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PURPOSE: The optimal management of fever without severe neutropenia (absolute neutrophil count [ANC] ≥500/µL) in pediatric patients with cancer is undefined. The previously proposed Esbenshade Vanderbilt (EsVan) models accurately predict bacterial bloodstream infections (BSIs) in this population and provide risk stratification to aid management, but have lacked prospective external validation. MATERIALS AND METHODS: Episodes of fever with a central venous catheter and ANC ≥500/µL occurring in pediatric patients with cancer were prospectively collected from 18 academic medical centers. Variables included in the EsVan models and 7-day clinical outcomes were collected. Five versions of the EsVan models were applied to the data with calculation of C-statistics for both overall BSI rate and high-risk organism BSI (gram-negative and Staphylococcus aureus BSI), as well as model calibration. RESULTS: In 2,565 evaluable episodes, the BSI rate was 4.7% (N = 120). Complications for the whole cohort were rare, with 1.1% (N = 27) needing intensive care unit (ICU) care by 7 days, and the all-cause mortality rate was 0.2% (N = 5), with only one potential infection-related death. C-statistics ranged from 0.775 to 0.789 for predicting overall BSI, with improved accuracy in predicting high-risk organism BSI (C-statistic 0.800-0.819). Initial empiric antibiotics were withheld in 14.9% of episodes, with no deaths or ICU admissions attributable to not receiving empiric antibiotics. CONCLUSION: The EsVan models, especially EsVan2b, perform very well prospectively across multiple academic medical centers and accurately stratify risk of BSI in episodes of non-neutropenic fever in pediatric patients with cancer. Implementation of routine screening with risk-stratified management for non-neutropenic fever in pediatric patients with cancer could safely reduce unnecessary antibiotic use.
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Bacteriemia , Infecciones Bacterianas , Infecciones , Neoplasias , Sepsis , Humanos , Niño , Estudios Prospectivos , Bacteriemia/diagnóstico , Bacteriemia/epidemiología , Bacteriemia/microbiología , Fiebre/diagnóstico , Fiebre/etiología , Neoplasias/complicaciones , Sepsis/diagnóstico , Antibacterianos/uso terapéuticoRESUMEN
The Practice Guidelines Committee of the American Society for Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to update its 2009 compendium-style infectious disease guidelines for hematopoietic cell transplantation (HCT). A completely new approach was taken with the goal of better serving clinical providers by publishing each standalone topic in the infectious disease series as a concise format of frequently asked questions (FAQ), tables, and figures. Adult and pediatric infectious disease and HCT content experts developed and then answered FAQs and finalized topics with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. This fifth guideline in the series focuses on Clostridioides difficile infection with FAQs that address the prevalence, incidence, clinical features, colonization versus infection, clinical complications, diagnostic considerations, pharmacological therapies for episodic or recurrent infection, and the roles of prophylactic antibiotics, probiotics, and fecal microbiota transplantation.
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Infecciones por Clostridium , Trasplante de Células Madre Hematopoyéticas , Adulto , Tratamiento Basado en Trasplante de Células y Tejidos , Niño , Infecciones por Clostridium/terapia , Trasplante de Microbiota Fecal , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Receptores de Trasplantes , Estados Unidos/epidemiologíaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Despite growing awareness of the biologic features underlying MLL-rearranged leukemia, targeted therapies for this leukemia have remained elusive and clinical outcomes remain dismal. MBNL1, a protein involved in alternative splicing, is consistently overexpressed in MLL-rearranged leukemias. We found that MBNL1 loss significantly impairs propagation of murine and human MLL-rearranged leukemia in vitro and in vivo. Through transcriptomic profiling of our experimental systems, we show that in leukemic cells, MBNL1 regulates alternative splicing (predominantly intron exclusion) of several genes including those essential for MLL-rearranged leukemogenesis, such as DOT1L and SETD1A. We finally show that selective leukemic cell death is achievable with a small molecule inhibitor of MBNL1. These findings provide the basis for a new therapeutic target in MLL-rearranged leukemia and act as further validation of a burgeoning paradigm in targeted therapy, namely the disruption of cancer-specific splicing programs through the targeting of selectively essential RNA binding proteins.
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Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica , Leucemia/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Unión al ARN/metabolismo , Empalme Alternativo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Trasplante de Médula Ósea , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Conjuntos de Datos como Asunto , Técnicas de Silenciamiento del Gen , Reordenamiento Génico , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Intrones/genética , Leucemia/tratamiento farmacológico , Leucemia/patología , Ratones , Ratones Noqueados , Cultivo Primario de Células , ARN Interferente Pequeño/metabolismo , Proteínas de Unión al ARN/antagonistas & inhibidores , Proteínas de Unión al ARN/genética , RNA-Seq , Quimera por Trasplante , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Germline PTEN (phosphatase and tensin homolog) mutations lead to inappropriate cell survival and growth, and a predisposition to multiple cancers. Some patients also have vascular anomalies (VAs), and it is unclear whether these patients have different phenotypes or oncologic risks. We conducted a two-institution retrospective cohort study to better understand the phenotypes of children and young adults with PTEN mutations, and to compare individuals with VA to those without. Almost half of the patients had thyroid tumors and nearly one quarter developed gastrointestinal tumors before 30 years of age. The presence of VA was positively associated with bulky overgrowth but did not appear to modify oncologic risk.
