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OBJECTIVE: The primary aim of this paper is to accelerate the number of randomized experimental studies of the reliability and validity in-home tele-neuropsychological testing (tele-np-t). METHOD: We conducted a critical review of the tele-neuropsychology literature. We discuss this research in the context of the United States' public and private healthcare payer systems, including the Centers for Medicare & Medicaid Services (CMS) and Current Procedural Terminology (CPT) coding system's telehealth lists, and existing disparities in healthcare access. RESULTS: The number of tele-np publications has been stagnant since the onset of the COVID-19 pandemic. There are less published experimental studies of tele-neuropsychology (tele-np), and particularly in-home tele-np-t, than other tele-np publications. There is strong foundational evidence of the acceptability, feasibility, and reliability of tele-np-t, but relatively few studies of the reliability and validity of in-home tele-np-t using randomization methodology. CONCLUSIONS: More studies of the reliability and validity of in-home tele-np-t using randomization methodology are necessary to support inclusion of tele-np-t codes on the CMS and CPT telehealth lists, and subsequently, the integration and delivery of in-home tele-np-t services across providers and institutions. These actions are needed to maintain equitable reimbursement of in-home tele-np-t services and address the widespread disparities in healthcare access.
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Neuropsicología , Pandemias , Anciano , Humanos , Estados Unidos , Neuropsicología/métodos , Reproducibilidad de los Resultados , Medicare , Pruebas Neuropsicológicas , PolíticasRESUMEN
ABSTRACT: Distinct diagnostic entities within BCR::ABL1-positive acute lymphoblastic leukemia (ALL) are currently defined by the International Consensus Classification of myeloid neoplasms and acute leukemias (ICC): "lymphoid only", with BCR::ABL1 observed exclusively in lymphatic precursors, vs "multilineage", where BCR::ABL1 is also present in other hematopoietic lineages. Here, we analyzed transcriptomes of 327 BCR::ABL1-positive patients with ALL (age, 2-84 years; median, 46 years) and identified 2 main gene expression clusters reproducible across 4 independent patient cohorts. Fluorescence in situ hybridization analysis of fluorescence-activated cell-sorted hematopoietic compartments showed distinct BCR::ABL1 involvement in myeloid cells for these clusters (n = 18/18 vs n = 3/16 patients; P < .001), indicating that a multilineage or lymphoid BCR::ABL1 subtype can be inferred from gene expression. Further subclusters grouped samples according to cooperating genomic events (multilineage: HBS1L deletion or monosomy 7; lymphoid: IKZF1-/- or CDKN2A/PAX5 deletions/hyperdiploidy). A novel HSB1L transcript was highly specific for BCR::ABL1 multilineage cases independent of HBS1L genomic aberrations. Treatment on current German Multicenter Study Group for Adult ALL (GMALL) protocols resulted in comparable disease-free survival (DFS) for multilineage vs lymphoid cluster patients (3-year DFS: 70% vs 61%; P = .530; n = 91). However, the IKZF1-/- enriched lymphoid subcluster was associated with inferior DFS, whereas hyperdiploid cases showed a superior outcome. Thus, gene expression clusters define underlying developmental trajectories and distinct patterns of cooperating events in BCR::ABL1-positive ALL with prognostic relevance.
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Proteínas de Fusión bcr-abl , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Humanos , Persona de Mediana Edad , Adulto Joven , Enfermedad Aguda , Deleción Cromosómica , Proteínas de Fusión bcr-abl/genética , Genómica , Hibridación Fluorescente in Situ , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMEN
Epstein-Barr virus (EBV)-associated diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) constitute a distinct clinicopathological entity in the current World Health Organization (WHO) classification. However, its genomic features remain sparsely characterized. Here, we combine whole-genome sequencing (WGS), targeted amplicon sequencing (tNGS), and fluorescence in situ hybridization (FISH) from 47 EBV + DLBCL (NOS) cases to delineate the genomic landscape of this rare disease. Integrated WGS and tNGS analysis clearly distinguished this tumor type from EBV-negative DLBCL due to frequent mutations in ARID1A (45%), KMT2A/KMT2D (32/30%), ANKRD11 (32%), or NOTCH2 (32%). WGS uncovered structural aberrations including 6q deletions (5/8 patients), which were subsequently validated by FISH (14/32 cases). Expanding on previous reports, we identified recurrent alterations in CCR6 (15%), DAPK1 (15%), TNFRSF21 (13%), CCR7 (11%), and YY1 (6%). Lastly, functional annotation of the mutational landscape by sequential gene set enrichment and network propagation predicted an effect on the nuclear factor κB (NFκB) pathway (CSNK2A2, CARD10), IL6/JAK/STAT (SOCS1/3, STAT3), and WNT signaling (FRAT1, SFRP5) alongside aberrations in immunological processes, such as interferon response. This first comprehensive description of EBV + DLBCL (NOS) tumors substantiates the evidence of its pathobiological independence and helps stratify the molecular taxonomy of aggressive lymphomas in the effort for future therapeutic strategies.
