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BACKGROUND AND PURPOSE: The antisense oligonucleotide nusinersen (Spinraza) regulates splicing of the survival motor neuron 2 (SMN2) messenger RNA to increase SMN protein expression. Nusinersen has improved ventilator-free survival and motor function outcomes in infantile onset forms of spinal muscular atrophy (SMA), treated early in the course of the disease. However, the response in later onset forms of SMA is highly variable and dependent on symptom severity and disease duration at treatment initiation. Therefore, we aimed to identify novel noninvasive biomarkers that could predict the response to nusinersen in type II and III SMA patients. METHODS: Thirty-four SMA patients were included. We applied next generation sequencing to identify microRNAs in the cerebrospinal fluid (CSF) as candidate biomarkers predicting response to nusinersen. Hammersmith Functional Motor Scale Expanded (HFMSE) was conducted at baseline and 6 months after initiation of nusinersen therapy to assess motor function. Patients changing by ≥3 or ≤0 points in the HFMSE total score were considered to be responders or nonresponders, respectively. RESULTS: Lower baseline levels of two muscle microRNAs (miR-206 and miR-133a-3p), alone or in combination, predicted the clinical response to nusinersen after 6 months of therapy. Moreover, miR-206 levels were inversely correlated with the HFMSE score. CONCLUSIONS: Lower miR-206 and miR-133a-3p in the CSF predict more robust clinical response to nusinersen treatment in later onset SMA patients. These novel findings have high clinical relevance for identifying early treatment response to nusinersen in later onset SMA patients and call for testing the ability of miRNAs to predict more sustained long-term benefit.
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Biomarcadores Farmacológicos , MicroARNs , Oligonucleótidos , Atrofias Musculares Espinales de la Infancia , Biomarcadores Farmacológicos/líquido cefalorraquídeo , Humanos , MicroARNs/líquido cefalorraquídeo , Músculos , Oligonucleótidos/uso terapéutico , Atrofias Musculares Espinales de la Infancia/líquido cefalorraquídeo , Atrofias Musculares Espinales de la Infancia/terapiaRESUMEN
PURPOSE: Abnormalities in cerebrospinal fluid (CSF) have been reported in Hurler syndrome, a fatal neurodegenerative lysosomal disorder. While no biomarker has predicted neurocognitive response to treatment, one of these abnormalities, glycosaminoglycan nonreducing ends (NREs), holds promise to monitor therapeutic efficacy. A trial of intrathecal enzyme replacement therapy (ERT) added to standard treatment enabled tracking of CSF abnormalities, including NREs. We evaluated safety, biomarker response, and neurocognitive correlates of change. METHODS: In addition to intravenous ERT and hematopoietic cell transplantation, patients (N = 24) received intrathecal ERT at four peritransplant time points; CSF was evaluated at each point. Neurocognitive functioning was quantified at baseline, 1 year, and 2 years posttransplant. Changes in CSF biomarkers and neurocognitive function were evaluated for an association. RESULTS: Over treatment, there were significant decreases in CSF opening pressure, biomarkers of disease activity, and markers of inflammation. Percent decrease in NRE from pretreatment to final intrathecal dose posttransplant was positively associated with percent change in neurocognitive score from pretreatment to 2 years posttransplant. CONCLUSION: Intrathecal ERT was safe and, in combination with standard treatment, was associated with reductions in CSF abnormalities. Critically, we report evidence of a link between a biomarker treatment response and neurocognitive outcome in Hurler syndrome.
