RESUMEN
Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification.
Asunto(s)
Edad de Inicio , Alelos , Encefalopatías/genética , Calcinosis/genética , Moléculas de Adhesión Celular/genética , Genes Recesivos , Adolescente , Adulto , Animales , Encefalopatías/diagnóstico por imagen , Calcinosis/diagnóstico por imagen , Niño , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , LinajeRESUMEN
This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on considerations for the comprehensive care of AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.
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Oncología Médica , Neoplasias , Humanos , Adolescente , Adulto Joven , Anciano , Neoplasias/diagnóstico , Neoplasias/terapia , Neoplasias/psicología , Consejo , Supervivencia , Factores de RiesgoRESUMEN
BACKGROUND: Few standard treatment options are available for patients with metastatic sarcomas. We did this trial to evaluate the efficacy, safety, and changes in the tumour microenvironment for durvalumab, an anti-PD-L1 drug, and tremelimumab, an anti-CTLA-4 drug, across multiple sarcoma subtypes. METHODS: In this single-centre phase 2 trial, done at The University of Texas MD Anderson Cancer Center (Houston, TX USA), patients aged 18 years or older with advanced or metastatic sarcoma with an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least one previous line of systemic therapy were enrolled in disease subtype-specific groups (liposarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma, osteosarcoma, alveolar soft-part sarcoma, chordoma, and other sarcomas). Patients received 1500 mg intravenous durvalumab and 75 mg intravenous tremelimumab for four cycles, followed by durvalumab alone every 4 weeks for up to 12 months. The primary endpoint was progression-free survival at 12 weeks in the intention-to-treat population (all patients who received at least one dose of treatment). Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02815995, and is completed. FINDINGS: Between Aug 17, 2016, and April 9, 2018, 62 patients were enrolled, of whom 57 (92%) received treatment and were included in the intention-to-treat population. With a median follow-up of 37·2 months (IQR 1·8-10·1), progression-free survival at 12 weeks was 49% (95% CI 36-61). 21 grade 3-4 treatment-related adverse events were reported, the most common of which were increased lipase (four [7%] of 57 patients), colitis (three [5%] patients), and pneumonitis (three [5%] patients). Nine (16%) patients had a treatment related serious adverse event. One patient had grade 5 pneumonitis and colitis. INTERPRETATION: The combination of durvalumab and tremelimumab is an active treatment regimen for advanced or metastatic sarcoma and merits evaluation in specific subsets in future trials. FUNDING: AstraZeneca.
Asunto(s)
Neoplasias Óseas , Colitis , Osteosarcoma , Neumonía , Sarcoma de Parte Blanda Alveolar , Neoplasias de los Tejidos Blandos , Anticuerpos Monoclonales , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Óseas/tratamiento farmacológico , Humanos , Osteosarcoma/tratamiento farmacológico , Sarcoma de Parte Blanda Alveolar/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/patología , Microambiente TumoralRESUMEN
OBJECTIVES: We reviewed our experience treating patients with localized extraskeletal Ewing sarcoma (EES) to determine optimal local management strategies for this rare disease. METHODS: Sixty patients with localized EES treated at our institution between 1994 and 2018 were reviewed. The Kaplan-Meier method was used to estimates disease outcomes. RESULTS: The median follow-up time was 74 months (interquartile range [IQR], 17-121). Half the patients (n = 30) received combined-modality local therapy (CMT) with both surgery and radiation therapy (RT), whereas the other half received single-modality local therapy (SMT) with either surgery or RT. All patients received chemotherapy. The 5-year overall survival was 76%. Twenty-two patients (37%) developed recurrence at a median time of 15 months (IQR, 5-56 months) resulting in 3-year progression-free survival (PFS) of 65%. On univariate analysis, the use of both neoadjuvant and adjuvant chemotherapy was associated with improved 5-year PFS (71% vs. 50%, p = .04) compared with those who received one or the other. Furthermore, 11 patients (18%) developed local recurrences at a median time of 14 months (IQR, 2-19 months), resulting in a 5-year local control (LC) rate of 77%. Use of CMT was not associated with improved LC (83% vs. 72% SMT, p = .41). Also, use of CMT was the only factor associated with poorer disease-specific survival (vs. SMT; hazard ratio, 3.4; p = .047; 95% confidence interval, 1.01-11.4). CONCLUSION: For patients with EES, CMT was not associated with a decreased rate of local relapse. These data suggest that SMT alone may be sufficient for LC in select patients. A multi-institutional collaborative effort should be considered to validate these findings. IMPLICATIONS FOR PRACTICE: Extraskeletal Ewing sarcoma is a rare chemosensitive sarcoma whose clinical course more closely follows Ewing sarcoma of bone rather than that of other soft tissue sarcomas. Based on this study, combined-modality local therapy did not confer a local control advantage compared with single-modality local therapy. Therefore, single-modality local therapy is likely adequate in select patients with favorable disease features, which has the advantage of ensuring prompt administration of systemic therapy. A multi-institutional collaborative effort is warranted to determine which patients may benefit from de-escalated local therapy.