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Infecciones por Virus de Epstein-Barr/complicaciones , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/virología , Adulto , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Femenino , Redes Reguladoras de Genes , Herpesvirus Humano 4/aislamiento & purificación , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Mutación , Secuenciación Completa del Genoma , Adulto JovenRESUMEN
PURPOSE: Infants treated for CNS malignancies experience a significantly poorer response to treatment and are particularly at risk for neuropsychological deficits. The literature is limited and inconsistent regarding cognitive outcomes among this group. We investigated predictors of cognitive outcomes in children treated for brain tumors during infancy as part of a large, prospective, multisite, longitudinal trial. PATIENTS AND METHODS: One hundred thirty-nine infants with a newly diagnosed CNS tumor were treated with chemotherapy, with or without focal proton or photon radiation therapy (RT). Cognitive assessments were conducted at baseline, 6 months, 1 year, and then annually for 5 years. The median length of follow-up was 816 days (26.8 months). Neurocognitive testing included assessment of intellectual functioning (intellectual quotient [IQ]), parent ratings of executive functioning and emotional and behavioral functioning, and socioeconomic status. RESULTS: At baseline, IQ, parent-reported working memory, and parent-reported adaptive functioning were worse than normative expectations. Baseline cognitive difficulties were associated with younger age at diagnosis and lower socioeconomic status. Linear mixed models did not demonstrate a decline in IQ over time. There were increased parent-reported attention and executive problems over time. Increased concerns were related to supratentorial tumor location and CSF diversion. There were no differences in cognitive outcomes based on treatment exposure (chemotherapy-only v chemotherapy with RT and proton v photon focal RT). CONCLUSION: Even before adjuvant therapy, young children with brain tumors experience cognitive difficulties that can affect quality of life. Changes in cognitive functioning over time were dependent on tumor location and surgical factors rather than adjuvant therapy. These findings may serve to guide treatment planning and indicate targets for cognitive monitoring and intervention.
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Neoplasias Encefálicas/complicaciones , Trastornos del Conocimiento/etiología , Preescolar , Trastornos del Conocimiento/patología , Femenino , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Masculino , Estudios ProspectivosRESUMEN
OBJECTIVE: To evaluate home-based teleneuropsychology in a pediatric cohort to determine if assessment via in-person and home-based videoconference yield similar results. The second objective was to determine the level of satisfaction with videoconference-based assessment among participants and caregivers. METHOD: Fifty-eight participants, aged 6-20 years, were recruited through specialty programs for pediatric demyelinating disorders. Each participant was administered the same brief neuropsychological battery of common measures twice, once during an in-person session and once during a remote home-based videoconference session. Order of sessions was counterbalanced and time between assessments ranged from 1 to 50 days. It was hypothesized that results obtained through in-person vs. remote videoconference sessions would not be significantly different and that most participants and caregivers would rate the experience with teleneuropsychology as satisfactory. RESULTS: Mann-Whitney U tests showed no significant differences in results obtained in the in-person first vs. remote videoconference first sessions or the change in performance across sessions. Satisfaction ratings by participants and caregivers were largely favorable for the use of the videoconference testing format. CONCLUSIONS: The current study is the first to validate home-based teleneuropsychology and is the first to validate teleneuropsychological assessment in a pediatric sample. Future studies should replicate these findings as well as expand on sample size, diversity of populations evaluated, and the assessment tools administered. Careful consideration of ethical and practical factors should be given before providing pediatric teleneuropsychology services.
