RESUMEN
OBJECTIVE: The current analysis of the MAXIMISE trial was conducted to investigate the presence of post-inflammatory and degenerative spinal changes and inflammatory changes in spinal processes identified in baseline MRIs and their potential for predicting differential treatment effects in a cohort of PsA patients with axial manifestations. METHODS: Baseline spinal MRIs from the MAXIMISE trial were re-read to identify additional inflammatory (spinal process), post-inflammatory, and degenerative changes, and investigate the differential treatment effect of these imaging features using logistic regression modelling. RESULTS: In addition to bone marrow oedema assessed at primary analysis, spinal process inflammation and post-inflammatory changes evaluated by FAt Spondyloarthritis Spine Score were documented in 11.1% and 20.2% patients, respectively. At least one type of degenerative change was noted in 64% patients, with Pfirrmann grade ≥3 (51.1%) being the most common. Combining primary and re-read MRI findings, 67.1% of patients presented with inflammatory or post-inflammatory changes while 21.2% had degenerative changes alone. Although not statistically significant, post-inflammatory changes were associated with a trend for better efficacy outcomes in terms of ASAS20, ASAS40 and BASDAI50 responses; a trend for worse outcomes was observed in the presence of degenerative changes. CONCLUSION: The current analysis revealed the occurrence of additional inflammatory and post-inflammatory changes suggestive of axial PsA (axPsA) and a trend for better clinical outcomes for patients treated with secukinumab. These results elucidate the imaging characteristics and improve our current understanding of axPsA thereby supporting the interpretation of future trials. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02721966.
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Artritis Psoriásica , Espondiloartritis , Humanos , Artritis Psoriásica/diagnóstico por imagen , Artritis Psoriásica/tratamiento farmacológico , Artritis Psoriásica/complicaciones , Inflamación/complicaciones , Columna Vertebral/diagnóstico por imagen , Columna Vertebral/patología , Espondiloartritis/diagnóstico por imagen , Espondiloartritis/tratamiento farmacológico , Espondiloartritis/complicaciones , Imagen por Resonancia Magnética/métodosRESUMEN
Bulbar function in spinal muscular atrophy has been defined as the ability to meet nutritional needs by mouth while maintaining airway protection and communicate verbally. The effects of disease-modifying treatment on bulbar function are not clear. A multidisciplinary team conducted post-hoc analyses of phase 3 SPR1NT trial data to evaluate bulbar function of infants at risk for spinal muscular atrophy who received one-time gene replacement therapy (onasemnogene abeparvovec) before symptom onset. Three endpoints represented adequate bulbar function in SPR1NT: (1) absence of physiologic swallowing impairment, (2) full oral nutrition, and (3) absence of adverse events indicating pulmonary instability. Communication was not assessed in SPR1NT. We descriptively assessed numbers/percentages of children who achieved each endpoint and all three collectively. SPR1NT included infants <6 postnatal weeks with two (n = 14) or three (n = 15) copies of the survival motor neuron 2 gene. At study end (18 [two-copy cohort] or 24 [three-copy cohort] months of age), 100% (29/29) of patients swallowed normally, achieved full oral nutrition, maintained pulmonary stability, and achieved the composite endpoint. When administered to infants before clinical symptom onset, onasemnogene abeparvovec allowed children at risk for spinal muscular atrophy to achieve milestones within published normal ranges of development and preserve bulbar function.