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Terapia de Reemplazo Enzimático/métodos , Inyecciones Espinales/métodos , Mucopolisacaridosis I/tratamiento farmacológico , Biomarcadores Farmacológicos/líquido cefalorraquídeo , Preescolar , Femenino , Glicosaminoglicanos/análisis , Glicosaminoglicanos/líquido cefalorraquídeo , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Masculino , Mucopolisacaridosis I/fisiopatología , Resultado del TratamientoRESUMEN
INTRODUCTION: All recent phase 3 trials of potentially disease-modifying therapies for Alzheimer's disease (AD) have so far failed. Potential reasons include enrolling subjects whose disease is too advanced or who do not have AD pathology, or simply incorrect drug targets. The goal of disease-modifying AD trials is to halt the progress of neuronal damage and death and this can be assessed in vivo using cerebrospinal fluid (CSF) biomarkers. Areas covered: The authors conducted a literature search of the use of CSF biomarkers in disease-modifying AD clinical trials using PubMed. The authors show that CSF biomarkers have only sparsely been used as outcome measures, and where they have, only in small subsets of patients. No clinical trials have yet showed any substantial effects on CSF biomarkers of neurodegeneration. Expert commentary: In future trials, the authors advocate that CSF biomarkers be used more extensively to optimize the chance of detecting positive drug effects. This includes the identification of potential AD patients - already in the early prodromal stage - for inclusion, for stratification, as readout i.e. proximity markers for changes in axonal/neurodegeneration between treatment and placebo groups - this also enables proof of principle verification in the discovery/dose finding phase, and for monitoring of side effects.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores Farmacológicos/líquido cefalorraquídeo , Neuronas/patología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Humanos , Terapia Molecular Dirigida , Síntomas ProdrómicosRESUMEN
INTRODUCTION: SEP-432 is a triple monoamine reuptake inhibitor of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), based on in vitro binding studies. We sought evidence that SEP-432 engages these monoamine systems by measuring concentrations of monoamines and/or their main metabolites in cerebrospinal fluid (CSF) and plasma and comparing results to duloxetine, a dual reuptake inhibitor of NE and 5-HT. METHODS: Eighteen healthy normal subjects received either SEP-432 (300 mg/day), duloxetine (60 mg/day), or placebo for 14 days in-clinic (double blind) with CSF and plasma collections at baseline (single lumbar puncture) and Day 14 (24-h CSF and plasma collection). Concentrations of monoamines and their metabolites, as well as pharmacokinetic concentrations of SEP-432 and metabolite, were quantified by liquid chromatography-tandem mass spectrometry. RESULTS: Compared to placebo in the Day 14 area under the curve 24-h (AUC0-24 h ) analysis, SEP-432 significantly (P < 0.05) decreased the NE metabolite dihydroxyphenylglycol (DHPG) in CSF and plasma, decreased 5-HT in plasma, and did not affect DA metabolites, while duloxetine had significant effects on DHPG and 5-HT. Time-matched baseline to Day 14 biomarker comparisons confirmed these findings. CONCLUSION: CSF monoamine biomarkers confirmed central NET activity for SEP-432 and duloxetine's dual reuptake inhibition.
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Biomarcadores Farmacológicos/sangre , Biomarcadores Farmacológicos/líquido cefalorraquídeo , Clorhidrato de Duloxetina/farmacología , Neurotransmisores/sangre , Neurotransmisores/líquido cefalorraquídeo , Inhibidores de la Captación de Neurotransmisores/farmacología , Adulto , Monoaminas Biogénicas/sangre , Monoaminas Biogénicas/líquido cefalorraquídeo , Cromatografía Líquida de Alta Presión , Ciclohexanoles/farmacología , Dimetilaminas/farmacología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Electrocardiografía , Femenino , Voluntarios Sanos , Humanos , Masculino , Metoxihidroxifenilglicol/análogos & derivados , Metoxihidroxifenilglicol/metabolismo , Persona de Mediana Edad , Espectrometría de Masas en Tándem , Factores de Tiempo , Adulto JovenRESUMEN
Introduction: The RARa is a transcription factor playing important role in such processes as proliferation, differentiation and apoptosis of cells in norm and in tumor. At the same time, it is little known about significance of expression of two major products of transcription of gene RARa - isoforms RARa and RARa - in pathogenesis of solid and non-solid tumors, including multiple myeloma. The actual data testify ambiguity of input made by isoforms RARa and RARa into processes of tumor development and progression of malignant tumors. The results: It was established that higher level of expression of isoform RARa in combination with increased expression of isoform RARß (group 1) statistically reliable associated with lesser decreasing of concentration of Bence Jones protein in urine of patients in the result of applied treatment and, therefore, lesser effectiveness of response to standard treatment according protocol M-2 in comparison with group II which included patients with lesser levels of expression of RARa and RARß (32.8% and 62.8% for groups I and II correspondingly; p=0.037). The analysis of indices of survival of examined patients in groups I and II demonstrated that median of total survival of patients from group I was reliably lower than in patients included into group II (30 and 84 correspondingly; p=0.046). Conclusion: The results of study demonstrate that increased level of expression in the first instance of isoform RARa in combination with hyper-expression of isoform RARß but not RARa can have unfavorable significance in case of evaluation of response to medicinal therapy and prognosis of total survival in patients with multiple melanoma.