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Satisfacción Personal , Comunicación por Videoconferencia , Adolescente , Adulto , Niño , Humanos , Pruebas Neuropsicológicas , Adulto JovenRESUMEN
Objective: Despite expansion of telecommunication strategies across health services and data supporting feasibility of videoconference-based neuropsychological assessment, relatively little is known about teleneuropsychology (TeleNP) use in practice. The current COVID-19 pandemic provides an opportunity for greater use of TeleNP and understanding of neuropsychologists' experience with this unique assessment medium.Methods: During the course of a no-cost global webinar related to practical/ethical considerations of TeleNP practice, attendees were invited to engage in a 26-question survey about their TeleNP use and related COVID-19 concerns. TeleNP practices before the COVID-19 pandemic and early on during the global outbreak were queried among survey participants, along with examination of TeleNP intentions following COVID-19.Results: Multiple countries were represented across five continents, with two-thirds of respondents being from the United States. Approximately one-fourth of respondents reported using TeleNP for clinical interview, feedback, and intervention prior to the onset of the COVID-19 pandemic, and approximately one-tenth of individuals used TeleNP for testadministration. Increased use of TeleNP for clinical interview, feedback, and intervention was reported within the first few weeks of the global COVID-19 outbreak, though the use of TeleNP for testing remained relatively unchanged. Most respondents indicated an intention for future use of TeleNP.Conclusions: Our findings suggest the use of TeleNP is increasing, although use of remote TeleNP testing is still developing. Findings also illustrate increasing use of TeleNP in the context of the COVID-19 pandemic and encourage follow-up investigation in future studies to understand the changing practices and rates of TeleNP provision over time.
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Betacoronavirus , Infecciones por Coronavirus/terapia , Internacionalidad , Neuropsicología/tendencias , Neumonía Viral/terapia , Encuestas y Cuestionarios , Telemedicina/tendencias , Adulto , COVID-19 , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/psicología , Atención a la Salud/métodos , Atención a la Salud/tendencias , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Neuropsicología/métodos , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/psicología , SARS-CoV-2 , Telemedicina/métodosRESUMEN
OBJECTIVE: The Inter Organizational Practice Committee convened a workgroup to provide rapid guidance about teleneuropsychology (TeleNP) in response to the COVID-19 pandemic. METHOD: A collaborative panel of experts from major professional organizations developed provisional guidance for neuropsychological practice during the pandemic. The stakeholders included the American Academy of Clinical Neuropsychology/American Board of Clinical Neuropsychology, the National Academy of Neuropsychology, Division 40 of the American Psychological Association, the American Board of Professional Neuropsychology, and the American Psychological Association Services, Inc. The group reviewed literature; collated federal, regional, and state regulations and information from insurers; and surveyed practitioners to identify best practices. RESULTS: Literature indicates that TeleNP may offer reliable and valid assessments, but clinicians need to consider limitations, develop new informed consent procedures, report modifications of standard procedures, and state limitations to diagnostic conclusions and recommendations. Specific limitations affect TeleNP assessments of older adults, younger children, individuals with limited access to technology, and individuals with other individual, cultural, and/or linguistic differences. TeleNP may be contraindicated or infeasible given specific patient characteristics, circumstances, and referral questions. Considerations for billing TeleNP services are offered with reservations that clinicians must verify procedures independently. Guidance about technical issues and "tips" for TeleNP procedures are provided. CONCLUSION: This document provides provisional guidance with links to resources and established guidelines for telepsychology. Specific recommendations extend these practices to TeleNP. These recommendations may be revised as circumstances evolve, with updates posted continuously at IOPC.online.