Asunto(s)
Neoplasias Óseas , Sarcoma de Ewing , Sarcoma , Neoplasias de los Tejidos Blandos , Neoplasias Óseas/tratamiento farmacológico , Terapia Combinada , Humanos , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Sarcoma de Ewing/tratamiento farmacológico , Resultado del TratamientoRESUMEN
PURPOSE: Metastatic phyllodes tumors of the breast (MPT) are rare breast neoplasms, limiting development of standardized treatment approaches. We sought to characterize the largest group of MPT thus far reported, evaluating systemic therapy outcomes. METHODS: Adult patients diagnosed with MPT between 1993 and 2015 and followed at MD Anderson Cancer Center were selected for retrospective chart review. Systemic therapy was sorted into: adriamycin/ifosfamide (AI), other anthracycline regimens, other ifosfamide regimens, gemcitabine-based regimens, and other. Given one patient may have received more than one regimen, we assumed that the effects of each regimen were independent from previous therapy. Median overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Log-rank test was performed to evaluate the difference in OS between patient characteristics groups, and the differences in PFS between the five chemotherapy regimens. RESULTS: We identified 50 MPT patients, with 31 patients receiving 61 systemic regimens. Median OS was 10.7 months (95% CI: 8.67, 16.5). AI had a PFS of 9.10 months (95% CI: 5.03, 14.2), other ifosfamide regimens had a PFS of 5.10 months (95% CI: 0.67, 12.1), other anthracycline regimens had a PFS of 3.65 months (95% CI: 1.17, 7.90), gemcitabine-based regimens had a PFS of 2.80 months (95% CI: 1.83, 4.60), and other regimens had a PFS of 1.67 months (95% CI: 1.13, 7.77). CONCLUSION: MPT patients are a unique population with limited characterization to date. Our study demonstrates activity of multiple sarcoma-directed chemotherapy regimens, with ifosfamide-containing regimens having the longest PFS.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mama , Neoplasias de la Mama/tratamiento farmacológico , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.