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Trastornos de Deglución , Atrofia Muscular Espinal , Atrofias Musculares Espinales de la Infancia , Niño , Humanos , Lactante , Atrofia Muscular Espinal/genética , Neuronas Motoras , Terapia Genética , Deglución , Atrofias Musculares Espinales de la Infancia/terapia , Atrofias Musculares Espinales de la Infancia/tratamiento farmacológicoRESUMEN
BACKGROUND: Improvement and maintenance of bulbar function are goals of disease-modifying treatments for spinal muscular atrophy (SMA). Lack of standardized measures and a widely accepted definition of bulbar function represents a gap in SMA care. OBJECTIVE: A multidisciplinary team conducted post-hoc analyses of pooled data from one phase 1 (START) and two phase 3 (STR1VE-US, STR1VE-EU) studies to define and evaluate bulbar function of infants with SMA type 1 after receiving one-time gene replacement therapy, onasemnogene abeparvovec. METHODS: We defined bulbar function as the ability to meet nutritional needs while maintaining airway protection and the ability to communicate verbally. Four endpoints represented adequate bulbar function: (1) absence of clinician-identified physiologic swallowing impairment, (2) receiving full oral nutrition, (3) absence of adverse events indicating pulmonary instability, and (4) the ability to vocalize at least two different, distinct vowel sounds. We descriptively assessed numbers/percentages of patients who achieved each endpoint and all four collectively. Patients were followed until 18 months old (STR1VE-US and STR1VE-EU) or 24 months (START) post-infusion. RESULTS: Overall, 65 patients were analyzed for swallowing, nutrition intake, and adverse events, and 20 were analyzed for communication. At study end, 92% (60/65) of patients had a normal swallow, 75% (49/65) achieved full oral nutrition, 92% (60/65) had no evidence of pulmonary instability, 95% (19/20) met the communication endpoint, and 75% (15/20) achieved all four bulbar function components in the composite endpoint. CONCLUSIONS: In these three clinical trials, patients with SMA type 1 who received onasemnogene abeparvovec achieved and maintained the bulbar function criteria utilized within this investigation.
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Trastornos de Deglución , Atrofia Muscular Espinal , Atrofias Musculares Espinales de la Infancia , Lactante , Humanos , Atrofias Musculares Espinales de la Infancia/tratamiento farmacológico , Atrofia Muscular Espinal/genética , Trastornos de Deglución/etiología , Trastornos de Deglución/terapia , Deglución , Terapia GenéticaRESUMEN
OBJECTIVES: To investigate patient characteristics predictive of response to secukinumab in patients with psoriatic arthritis (PsA) with axial manifestations. METHODS: In a post-hoc analysis from the MAXIMISE trial (NCT02721966) in patients with PsA and axial manifestations, we tested the hypothesis that the OR of the effect of treatment on the primary endpoint of the trial (Assessment of SpondyloArthritis international Society (ASAS) 20 responder status at week 12) would be different depending on 12 prespecified predictor variables. We applied a two-model logistic regression approach, a main effects and an interaction model. RESULTS: The OR (95% CI) for ASAS20 response for the presence of nail dystrophy was 3.2 (95% CI 0.93 to 10.99) in the secukinumab 150 mg group and 5.0 (95% CI 1.47 to 17.19) in the secukinumab 300 mg group compared with the placebo group (p=0.029). Odds of being a responder were similar in men and women in the secukinumab groups, though men fared worse than women in the placebo group (p=0.039). Current smokers were less likely to be ASAS20 responders compared with never smokers regardless of the treatment group (p=0.589). CONCLUSION: Nail dystrophy was identified as a predictor of response to secukinumab in patients with PsA with axial manifestations in the MAXIMISE trial. These findings may be explained by the nail-entheseal concept as part of the axial phenotype in PsA .