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Biomarcadores Farmacológicos/líquido cefalorraquídeo , Mieloma Múltiple/genética , Receptores de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/genética , Adulto , Anciano , Apoptosis/efectos de los fármacos , Carmustina/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/líquido cefalorraquídeo , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Pronóstico , Isoformas de Proteínas/genética , Vincristina/administración & dosificaciónRESUMEN
INTRODUCTION: Alzheimer's disease brains are characterized by extracellular plaques containing the aggregated amyloid ß42 (Aß42) peptide and intraneuronal tangles containing hyperphosphorylated tau. Aß42 is produced by sequential processing of the amyloid precursor protein (APP) by ß-secretase followed by γ-secretase. Substantial efforts have been put into developing pharmaceuticals preventing the production or increasing the clearance of Aß42. However, treatments inhibiting γ-secretase have proven disappointing due to off-target effects. To circumvent these effects, γ-secretase modulators (GSMs) have been developed, which rather than inhibiting γ-secretase shift its preference into producing less aggregation-prone shorter Aß peptides. Belonging to the same family of proteins as APP, amyloid-like protein 1 (APLP1) is also a substrate for γ-secretase. Herein we investigated whether the GSM E2012 affects APLP1 processing in the central nervous system by measuring APLP1 peptide levels in cerebrospinal fluid (CSF) before and after E2012 treatment in dogs. METHODS: An in-house monoclonal APLP1 antibody, AP1, was produced and utilized for immunopurification of APLP1 from human and dog CSF in a hybrid immuno-affinity mass spectrometric method. Seven dogs received a single dose of 20 or 80 mg/kg of E2012 in a randomized cross-over design and CSF was collected prior to and 4, 8 and 24 hours after dosing. RESULTS: We have identified 14 CSF APLP1 peptides in humans and 12 CSF APLP1 peptides in dogs. Of these, seven were reproducibly detectable in dogs who received E2012. We found a dose-dependent relative increase of the CSF peptides APLP1ß17, 1ß18 and 1ß28 accompanied with a decrease of 1ß25 and 1ß27 in response to E2012 treatment. All peptides reverted to baseline over the time of sample collection. CONCLUSION: We show an in vivo effect of the GSM E2012 on the processing of APLP1 which is measurable in CSF. These data suggest that APLP1 peptides may be used as biomarkers to monitor drug effects of GSMs on γ-secretase processing in clinical trials. However, this requires further investigation in larger cohorts, including studies in man.