Asunto(s)
Mutación con Ganancia de Función , Estudios de Asociación Genética , Genotipo , Helicasa Inducida por Interferón IFIH1/genética , Fenotipo , Alelos , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Enfermedades Autoinmunes del Sistema Nervioso/genética , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Helicasa Inducida por Interferón IFIH1/química , Masculino , Modelos Moleculares , Malformaciones del Sistema Nervioso/diagnóstico , Malformaciones del Sistema Nervioso/genética , Conformación Proteica , Relación Estructura-ActividadRESUMEN
Variants in the FIG4 gene, which encodes a phosphatidylinositol-3,5-bisphosphatase lead to obstruction of endocytic trafficking, causing accumulation of enlarged vesicles in murine peripheral neurons and fibroblasts. Bi-allelic pathogenic variants in FIG4 are associated with neurological disorders including Charcot-Marie-Tooth disease type-4J (CMT4J) and Yunis-Varón syndrome (YVS). We present four probands from three unrelated families, all homozygous for a recurrent FIG4 missense variant c.506A>C p.(Tyr169Ser), with a novel phenotype involving features of both CMT4J and YVS. Three presented with infant-onset dystonia and one with hypotonia. All have depressed lower limb reflexes and distal muscle weakness, two have nerve conduction studies (NCS) consistent with severe sensorimotor demyelinating peripheral neuropathy and one had NCS showing patchy intermediate/mildly reduced motor conduction velocities. All have cognitive impairment and three have swallowing difficulties. MRI showed cerebellar atrophy and bilateral T2 hyperintense medullary swellings in all patients. These children represent a novel clinicoradiological phenotype and suggest that phenotypes associated with FIG4 missense variants do not neatly fall into previously described diagnoses but can present with variable features. Analysis of this gene should be considered in patients with central and peripheral neurological signs and medullary radiological changes, providing earlier diagnosis and informing reproductive choices.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Displasia Cleidocraneal/genética , Displasia Ectodérmica/genética , Flavoproteínas/genética , Predisposición Genética a la Enfermedad , Deformidades Congénitas de las Extremidades/genética , Micrognatismo/genética , Monoéster Fosfórico Hidrolasas/genética , Edad de Inicio , Enfermedad de Charcot-Marie-Tooth/complicaciones , Enfermedad de Charcot-Marie-Tooth/patología , Niño , Preescolar , Displasia Cleidocraneal/complicaciones , Displasia Cleidocraneal/patología , Distonía/complicaciones , Distonía/genética , Distonía/patología , Displasia Ectodérmica/complicaciones , Displasia Ectodérmica/patología , Femenino , Genotipo , Humanos , Deformidades Congénitas de las Extremidades/complicaciones , Deformidades Congénitas de las Extremidades/patología , Masculino , Micrognatismo/complicaciones , Micrognatismo/patología , Hipotonía Muscular/complicaciones , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Mutación/genética , Linaje , FenotipoRESUMEN
We report the clinical and molecular characterization of a novel biallelic mutation in the CSF1R gene leading to an autosomal recessive form of childhood onset leukoencephalopathy in a consanguineous family. The female child experienced acute encephalopathy at the age of 2 years, followed by spasticity and loss of all achieved milestones over 6 months. Her elder brother presented with encephalopathy at 4 years of age, with a subsequent loss of all achieved milestones over 8 months. Brain imaging in both children revealed multiple well-defined areas of calcification in the parietal and frontal regions and the occipital horns of both lateral ventricles. Clinical exome trio analysis showed homozygosity for a p.T833M mutation in CSF1R in the girl. Heterozygous family members, including both parents, were asymptomatic, with the eldest being 68 years of age. Total CSF1R protein expression levels were normal as compared with wild-type allele, but CSF1 ligand dependent autophosphorylation was consistent with a hypomorphic allele.
Asunto(s)
Leucoencefalopatías , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Preescolar , Consanguinidad , Resultado Fatal , Femenino , Humanos , Leucoencefalopatías/genética , Leucoencefalopatías/patología , Leucoencefalopatías/fisiopatología , Masculino , LinajeRESUMEN
BACKGROUND: A homozygous founder mutation in MTPAP/TENT6, encoding mitochondrial poly(A) polymerase (MTPAP), was first reported in six individuals of Old Order Amish descent demonstrating an early-onset, progressive spastic ataxia with optic atrophy and learning difficulties. MTPAP contributes to the regulation of mitochondrial gene expression through the polyadenylation of mitochondrially encoded mRNAs. Mitochondrial mRNAs with severely truncated poly(A) tails were observed in affected individuals, and mitochondrial protein expression was altered. OBJECTIVE: To determine the genetic basis of a perinatal encephalopathy associated with stereotyped neuroimaging and infantile death in three patients from two unrelated families. METHODS: Whole-exome sequencing was performed in two unrelated patients and the unaffected parents of one of these individuals. Variants and familial segregation were confirmed by Sanger sequencing. Polyadenylation of mitochondrial transcripts and de novo synthesis of mitochondrial proteins were assessed in patient's fibroblasts. RESULTS: Compound heterozygous p.Ile428Thr and p.Arg523Trp substitutions in MTPAP were recorded in two affected siblings from one family, and a homozygous p.Ile385Phe missense variant identified in a further affected child from a second sibship. Mitochondrial poly(A) tail analysis demonstrated shorter posttranscriptional additions to the mitochondrial transcripts, as well as an altered expression of mitochondrial proteins in the fibroblasts of the two siblings compared with healthy controls. CONCLUSION: Mutations in MTPAP likely cause an autosomal recessive perinatal encephalopathy with lethality in the first year of life.
