazol/uso terapéuticoRESUMEN
Introduction: Survival rates of pediatric acute myeloid leukemia (AML) in low- and middle-income countries (LMICs) seem extremely poor, and the available literature on the matter is scarce. Accordingly, there is a limited understanding of poor treatment outcomes seen in this population.Areas covered: We provide an overview of the available literature with respect to treatment outcomes of pediatric AML in LMICs yielding poor outcomes compared to high-income countries. Moreover, treatment outcomes vary markedly between LMICs. In addition, there is a wide variation among studies in how treatment outcomes are reported and analyzed.Expert opinion: The substantially inferior treatment outcomes of pediatric AML in LMICs emphasize the unprecedented importance of global initiatives and international collaborations to improve the survival of these patients. A coordinated approach is necessary to carry out country-specific situational analyses. These analyses will result in operational plans on how to structurally implement childhood cancer registries, align healthcare infrastructure, build on capacities, and provide universal health coverage in LMICs. In addition, we strongly recommend that, in the future, LMICs document, analyze, and publish pediatric AML treatment outcomes in a more structured and uniform manner.