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Neuropsicología/métodos , Telemedicina/métodos , Comunicación por Videoconferencia , Betacoronavirus , COVID-19 , Infecciones por Coronavirus/epidemiología , Humanos , Consentimiento Informado , Seguro de Salud , Concesión de Licencias , Medicaid , Medicare , Pruebas Neuropsicológicas , Pandemias , Neumonía Viral/epidemiología , Mecanismo de Reembolso , SARS-CoV-2 , Sociedades Científicas , Encuestas y Cuestionarios , Estados Unidos/epidemiologíaRESUMEN
Objective: The Inter Organizational Practice Committee (IOPC) convened a workgroup to provide rapid guidance about teleneuropsychology (TeleNP) in response to the COVID-19 pandemic.Method: A collaborative panel of experts from major professional organizations developed provisional guidance for neuropsychological practice during the pandemic. The stakeholders included the American Academy of Clinical Neuropsychology/American Board of Clinical Neuropsychology, the National Academy of Neuropsychology, Division 40 of the American Psychological Association, the American Board of Professional Neuropsychology, and the American Psychological Association Services, Inc. The group reviewed literature, collated federal, regional and state regulations and information from insurers, and surveyed practitioners to identify best practices.Results: Literature indicates that TeleNP may offer reliable and valid assessments, but clinicians need to consider limitations, develop new informed consent procedures, report modifications of standard procedures, and state limitations to diagnostic conclusions and recommendations. Specific limitations affect TeleNP assessments of older adults, younger children, individuals with limited access to technology, and individuals with other individual, cultural, and/or linguistic differences. TeleNP may be contraindicated or infeasible given specific patient characteristics, circumstances, and referral questions. Considerations for billing TeleNP services are offered with reservations that clinicians must verify procedures independently. Guidance about technical issues and "tips" for TeleNP procedures are provided.Conclusion: This document provides provisional guidance with links to resources and established guidelines for telepsychology. Specific recommendations extend these practices to TeleNP. These recommendations may be revised as circumstances evolve, with updates posted continuously at OPC.online.
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Betacoronavirus , Infecciones por Coronavirus/terapia , Neuropsicología/normas , Pandemias , Neumonía Viral/terapia , Guías de Práctica Clínica como Asunto/normas , Telemedicina/normas , Academias e Institutos/normas , Comités Consultivos/normas , COVID-19 , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/psicología , Humanos , Pruebas Neuropsicológicas , Neuropsicología/métodos , Neumonía Viral/epidemiología , Neumonía Viral/psicología , SARS-CoV-2 , Encuestas y Cuestionarios , Telemedicina/métodos , Estados Unidos/epidemiologíaRESUMEN
IMPORTANCE: Patients afflicted with rare diseases often have a delay in diagnosis and treatment. Understanding the prevalence and impact of delayed diagnosis in transverse myelitis could trigger directed educational initiatives to increase clinician awareness and improve care. OBJECTIVE: To determine if symptoms at onset or care provider initially approached was associated with time to diagnosis, treatment or outcome in patients with transverse myelitis. DESIGN: This was an online patient and caregiver standardized survey to collect data about the initial medical experience. Patients were recruited through social media to complete a survey about initial symptoms, care provider approached for diagnosis, first events (hospital admission, testing, sent home, etc.), first diagnosis, time to treatment and outcomes. The data was collected by an independent, non-profit patient advocacy organization (The Transverse Myelitis Association) and provided to researchers for analysis. SETTING: This was an online survey of a prevalent cohort of individuals diagnosis with transverse myelitis. PARTICIPANTS: Patients with various autoimmune disorders responded to the survey. These included patients with multiple sclerosis, neuromyelitis optica, acute disseminated encephalomyelitis and idiopathic transverse myelitis. Only data about patients, greater than a year of age, with a diagnosis of transverse myelitis were included in the study.
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Diagnóstico Tardío , Errores Diagnósticos , Mielitis Transversa/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Encuestas Epidemiológicas , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mielitis Transversa/epidemiología , Mielitis Transversa/fisiopatología , Mielitis Transversa/terapia , Medios de Comunicación Sociales , Adulto JovenRESUMEN
Aspartylglucosaminuria is a lysosomal storage disorder enriched in Finland. We report on a pair of non-Finnish siblings with aspartylglucosaminuria with autofluorescent inclusion bodies on optical coherence tomography, a finding not previously reported in this disorder. We performed a record review, neurological and neuropsychological evaluation, brain MRI, and optical coherence tomography for each patient. They are compound heterozygous for a 34-kb deletion and a c.365C>A novel variant of the AGA gene. Autofluorescent inclusion bodies were found on optical coherence tomography in the older, more severely affected brother. We hypothesize the finding represents a noninvasive biomarker of disease severity for aspartylglucosaminuria.