Asunto(s)
Encefalopatías/genética , Encefalopatías/metabolismo , ARN Polimerasas Dirigidas por ADN/genética , Fibroblastos/metabolismo , Proteínas Mitocondriales/metabolismo , Femenino , Humanos , Lactante , Muerte del Lactante , Masculino , Proteínas Mitocondriales/genética , Linaje , Secuenciación del ExomaRESUMEN
Comprehensive reviews of the clinical characteristics and pathogenesis of Aicardi-Goutières syndrome (AGS), particularly its contextualization within a putative type I interferonopathy framework, already exist. However, recent reports of attempts at treatment suggest that an assessment of the field from a therapeutic perspective is warranted at this time. Here, we briefly summarize the neurological phenotypes associated with mutations in the seven genes so far associated with AGS, rehearse current knowledge of the pathology as it relates to possible treatment approaches, critically appraise the potential utility of therapies, and discuss the challenges in assessing clinical efficacy. WHAT THIS PAPER ADDS: Progress in understanding AGS disease pathogenesis has led to the first attempts at targeted treatment. Further rational therapies are expected to become available in the short- to medium-term.
Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/terapia , Malformaciones del Sistema Nervioso/terapia , Enfermedades Autoinmunes del Sistema Nervioso/etiología , Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Humanos , Malformaciones del Sistema Nervioso/etiología , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/inmunologíaRESUMEN
The lipid phosphatase gene FIG4 is responsible for Yunis-Varón syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same G > A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in read-through from exon 20 into intron 20 and truncation of the final 115 C-terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defects in the FIG4 null mouse and the known role of FIG4 in oligodendrocyte maturation. The families described here the expanded clinical spectrum of FIG4 deficiency to include leukoencephalopathy.
Asunto(s)
Alelos , Enfermedades Desmielinizantes/diagnóstico , Enfermedades Desmielinizantes/genética , Flavoproteínas/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mutación , Monoéster Fosfórico Hidrolasas/genética , Niño , Preescolar , Análisis Mutacional de ADN , Enfermedades Desmielinizantes/metabolismo , Fibroblastos/metabolismo , Genotipo , Humanos , Patrón de Herencia , Imagen por Resonancia Magnética , Masculino , Neuroimagen , Linaje , FenotipoRESUMEN
AIM: To test the hypothesis that children and young people with neurological conditions who missed outpatient appointments have more emergency inpatient admissions and Accident and Emergency centre (A&E) visits than those who missed none. METHOD: Retrospective cohort of individuals aged up to 19 years with neurological conditions, identified from routine hospital data in England, UK from April 1st, 2003 to March 31st, 2015 using an International Statistical Classification of Diseases and Related Health Problems, coding framework. Counts of emergency inpatient admissions and A&E visits per person per year were modelled (random intercept negative binomial regression) with outpatient attendance the independent variable of interest. RESULTS: The cohort numbered 524 613 individuals. Those who missed outpatient appointments had 19 per cent (95% confidence interval [CI] 18-19) more emergency inpatient admissions and 16 per cent (95% CI 15-17) more A&E visits per year than those who missed none. 'Did not attends' had a larger increase in unplanned health care than patient or provider cancellations. If no appointments were missed, the models predict there would have been 107 000 fewer A&E visits from 2007/2008 to 2014/2015 and 104 000 fewer emergency inpatient admissions from 2003/2004 to 2014/2015. INTERPRETATION: Missed outpatient appointments were associated with increased unplanned health care. Improving outpatient attendance may have the potential to reduce emergency inpatient admissions and A&E visits. WHAT THIS PAPER ADDS: Missed outpatient appointments by children and young people with neurological conditions are associated with increased unplanned health care. Both emergency inpatient admissions and Accident and Emergency centre visits are increased. 'Did not attends' are more strongly associated with unplanned health care than cancellations.