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Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Imidazoles/farmacología , Piperidinas/farmacología , Secuencia de Aminoácidos , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/inmunología , Animales , Anticuerpos Monoclonales/aislamiento & purificación , Biomarcadores Farmacológicos/líquido cefalorraquídeo , Estudios Cruzados , Perros , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunoprecipitación , Ratones Endogámicos BALB C , Distribución Aleatoria , Espectrometría de Masas en TándemRESUMEN
Multiple sclerosis (MS) is characterized by episodes of inflammatory damage to myelin and oligodendrocytes in the central nervous system mediated by T, B, and Natural killer lymphocytes of various types, antibody and complement, dendritic cells, macrophages, microglia, and secreted cytokines and chemokines. These relapses cause significant neurologic dysfunction, which is only partially reversible, and eventual secondary progressive neurologic decline frequently occurs. Interferon-beta (IFNß) has been a mainstay of MS treatment for more than 20 years after being proven to reduce relapse frequency and development of new lesions on magnetic resonance imaging. However, patient response is highly variable and the exact mechanisms of action are not fully understood. Breakthrough relapses and secondary progressive neurologic decline remain significant concerns in long-term MS treatment. Biomarkers may help elucidate the beneficial effects of IFNß in MS and possibly guide therapeutic decision making given the variety of different therapies now available with varying mechanisms of action and risks. Various serum and cerebrospinal fluid candidate biomarkers have been described, but none have yet been proven to carry sufficient predictive reliability for routine clinical use.
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Biomarcadores Farmacológicos , Inmunoterapia/métodos , Interferón beta/uso terapéutico , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/terapia , Animales , Biomarcadores Farmacológicos/sangre , Biomarcadores Farmacológicos/líquido cefalorraquídeo , Toma de Decisiones , Humanos , Esclerosis Múltiple/inmunología , Pronóstico , Recurrencia , Resultado del TratamientoRESUMEN
Drug candidates directed against amyloid-ß (Aß) are mainstream in Alzheimer's disease (AD) drug development. Active and passive Aß immunotherapy is the principle that has come furthest, both in number and in stage of clinical trials. However, an increasing number of reports on major difficulties in identifying any clinical benefit in phase II-III clinical trials on this type of anti-Aß drug candidates have caused concern among researchers, pharmaceutical companies, and other stakeholders. This has provided critics of the amyloid cascade hypothesis with fire for their arguments that Aß deposition may merely be a bystander, and not the cause, of the disease or that the amyloid hypothesis may only be valid for the familial form of AD. On the other hand, most researchers argue that it is the trial design that will need refinement to allow for identifying a positive clinical effect of anti-Aß drugs. A consensus in the field is that future trials need to be performed in an earlier stage of the disease and that biomarkers are essential to guide and facilitate drug development. In this context, it is reassuring that, in contrast to most brain disorders, research advances in the AD field have led to both imaging (magnetic resonance imaging (MRI) and PET) and cerebrospinal fluid (CSF) biomarkers for the central pathogenic processes of the disease. AD biomarkers will have a central role in future clinical trials to enable early diagnosis, and Aß biomarkers (CSF Aß42 and amyloid PET) may be essential to allow for testing a drug on patients with evidence of brain Aß pathology. Pharmacodynamic Aß and amyloid precursor protein biomarkers will be of use to verify target engagement of a drug candidate in humans, thereby bridging the gap between mechanistic data from transgenic AD models (that may not be relevant to the neuropathology of human AD) and large and expensive phase III trials. Last, downstream biomarker evidence (CSF tau proteins and MRI volumetry) that the drug ameliorates neurodegeneration will, together with beneficial clinical effects on cognition and functioning, be essential for labeling an anti-Aß drug as disease modifying.