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Immune-mediated central nervous system (CNS) demyelinating diseases impact various areas of the brain, optic nerves, and/or spinal cord and can result in a wide range of neurologic symptoms including adverse cognitive outcomes. Neuropsychological outcomes in adult multiple sclerosis (MS) are well documented, while literature on such outcomes in pediatric cohorts is more limited. Furthermore, literature on neuropsychological outcomes in pediatric acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO), and transverse myelitis (TM) is even more limited. This paper is the first to review what is known about neuropsychological outcomes associated with immune-mediated CNS demyelinating diseases, with a focus on pediatric MS, ADEM, NMO, and TM. Additionally, this review illuminates the need to clarify differences in neuropsychological sequelae between conditions, characterize longitudinal cognitive outcomes, and investigate neuropsychological outcomes in relation to clinical variables (e.g., age of onset, disease duration, number of relapses) and psychosocial variables (e.g., fatigue, emotional problems, behavioral functioning) to better understand neuropsychological outcomes associated with these conditions.
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Enfermedades Desmielinizantes/psicología , Esclerosis Múltiple/diagnóstico , Neuropsiquiatría/métodos , Niño , Enfermedades Desmielinizantes/patología , Femenino , Humanos , Masculino , Esclerosis Múltiple/patologíaRESUMEN
It has been proposed previously that extrinsic motivation may enable survivors of childhood medulloblastoma to significantly improve aspects of neurocognitive performance. In healthy populations, enhanced motivation has been shown to promote academic fluency, a domain likely more relevant to the educational outcomes of pediatric medulloblastoma survivors than academic skill development. The present study investigates the effect of enhanced extrinsic motivation on fluent (i.e., accurate and efficient) academic performance in pediatric medulloblastoma survivors. Participants were 36 children, ages 7-18, who had completed treatment for medulloblastoma. Participants completed a neuropsychological battery that included administration of equivalent tasks on Forms A and B of the Woodcock-Johnson III Tests of Achievement. Half were randomly assigned to an incentive condition prior to the administration of Form B. Provision of a performance-based incentive resulted in statistically significant improvement, but not normalization of function, in performance on measures of academic fluency. No demographic, treatment-related, academic, neuropsychological, or self-perception variables predicted response to incentive. Findings suggest that academic performance of survivors may significantly improve under highly motivating conditions. In addition to implications for educational services, this finding raises the novel possibility that decreased motivation represents an inherent neuropsychological deficit in this population and provides a rationale for further investigation of factors affecting individual differences in motivational processes. Further, by examining effort in a context where effort is not inherently suspect, present findings also significantly contribute to the debate regarding the effects of effort and motivation on neuropsychological performance.
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Logro , Neoplasias Cerebelosas/psicología , Meduloblastoma/psicología , Motivación , Sobrevivientes/psicología , Adolescente , Niño , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas/estadística & datos numéricosRESUMEN
OBJECTIVE: Fatigue, depression, anxiety, and executive dysfunction are associated with multiple sclerosis (MS) in adults. Existing research suggests similar problems in pediatric MS, but relationships between these variables have not been investigated. This study investigates the associations between executive functioning and fatigue, emotional functioning, age of onset, and disease duration in pediatric MS. METHODS: Twenty-six MS or Clinically Isolated Syndrome (CIS) patients, ages 7 to 18, were evaluated through a multidisciplinary demyelinating diseases clinic. Participants completed neuropsychological screening including Verbal Fluency, Digit Span, and Trail-Making Test. Parents completed rating forms of behavioral, emotional, and executive functioning. Patients and parents completed questionnaires related to the patient's quality of life and fatigue. Pearson's correlation coefficients were calculated to investigate relationships between fatigue, emotional functioning, and executive functioning, as well as to examine correlations between parent and child reports of fatigue. RESULTS: Rates of parent-reported anxiety, depression, fatigue, and executive dysfunction varied widely. Means were below average on the Trail-Making Test and average on Verbal Fluency and Digit Span, though scores varied widely. Various fatigue and emotional functioning indices-but not age of onset or disease duration-significantly correlated with various performance-based measures of executive functioning. CONCLUSION: Results indicate pediatric MS is associated with some degree of fatigue, emotional difficulties, and executive dysfunction, the latter of which is associated with the two former. Notably, age of onset and disease duration did not significantly correlate with executive functioning. Results advance understanding of psychological and clinical variables related to neurocognitive outcomes in pediatric MS.