ATENCIÓN AMBULATORIA SIN CITA Y ATENCIÓN MÉDICA NO PLANIFICADA PARA NIÑOS Y JÓVENES CON AFECCIONES NEUROLÓGICAS: UN ESTUDIO DE COHORTE RETROSPECTIVO: OBJETIVO: Evaluar la hipótesis de que los niños y los jóvenes con afecciones neurológicas que faltaron a las citas para pacientes ambulatorios tienen más ingresos de pacientes hospitalizados de emergencia, y visitas de accidentes y de emergencia, que aquellos que no faltaron a ninguno. MÉTODO: Cohorte retrospectiva de individuos de hasta 19 años con afecciones neurológicas, identificada a partir de datos hospitalarios de rutina en Inglaterra desde el 1 de abril de 2003 hasta el 31 de marzo de 2015 mediante una Clasificación Internacional de Enfermedades, 10ª Revisión, como marco de codificación. Utilizando modelos estadísticos se consideraron los numeros de ingresos de pacientes hospitalizados de emergencia y las visitas de accidentes y emergencias por persona por año (intercepción aleatoria de regresión binomial negativa) con asistencia ambulatoria como variable independiente de interés. RESULTADOS: La cohorte incluyo 524.613 individuos. Aquellos que faltaron a las citas para pacientes ambulatorios tuvieron un 19% (95% intervalo de confianza [IC] 18-19) más hospitalizaciones de emergencia y un 16% (95% CI 15-17) más visitas de accidentes y emergencias por año que aquellos que no faltaron a ninguna. "No asistió" tuvo un aumento mayor en la atención no planificada que las cancelaciones de pacientes o proveedores. Si no se faltara a ninguna cita, los modelos predicen que habría habido 107.000 visitas de accidentes y emergencias menos de 2007/2008 a 2014/2015 y 104.000 menos hospitalizaciones de emergencia para pacientes hospitalizados de 2003/2004 a 2014/2015. INTERPRETACIÓN: Las citas ambulatorias perdidas se asociaron con una mayor atención no planificada. Mejorar la asistencia ambulatoria puede tener el potencial de reducir las admisiones de pacientes hospitalizados de emergencia y las visitas de accidentes y emergencias.
NÃO-COMPARECIMENTO A CONSULTAS AGENDADAS E CUIDADO EM SAÚDE NÃO PLANEJADO PARA CRIANÇAS E JOVENS COM CONDIÇÕES NEUROLÓGICAS: UM ESTUDO DE COORTE RETROSPECTIVO: OBJETIVO: Testar a hipótese de que crianças e jovens com condições neurológicas que perderam consultas agendadas têm mais admissões de internações de emergência, de acidentes e visitas de emergência do que os que não perderam nenhuma consulta. MÉTODO: Uma coorte retrospectiva com idade de até 19 anos com condições neurológicas, identificada a partir de dados de rotina de um hospital na Inglaterra de 1 de abril de 2003 a 31 de março de 2015, usando o sistema de códigos da Classificação Internacional de Doenças, 10a edição. Quantidades de admissões em internações de emergência, e visitas de emergência e de acidentes por pessoa por ano foram modeladas (regressão binomial com intercepto aleatório negative), com frequência em consultas sendo a variável de interesse. RESULTADOS: A coorte atingiu 524.613 indivíduos. Aqueles que perderam consultas agendadas tiveram 19% (intervalo de confiança [IC] 95% 18-19) mais internações de emergência e 16% (IC 95% 15-17) mais visitas de acidente e emergência por ano do que aqueles que não perderam nenhuma. "Não comparecimentos" tiveram maior aumento de cuidado não planejado do que cancelamentos por parte do paciente ou professional. Se nenhuma consulta fosse perdida, os modelos predizem que haveria 107.000 menos visitas de emergência de 2007/2008 a 2014/2015 e 104.000 menos internações de emergência de 2003/2004 a 2014/2015. INTERPRETAÇÃO: Consultas perdidas foram associadas com aumento de cuidado não planejado. Melhorar a frequência a consultas pode ter o potencial de reduzir internações de emergência e visitas de emergência e de acidentes.