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Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/inmunología , Péptidos beta-Amiloides/antagonistas & inhibidores , Biomarcadores Farmacológicos/metabolismo , Ensayos Clínicos como Asunto/métodos , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/inmunología , Péptidos beta-Amiloides/metabolismo , Biomarcadores Farmacológicos/líquido cefalorraquídeo , Encéfalo/metabolismo , Ensayos Clínicos como Asunto/normas , Descubrimiento de Drogas/métodos , Humanos , NeuroimagenRESUMEN
Research progress has provided detailed understanding of the molecular pathogenesis of Alzheimer disease (AD). This knowledge has been translated into new drug candidates with putative disease-modifying effects, which are now being tested in clinical trials. The promise of effective therapy has created a great need for biomarkers able to detect AD in the predementia phase, because drugs will probably be effective only if neurodegeneration is not too advanced. In this chapter, cerebrospinal fluid (CSF) and plasma biomarkers are reviewed. The core CSF biomarkers total tau (T-tau), phosphorylated tau (P-tau) and the 42 amino acid form of ß-amyloid (Aß42) reflect AD pathology, and have high diagnostic accuracy to diagnose AD with dementia and prodromal AD in mild cognitive impairment cases. The rationale for the use of CSF biomarkers to identify and monitor the mechanism of action of new drug candidates is also outlined in this chapter.
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Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas del Líquido Cefalorraquídeo/metabolismo , Proteínas tau/líquido cefalorraquídeo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/líquido cefalorraquídeo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/sangre , Ácido Aspártico Endopeptidasas/líquido cefalorraquídeo , Ácido Aspártico Endopeptidasas/metabolismo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Biomarcadores Farmacológicos/sangre , Biomarcadores Farmacológicos/líquido cefalorraquídeo , Humanos , Isomerismo , Marcaje Isotópico/métodos , Neuritis/diagnóstico , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Proteínas de Neurofilamentos/metabolismo , Estrés Oxidativo/fisiología , Fosforilación , Proteínas tau/sangreRESUMEN
La papa, cultivo de importancia a nivel mundial es gravemente afectado por gota, enfermedad ocasionada por el oomycete Phytophthora infestans. Actualmente la forma más efectiva para combatir la enfermedad es mediante el desarrollo de cultivares resistentes al patógeno. Para esto, una estrategia es identificar genes que confieran resistencia al patógeno, para lo cual se buscan marcadores asociados con el carácter de resistencia. En este estudio se evaluaron marcadores moleculares tipo SCAR (Sequence Characterized Amplified Region): CosA, GP179, BA47f2 y Prp1 asociados con resistencia a P. infestans y el gen de resistencia R1, en 22 cultivares tetraploides pertenecientes a la subespecie andigena y cinco especies silvestres. Se evaluó el polimorfismo y se determinó si los alelos polimórficos permitían diferenciar genotipos resistentes de susceptibles. Se comparó el tamaño de los fragmentos obtenidos con los fragmentos esperados asociados con resistencia de acuerdo a reportes. El análisis se realizó considerando presencia/ausencia de los fragmentos: CosA210, CosA250, R11400, R11800, BA47f2500, GP179570, Prp1300, Prp1600, y Prp1900. Los resultados indicaron que en los cultivares tetraploides y silvestres, se presentaron polimorfismos en todos los marcadores evaluados, con excepción del marcador GP179. No se encontró correlación entre el rasgo de resistencia y los alelos. Los resultados de este estudio muestran que hay repuesta diferencial a los marcadores entre las subsp. tuberosum y subsp. Andigena.
Potato is an important worldwide crop seriously affected by late blight disease caused by the oomycete Phytophthora infestans. Currently, the most effective way to control the disease is developing resistant cultivars to the pathogen by identifying genes that confer resistance to the pathogen. For this purpose it is important to find molecular markers associated with the trait. In this study, the SCAR (Sequence Characterized Amplified Region) markers: CosA, GP179, BA47f2 y Prp1, associated with late blight and the resistant gen R1 were evaluated in 22 tetraploid cultivars from subspecie andigena and five wild potato species. Polymorphism was evaluated and it was evaluated if polymorphic alleles allow differentiating resistant from susceptible genotypes. The fragment length for each marker was compared to the allele size reported associated to resistance. The analysis considered the presence/absence of the fragments: CosA210, CosA250, R11400, R11800, BA47f2500, GP179570, Prp1300, Prp1600 and Prp1900. The results indicated that both, tetraploid cultivars and wild potatoes, showed polymorphisms with all these markers, except with the GP179 marker. It was not found correlation between resistance and the presence of specific alleles. Evidence found in this study indicates that results obtained with molecular markers differed between subsp. tuberosum and subsp. andigena.