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Neoplasias Gastrointestinales/patología , Mutación , Neovascularización Patológica/complicaciones , Fosfohidrolasa PTEN/genética , Neoplasias de la Tiroides/patología , Malformaciones Vasculares/complicaciones , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Neoplasias Gastrointestinales/etiología , Neoplasias Gastrointestinales/genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Fenotipo , Pronóstico , Estudios Retrospectivos , Neoplasias de la Tiroides/etiología , Neoplasias de la Tiroides/genética , Adulto JovenRESUMEN
The thalassemias are genetically complex and usually autosomal recessive. We describe 5 unrelated individuals with non-transfusion-dependent ß-thalassemia (NTDT), some with apparently dominant transmission, because of a single ß-thalassemia mutation coinherited with a triplicated α-globin locus. Each had an initial, incorrect diagnosis of ß-thalassemia trait. The correct diagnosis of NTDT was made at a mean of 7 years of age. Despite reports of this compound genotype causing NTDT, it remains unfamiliar to many clinicians. To increase awareness, we highlight its varied and sometimes subtle clinical and laboratory features and the need for comprehensive genetic testing for timely and correct diagnosis.
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Diagnóstico Tardío/prevención & control , Duplicación de Gen , Pruebas Genéticas/normas , Conocimientos, Actitudes y Práctica en Salud , Mutación , Globinas alfa/genética , Talasemia beta/diagnóstico , Adolescente , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lactante , Masculino , Evaluación de Necesidades , Fenotipo , Pronóstico , Talasemia beta/genéticaAsunto(s)
Isquemia Encefálica/complicaciones , Hemoglobinopatías/complicaciones , Hemoglobinas Anormales/genética , Hidroxiurea/efectos adversos , Metahemoglobinemia/inducido químicamente , Enfermedad de Moyamoya/complicaciones , Aspirina/administración & dosificación , Aspirina/uso terapéutico , Isquemia Encefálica/sangre , Isquemia Encefálica/genética , Isquemia Encefálica/terapia , Niño , Femenino , Hemoglobinopatías/sangre , Hemoglobinopatías/genética , Hemoglobinopatías/terapia , Humanos , Hidroxiurea/uso terapéutico , Metahemoglobinemia/sangre , Enfermedad de Moyamoya/sangre , Enfermedad de Moyamoya/genética , Enfermedad de Moyamoya/terapia , Resultado del TratamientoRESUMEN
BACKGROUND: At diagnosis, there are prognostic implications of low-level leukemic blasts (CNS 2) in the cerebrospinal fluid (CSF) of patients with acute lymphoblastic leukemia (ALL). However, the significance of post-induction CNS 2 results and the impact of equipment on CNS 2 prevalence have not been well studied. PROCEDURE: A single-institution retrospective cohort study was conducted to analyze the outcome of patients with ≥1 post-induction CNS 2. A subanalysis compared the proportion of CNS 2 CSF results using 2 different cytocentrifuges; the Shandon Cytospin used from 2005 to 2008 and the Wescor Cytopro used from 2010 to 2014. RESULTS: Over 4500 post-induction CSF samples were analyzed, of which 59 were CNS 2. In covariate-adjusted analyses, post-induction CNS 2 did not significantly increase relapse risk. The proportion of CNS 2 results increased 4.3-fold in noninfants and 6.3-fold in infants using the Wescor Cytopro. Cytocentrifuge machine did not affect CNS 3 prevalence. CONCLUSIONS: These findings support our current practice of not changing management based on a post-induction CNS 2 CSF and highlight how equipment changes can significantly influence testing results. More data are needed to analyze relapse by subpopulations, such as those with repeated CNS 2 findings.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Líquido Cefalorraquídeo/química , Quimioterapia de Inducción/métodos , Recuento de Leucocitos/instrumentación , Recurrencia Local de Neoplasia/líquido cefalorraquídeo , Leucemia-Linfoma Linfoblástico de Células Precursoras/líquido cefalorraquídeo , Adolescente , Niño , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Hemophagocytic lymphohistiocytosis (HLH) is characterized by dysregulated immune activation. Primary HLH involves hereditary deficits in cytotoxic lymphocytes while secondary HLH is triggered by extrinsic factors. The HLH-2004 criteria are widely used for clinical diagnosis, yet their specificity for HLH or their ability to differentiate primary from secondary disease is unclear, potentially leading to inappropriate treatment. We describe several cases where fulfillment of HLH-2004 criteria obscured the diagnoses of underlying malignancies and delayed curative management. These issues are remedied without waiting for genetic testing results through an alternative diagnostic approach using flow cytometry-based immunologic assays and a thorough investigation for malignancy.
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Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/etiología , Linfoma/complicaciones , Linfoma/diagnóstico , Síndromes Paraneoplásicos/diagnóstico , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Adulto JovenRESUMEN
Behcet disease is a potentially life-threatening multisystemic vasculitis with thrombotic tendency. Mucocutaneous ulcers, arthritis, and uveitis are the most recognizable features, but may be absent at the time of medical evaluation. We report a case in which a 8-year old patient presented with spontaneous bilateral lower extremity deep venous thromboses, and screening for rheumatologic symptoms led to diagnosing Behcet. This case demonstrates that deep venous thromboses can be the initial event bringing a patient with Behcet to medical attention, highlighting the importance of screening for underlying rheumatologic diseases in pediatric patients who present with unprovoked thrombosis.