Asunto(s)
Atención Ambulatoria , Servicios Médicos de Urgencia , Enfermedades del Sistema Nervioso/terapia , Pacientes no Presentados , Adolescente , Citas y Horarios , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Análisis Multivariante , Enfermedades del Sistema Nervioso/epidemiología , Aceptación de la Atención de Salud , Admisión del Paciente , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
We describe progressive spastic paraparesis in two male siblings and the daughter of one of these individuals. Onset of disease occurred within the first decade, with stiffness and gait difficulties. Brisk deep tendon reflexes and extensor plantar responses were present, in the absence of intellectual disability or dermatological manifestations. Cerebral imaging identified intracranial calcification in all symptomatic family members. A marked upregulation of interferon-stimulated gene transcripts was recorded in all three affected individuals and in two clinically unaffected relatives. A heterozygous IFIH1 c.2544T>G missense variant (p.Asp848Glu) segregated with interferon status. Although not highly conserved (CADD score 10.08 vs. MSC-CADD score of 19.33) and predicted as benign by in silico algorithms, this variant is not present on publically available databases of control alleles, and expression of the D848E construct in HEK293T cells indicated that it confers a gain-of-function. This report illustrates, for the first time, the occurrence of autosomal-dominant spastic paraplegia with intracranial calcifications due to an IFIH1-related type 1 interferonopathy.
Asunto(s)
Helicasa Inducida por Interferón IFIH1/genética , Paraparesia Espástica/genética , Algoritmos , Encefalopatías/genética , Calcinosis/genética , Femenino , Mutación con Ganancia de Función/genética , Células HEK293 , Heterocigoto , Humanos , Masculino , Mutación Missense/genética , LinajeRESUMEN
This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on treatment and management considerations for AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for AYA Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.
Asunto(s)
Neoplasias/diagnóstico , Neoplasias/terapia , Adolescente , Conducta , Terapia Combinada/métodos , Manejo de la Enfermedad , Femenino , Fertilidad , Humanos , Incidencia , Neoplasias/epidemiología , Neoplasias/etiología , Cuidados Paliativos , Embarazo , Complicaciones Neoplásicas del Embarazo , Cuidado Terminal , Adulto JovenRESUMEN
Mesenchymal chondrosarcoma is a rare but deadly form of chondrosarcoma that typically affects adolescents and young adults. While curative intent is possible for patients with localized disease, few options exist for patients in the unresectable/metastatic setting. Thus, it is imperative to understand the fusion-driven biology of this rare malignant neoplasm so as to lead to the future development of better therapeutics for this disease. This manuscript will briefly review the clinical and pathologic features of mesenchymal chondrosarcoma followed by an appraisal of existing data linked to the fusions, HEY1-NCOA2 and IRF2BP2-CDX1, and the associated downstream pathways.