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Biomarcadores/análisis , Biomarcadores/metabolismo , Biomarcadores/química , Biomarcadores Farmacológicos/análisis , Biomarcadores Farmacológicos/líquido cefalorraquídeo , Biomarcadores Farmacológicos/metabolismo , Biomarcadores Farmacológicos/químicaRESUMEN
As therapeutic options for multiple sclerosis widen, validated biomarkers of clinical disease activity are urgently needed. Reliable biomarkers would assist in choosing initial therapy, monitoring response to therapy, detecting subclinical disease activity, predicting and possibly preventing therapeutic failure, and hopefully improving both short (relapses) and long-term (disability) outcomes. The presence of oligoclonal bands in the cerebrospinal fluid is a well-validated biomarker that is useful in initial diagnosis. Neutralizing antibodies to interferon-beta are also useful in identifying treatment failure and possibly guiding changes in therapy. The discovery of antibodies to aquaporin-4 in patients with neuromyelitis optica delineates patients with a fundamentally different underlying pathophysiology and clinical course who may require alternate therapeutic approaches. While numerous other candidate biomarkers in serum and cerebrospinal fluid have been described, none so far have the validated reliability necessary for widespread clinical use. The availability of multiple genetic and protein microarray technology may assist in identifying more reliable candidate biomarkers or patterns of multiple biomarkers and improve specificity. The heterogeneity of multiple sclerosis may necessitate individualized biomarkers and therapeutic decisions within distinct subsets of patients.
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Biomarcadores Farmacológicos/sangre , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/tratamiento farmacológico , Biomarcadores Farmacológicos/líquido cefalorraquídeo , Marcadores Genéticos/efectos de los fármacos , Humanos , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Esclerosis Múltiple/sangre , Bandas Oligoclonales/sangre , Bandas Oligoclonales/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Valor Predictivo de las Pruebas , Análisis por Matrices de Proteínas/métodosRESUMEN
BACKGROUND: Recently, we have reported that EGFR mutation-specific antibodies performed well in immunohistochemical analysis, with good sensitivity. We investigated whether this method could detect non-small-cell lung cancer (NSCLC) carrying EGFR mutations in malignant effusions and cerebrospinal fluid (CSF), comparable to the peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamp assay. Furthermore, we compared activating EGFR mutations between primary and recurrent NSCLC. PATIENTS AND METHODS: Twenty-four patients with NSCLC effusions and CSF were examined by immunocytochemistry using antibodies specific for the E746-A750 deletion mutation in exon 19 and the L858R point mutation in exon 21. The PNA-LNA PCR clamp assay was used to detect the E746-A750 deletion at exon 19, L858R mutation at exon 21, and T790M mutation at exon 20. RESULTS: We were able to identify EGFR mutations in NSCLC effusion and CSF with a sensitivity of 100% (5/5) using the anti-delE746-A750 antibody and 100% (8/8) using the anti-L858R antibody. Furthermore, in samples without these EGFR mutations, immunocytochemistry with the two specific antibodies identified 91% (10/11) as negative for both the deletion and the point mutations in EGFR. Activating EGFR mutations decreased in recurrent NSCLC compared with primary NSCLC, and the T790M mutation was detected in recurrent NSCLC of patients receiving gefitinib treatment. CONCLUSIONS: Identification of EGFR mutations is important for patients with primary and recurrent NSCLC. Rapid and sensitive immunocytochemistry using mutation-specific antibodies to detect EGFR mutations will be useful for diagnosing responsiveness to EGFR-targeted drugs.