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Emociones , Función Ejecutiva , Fatiga/etiología , Trastornos Mentales/etiología , Esclerosis Múltiple/psicología , Adolescente , Ansiedad/etiología , Niño , Depresión/etiología , Fatiga/psicología , Femenino , Humanos , Masculino , Trastornos Mentales/psicología , Pruebas Neuropsicológicas , Calidad de Vida , Encuestas y CuestionariosRESUMEN
Multiple Sclerosis (MS), an autoimmune mediated disease of the central nervous system, has historically been considered a disease of young adulthood. However, there has been increasing recognition that the disease can occur in adolescence and even early childhood and recent years have witnessed a surge of studies documenting the clinical features of the disease as it pertains to this young population. The purpose of this article is to review the literature on MS in childhood and adolescence, including the clinical presentation of the disease in this group, neuropathology and pathogenesis, magnetic resonance imaging findings, as well as neuropsychological and psychosocial considerations.
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Esclerosis Múltiple/patología , Esclerosis Múltiple/psicología , Pediatría/métodos , Adolescente , Encéfalo/patología , Niño , Humanos , Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple/tratamiento farmacológico , Pruebas NeuropsicológicasRESUMEN
BACKGROUND: Transverse myelitis (TM) is an inflammatory disease of the spinal cord. In pediatric TM patients, cognitive and psychological problems have been described only anecdotally. OBJECTIVES: Study aims include describing cognitive dysfunction among a cohort of pediatric TM patients as well as qualitatively exploring the impact of depression, medication, and fatigue on cognitive functioning. METHODS: Twenty-four consecutive TM patients referred to a pediatric demyelinating diseases clinic completed neuropsychological screening. Means, standard deviations (SD), and percentages of patients performing at or below 1.0, 1.5, and 2.0 SD from the mean on tests administered are presented. RESULTS: Means were generally average across domains; however, scores ranged widely across subjects within each domain. The highest rate of deficits was observed in fine-motor speed/dexterity. Slightly higher frequencies of impairment were observed in attention and memory as compared to processing speed and verbal fluency. Results did not suggest a clear association between cognitive problems and depression or medication use but did suggest that fatigue may impact cognitive functioning. CONCLUSIONS: This study is the first to document cognitive deficits in pediatric TM and raises questions regarding our understanding of the central nervous system (CNS) injury associated with TM. Findings warrant further exploration of neuropsychological outcomes in TM to inform appropriate intervention.
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Trastornos del Conocimiento/etiología , Mielitis Transversa/psicología , Adolescente , Niño , Preescolar , Trastornos del Conocimiento/epidemiología , Femenino , Humanos , Masculino , Mielitis Transversa/complicaciones , Pruebas NeuropsicológicasRESUMEN
Double heterozygosity for disease-causing BRCA1 and BRCA2 mutations is a very rare condition in most populations. Here we describe genetic and clinical data of eight female double heterozygotes (DH) for BRCA1 and BRCA2 mutations found in a cohort of 8162 German breast/ovarian cancer families and compare it with the data of their single heterozygous relatives and of the index patients of the German Consortium for Hereditary Breast and Ovarian Cancer. Furthermore, we analyze the phenotypic features of these patients with respect to age at onset of first cancer, first breast/ovarian cancer and the number of disease manifestations and compare them to that of published Caucasian female DHs and their single heterozygous female relatives. German DHs were not significantly younger at diagnosis of first breast cancer than the single heterozygous index patients of the German Consortium. However, if the data of our study were pooled with that of the literature, DHs were substantially younger at onset of first cancer (mean age 40.4 years, 95 % CI = 36.6-44.1) than their single heterozygous female relatives (mean age 51.9 years, 95 % CI = 46.8-57.0). The two groups also differed concerning the onset of first breast cancer (mean age 40.6 years, 95 % CI = 36.6-44.5 vs. 52.6, 95 % CI = 47.5-57.6). In addition, DHs had a more severe disease than their female relatives carrying a single BRCA mutation (1.4 vs. 0.6 manifestations per person). In contrast to Ashkenazi Jewish females, Caucasian DH females might develop breast cancer at an earlier age and have a more severe disease than single heterozygous BRCA mutation carriers. Therefore, DHs may benefit from more intensive surveillance programs/follow-up care and prophylactic surgery.