Asunto(s)
Neoplasias Óseas/patología , Condrosarcoma Mesenquimal/patología , Proteínas de Fusión Oncogénica/genética , Neoplasias Óseas/genética , Condrosarcoma Mesenquimal/genética , Humanos , PronósticoRESUMEN
Alexander disease (AD) is a leukodystrophy caused by heterozygous mutations in the gene encoding the glial fibrillary acidic protein (GFAP). Currently, de novo heterozygous missense mutations in the GFAP gene are identified in over 95% of patients with AD. However, patients with biopsy-proven AD have been reported in whom no GFAP mutation has been identified. We report identical twin boys presenting in infancy with seizures and developmental delay in whom MR appearances were suggestive of AD with the exception of an unusual, bilateral, arc of calcification at the frontal white-gray junction. Initial mutation screening of the GFAP gene did not identify a mutation. Whole exome sequencing in both brothers revealed a de novo heterozygous in-frame deletion of the whole of exon 5 of the GFAP gene. Mutations in the GFAP gene are thought to result in a toxic effect of mutant GFAP disrupting the formation of the normal intermediate filament network and resulting in Rosenthal fiber formation, which has hitherto not been linked to exonic scale copy number variants in GFAP. Further studies on mutation negative AD patients are warranted to determine whether a similar mechanism underlies their disease.
Asunto(s)
Enfermedad de Alexander/genética , Exones/genética , Eliminación de Gen , Proteína Ácida Fibrilar de la Glía/genética , Enfermedad de Alexander/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Niño , Preescolar , Análisis Mutacional de ADN , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Tomógrafos Computarizados por Rayos XRESUMEN
BACKGROUND: Prognostic biomarkers for osteosarcoma (OS) at the time of diagnosis are lacking. Necrotic response of OS to preoperative chemotherapy correlates with survival and is determined 3-4 months after diagnosis. The purpose of this study is to identify biomarkers that will stratify patients into good or poor responders to chemotherapy at diagnosis and determine the role of potential biomarkers in OS pathogenesis. PROCEDURE: Because OS may be caused by disruptions of osteogenic differentiation, and the Notch pathway is one regulator of bone development, we examined the link between Notch effectors, OS differentiation, and OS outcome. We probed the R2: Genomics Analysis and Visualization Platform for RNA expression levels of Notch targets in mixed high-grade OS pretreatment biopsies. We used human OS cell lines in vitro and in mice to determine the role of the Notch target hairy/enhancer of split 4 (Hes4) in OS. RESULTS: We found that in OS patients, high expression of Hes4 is correlated with decreased metastasis-free and overall survival. Human OS cells that overexpress Hes4 are more immature and have an increased invasive capacity in vitro. This was not universal to all Notch effectors, as Hes1 overexpression induced opposing effects. When injected into NSG mice, Hes4-overexpressing OS cells produced significantly larger, more lytic tumors and significantly more metastases than did control cells. CONCLUSIONS: Hes4 overexpression promotes a more aggressive tumor phenotype by preventing osteoblastic differentiation of OS cells. Hes4 expression may allow for the stratification of patients into good or poor responders to chemotherapy at diagnosis.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Neoplasias Óseas/patología , Osteogénesis/fisiología , Osteosarcoma/patología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Biomarcadores de Tumor/genética , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/genética , Línea Celular Tumoral , Subunidad alfa 1 del Factor de Unión al Sitio Principal/biosíntesis , Células HEK293 , Humanos , Ratones , Trasplante de Neoplasias , Osteosarcoma/diagnóstico , Osteosarcoma/genética , Pronóstico , Factor de Transcripción Sp7 , Factores de Transcripción/biosíntesis , Trasplante Heterólogo , Resultado del TratamientoRESUMEN
PURPOSE: Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases. METHODS: We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations. RESULTS: We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy. CONCLUSIONS: Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.