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Biomarcadores Farmacológicos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , ADN , Receptores ErbB/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Biomarcadores Farmacológicos/análisis , Biomarcadores Farmacológicos/líquido cefalorraquídeo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Carcinoma de Pulmón de Células no Pequeñas/terapia , ADN/análisis , ADN/líquido cefalorraquídeo , Receptores ErbB/genética , Receptores ErbB/inmunología , Exones/genética , Femenino , Gefitinib , Humanos , Inmunohistoquímica/métodos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/fisiopatología , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Derrame Pleural Maligno , Reacción en Cadena de la Polimerasa/métodos , Quinazolinas/uso terapéutico , Recurrencia , Sensibilidad y Especificidad , Eliminación de Secuencia/genéticaRESUMEN
ObjetivoEstimar las relaciones dinámicas entre los fluidos craneoespinales (líquido cefalorraquídeo [LCR] y sangre) en el espacio ventricular, subaracnoideo cerebral y subaracnoideo espinal mediante la cuantificación de imágenes de resonancia magnética (RM) en contraste de fase.Material y métodosSe analizaron 15 sujetos voluntarios sanos en la misma franja horaria y bajo la misma intensidad de campo (3T). Para cada estudio se realizaron 4 exploraciones en contraste de fase: 2 secuencias para el cálculo de LCR (acueducto de Silvio y espacio perimedular C2-C3) y 2 para el cálculo del flujo sanguíneo (arterias carótidas internas y vertebrales, seno sagital superior y recto). En todos los sujetos se calcularon los parámetros de amplitud (volumen sistólico, flujo promedio, índices de pulsatibilidad y distensibilidad, amplitud del gradiente de presión absoluta y relación de volumen de fluido de LCR por ciclo) y temporales (retrasos frente a la entrada de flujo arterial).ResultadosRespecto a la entrada de sangre arterial, el desplazamiento de sangre venosa (al 22 y 38% del ciclo cardíaco en los senos recto y sagital superior, respectivamente) y del LCR (al 12 y 25% de ciclo cardíaco en el espacio perimedular C2-C3 y el acueducto de Silvio, respectivamente) describen la distribución de la pulsatibilidad de los fluidos intracraneales. Se obtienen índices de distensibilidad para los compartimientos encefálico y medular en una población normal.ConclusionesMediante los mapas de velocidad de flujo obtenidos con RM es posible describir de manera cuantitativa las relaciones dinámicas de los fluidos intracraneales e inferir el comportamiento elástico encefálico y medular (AU)
ObjectiveTo estimate the dynamic relations between cerebrospinal fluid (CSF) and blood in the cerebral and spinal subarachnoid spaces and in the ventricles by quantifying phase contrast magnetic resonance imaging (MRI).Material and methodsWe analyzed 15 healthy volunteers during the same time of day and using the same magnetic field strength (3T). Each study consisted of four phase contrast sequences: two to calculate the CSF (aqueduct of Sylvius and the C2-C3 perimedullary space) and two to calculate the blood flow (internal carotid and vertebral arteries, superior sagittal sinus, and straight sinus). We calculated the amplitude parameters (systolic volume, mean flow, pulsatility and compliance indexes, absolute pressure gradient, and ratio of CSF volume per cycle) and temporal parameters (delays respect to arterial flow).ResultsWith respect to the input of arterial blood, the displacement of venous blood (22% and 38% of the cardiac cycle in the straight sinus and superior sagittal sinus, respectively) and of CSF (12% and 25% of the cardiac cycle in the C2-C3 perimedullary space and in the aqueduct of Sylvius, respectively) show the distribution of the pulsatility of the intracranial fluids. We calculated the indexes of compliance of the encephalic and medullary compartments in normal subjects.ConclusionsIt is possible to quantitatively describe the dynamic relations between intracranial fluids and infer the elastic behavior of the brain and spinal canal by using flow velocity maps obtained with phase contrast MRI (AU)