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Neoplasias de la Mama/genética , Genes BRCA1 , Genes BRCA2 , Heterocigoto , Mutación , Adulto , Edad de Inicio , Anciano , Neoplasias de la Mama/epidemiología , Etnicidad/genética , Familia , Femenino , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Persona de Mediana Edad , Linaje , Fenotipo , Factores de RiesgoRESUMEN
Translocations involving immunoglobulin (IG) loci are the hallmarks of several subtypes of B-cell lymphoma. Common to these translocations is that cellular proto-oncogenes come under the influence of IG regulatory elements leading to deregulated expression. In case of a breakpoint in the IGH switch region, oncogene activation can take place on both derivative chromosomes, which means that in principle one translocation can result in concurrent activation of two genes. By fluorescence in situ hybridization (FISH), we identified a case of leukemic B-cell lymphoma in a child with an IGH break and unknown partner. Subsequent long-distance inverse PCR revealed fusion of IGH Sl in 14q32 and the 50 region of CBFA2T3 in 16q24.3, suggesting presence of the t(14;16)(q32;q24.3). Candidate oncogenes targeted through this translocation are CBFA2T3 and ACSF3, which could be activated on der(16) and der(14), respectively. FISH screening of a population-based cohort of B-cell lymphomas from a prospective trial for the treatment of lymphoma in childhood (BFM-NHL) identified additionally a follicular lymphoma Grade 3/diffuse large B-cell lymphoma with IGH-CBFA2T3/ACSF3 juxtaposition. Both lymphomas shared expression of CD10 and CD20 in the absence of TdT, suggesting a germinal center (GC) B-cell origin. Our data indicate that the CBFA2T3/ACSF3 locus is a novel recurrent oncogenic target of IGH translocations, which might contribute to the pathogenesis of pediatric GC-derived B-cell lymphoma.
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Coenzima A Ligasas/genética , Genes de las Cadenas Pesadas de las Inmunoglobulinas , Linfoma de Células B/genética , Proteínas Represoras/genética , Translocación Genética , Proteínas Supresoras de Tumor/genética , Adolescente , Antígenos CD20/biosíntesis , Niño , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 16/genética , Femenino , Centro Germinal/patología , Centro Germinal/fisiología , Humanos , Hibridación Fluorescente in Situ , Linfoma de Células B/patología , Linfoma Folicular/genética , Masculino , Neprilisina/biosíntesisRESUMEN
ALK positive diffuse large B-cell lymphomas (DLBCL) are a distinct lymphoma subtype associated with a poor outcome. Most of them feature a t(2;17) encoding a clathrin (CLTC)-ALK fusion protein. The contribution of deregulated ALK-activity in the pathogenesis and maintenance of these DLBCLs is not yet known. We established and characterized the first CLTC-ALK positive DLBCL cell line (LM1). LM1 formed tumors in NOD-SCID mice. The selective ALK inhibitor NVP-TAE684 inhibited growth of LM1 cells in vitro at nanomolar concentrations. NVP-TAE684 repressed ALK-activated signalling pathways and induced apoptosis of LM1 DLBCL cells. Inhibition of ALK-activity resulted in sustained tumor regression in the xenotransplant tumor model. These data indicate a role of CLTC-ALK in the maintenance of the malignant phenotype thereby providing a rationale therapeutic target for these otherwise refractory tumors.