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Enfermedades Autoinmunes/genética , Discapacidad Intelectual/genética , Lupus Eritematoso Sistémico/genética , Mutación , Osteocondrodisplasias/genética , Púrpura Trombocitopénica Idiopática/genética , Fosfatasa Ácida Tartratorresistente/genética , Adolescente , Adulto , Alelos , Autoanticuerpos/biosíntesis , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Huesos/inmunología , Huesos/patología , Encéfalo/inmunología , Encéfalo/patología , Niño , Preescolar , Femenino , Expresión Génica , Genotipo , Humanos , Discapacidad Intelectual/inmunología , Discapacidad Intelectual/patología , Interferón Tipo I/genética , Interferón Tipo I/inmunología , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/patología , Masculino , Osteocondrodisplasias/inmunología , Osteocondrodisplasias/patología , Linaje , Fenotipo , Púrpura Trombocitopénica Idiopática/inmunología , Púrpura Trombocitopénica Idiopática/patología , Fosfatasa Ácida Tartratorresistente/deficiencia , Fosfatasa Ácida Tartratorresistente/inmunologíaRESUMEN
The Aicardi-Goutières syndrome (AGS) was first described in 1984, and over the following years was defined by the clinical and radiological features of an early onset, severe, neurologic disorder with intracranial calcification, leukoencephalopathy, and cerebral atrophy, usually associated with a cerebrospinal fluid (CSF) pleocytosis and elevated CSF interferon α activity. It is now recognized that mutations in any of the following seven genes may result in the classical AGS phenotype: TREX1 (AGS1), RNASEH2A (AGS2), RNASEH2B (AGS3), RNASEH2C (AGS4), SAMHD1 (AGS5), ADAR1 (AGS6), and IFIH1 (AGS7). All of these genes encode proteins involved in nucleotide metabolism and/or sensing. Mutations in these genes result in the induction of type 1 interferon production and an upregulation of interferon stimulated genes. As more patients harboring mutations in these genes have been described, in particular facilitated by the advent of whole exome sequencing, a remarkably broad spectrum of associated neurologic phenotypes has been revealed, which we summarize here. We propose that the term AGS has continued clinical utility in the designation of a characteristic phenotype, which suggests relevant diagnostic investigations and can inform outcome predictions. However, we also suggest that the use of the term "type 1 interferonopathy" is appropriate for the wider spectrum of disease consequent upon dysfunction of these genes and proteins since it implies the possibility of a common "anti-interferon" approach to therapy as such treatments become available.
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Enfermedades Autoinmunes del Sistema Nervioso/genética , Mutación/genética , Malformaciones del Sistema Nervioso/genética , Adenosina Desaminasa/genética , Enfermedades Autoinmunes del Sistema Nervioso/líquido cefalorraquídeo , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico por imagen , Exodesoxirribonucleasas/genética , Estudios de Asociación Genética , Humanos , Helicasa Inducida por Interferón IFIH1/genética , Interferones/líquido cefalorraquídeo , Imagen por Resonancia Magnética , Proteínas de Unión al GTP Monoméricas/genética , Malformaciones del Sistema Nervioso/líquido cefalorraquídeo , Malformaciones del Sistema Nervioso/diagnóstico por imagen , Fosfoproteínas/genética , Proteínas de Unión al ARN/genética , Ribonucleasa H/genética , Proteína 1 que Contiene Dominios SAM y HDRESUMEN
Primary familial brain calcification (PFBC) is a heterogeneous neuropsychiatric disorder, with affected individuals presenting a wide variety of motor and cognitive impairments, such as migraine, parkinsonism, psychosis, dementia, and mood swings. Calcifications are usually symmetrical, bilateral, and found predominantly in the basal ganglia, thalamus, and cerebellum. So far, variants in three genes have been linked to PFBC: SLC20A2, PDGFRB, and PDGFB. Variants in SLC20A2 are responsible for most cases identified so far and, therefore, the present review is a comprehensive worldwide summary of all reported variants to date. SLC20A2 encodes an inorganic phosphate transporter, PiT-2, widely expressed in various tissues, including brain, and is part of a major family of solute carrier membrane transporters. Fifty variants reported in 55 unrelated patients so far have been identified in families of diverse ethnicities and only few are recurrent. Various types of variants were detected (missense, nonsense, frameshift) including full or partial SLC20A2 deletions. The recently reported SLC20A2 knockout mouse will enhance our understanding of disease mechanism and allow for screening of therapeutic compounds. In the present review, we also discuss the implications of these recent exciting findings and consider the possibility of treatments based on manipulation of inorganic phosphate homeostasis.