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Anticuerpos Monoclonales Humanizados , Artritis Psoriásica , Anticuerpos Monoclonales Humanizados/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Femenino , Humanos , MasculinoRESUMEN
PURPOSE: Conventional staging methods are inadequate to identify patients with stage II colon cancer (CC) who are at high risk of recurrence after surgery with curative intent. ColDx is a gene expression, microarray-based assay shown to be independently prognostic for recurrence-free interval (RFI) and overall survival in CC. The objective of this study was to further validate ColDx using formalin-fixed, paraffin-embedded specimens collected as part of the Alliance phase III trial, C9581. PATIENTS AND METHODS: C9581 evaluated edrecolomab versus observation in patients with stage II CC and reported no survival benefit. Under an initial case-cohort sampling design, a randomly selected subcohort (RS) comprised 514 patients from 901 eligible patients with available tissue. Forty-nine additional patients with recurrence events were included in the analysis. Final analysis comprised 393 patients: 360 RS (58 events) and 33 non-RS events. Risk status was determined for each patient by ColDx. The Self-Prentice method was used to test the association between the resulting ColDx risk score and RFI adjusting for standard prognostic variables. RESULTS: Fifty-five percent of patients (216 of 393) were classified as high risk. After adjustment for prognostic variables that included mismatch repair (MMR) deficiency, ColDx high-risk patients exhibited significantly worse RFI (multivariable hazard ratio, 2.13; 95% CI, 1.3 to 3.5; P < .01). Age and MMR status were marginally significant. RFI at 5 years for patients classified as high risk was 82% (95% CI, 79% to 85%), compared with 91% (95% CI, 89% to 93%) for patients classified as low risk. CONCLUSION: ColDx is associated with RFI in the C9581 subsample in the presence of other prognostic factors, including MMR deficiency. ColDx could be incorporated with the traditional clinical markers of risk to refine patient prognosis.
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Neoplasias del Colon/genética , Recurrencia Local de Neoplasia/genética , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino , Ensayos Clínicos Fase III como Asunto , Estudios de Cohortes , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Neoplasias del Colon/cirugía , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: There is no method routinely used to predict response to anthracycline and cyclophosphamide-based chemotherapy in the clinic; therefore patients often receive treatment for breast cancer with no benefit. Loss of the Fanconi anemia/BRCA (FA/BRCA) DNA damage response (DDR) pathway occurs in approximately 25% of breast cancer patients through several mechanisms and results in sensitization to DNA-damaging agents. The aim of this study was to develop an assay to detect DDR-deficient tumors associated with loss of the FA/BRCA pathway, for the purpose of treatment selection. METHODS: DNA microarray data from 21 FA patients and 11 control subjects were analyzed to identify genetic processes associated with a deficiency in DDR. Unsupervised hierarchical clustering was then performed using 60 BRCA1/2 mutant and 47 sporadic tumor samples, and a molecular subgroup was identified that was defined by the molecular processes represented within FA patients. A 44-gene microarray-based assay (the DDR deficiency assay) was developed to prospectively identify this subgroup from formalin-fixed, paraffin-embedded samples. All statistical tests were two-sided. RESULTS: In a publicly available independent cohort of 203 patients, the assay predicted complete pathologic response vs residual disease after neoadjuvant DNA-damaging chemotherapy (5-fluorouracil, anthracycline, and cyclophosphamide) with an odds ratio of 3.96 (95% confidence interval [Cl] =1.67 to 9.41; P = .002). In a new independent cohort of 191 breast cancer patients treated with adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, a positive assay result predicted 5-year relapse-free survival with a hazard ratio of 0.37 (95% Cl = 0.15 to 0.88; P = .03) compared with the assay negative population. CONCLUSIONS: A formalin-fixed, paraffin-embedded tissue-based assay has been developed and independently validated as a predictor of response and prognosis after anthracycline/cyclophosphamide-based chemotherapy in the neoadjuvant and adjuvant settings. These findings warrant further validation in a prospective clinical study.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Daño del ADN/efectos de los fármacos , ADN de Neoplasias/efectos de los fármacos , Anemia de Fanconi/metabolismo , Adulto , Anciano , Antraciclinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/genética , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Epirrubicina/administración & dosificación , Anemia de Fanconi/genética , Femenino , Fluorouracilo/administración & dosificación , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Oportunidad Relativa , Análisis de Secuencia por Matrices de Oligonucleótidos , Estudios ProspectivosRESUMEN
PURPOSE: Current prognostic factors are poor at identifying patients at risk of disease recurrence after surgery for stage II colon cancer. Here we describe a DNA microarray-based prognostic assay using clinically relevant formalin-fixed paraffin-embedded (FFPE) samples. PATIENTS AND METHODS: A gene signature was developed from a balanced set of 73 patients with recurrent disease (high risk) and 142 patients with no recurrence (low risk) within 5 years of surgery. RESULTS: The 634-probe set signature identified high-risk patients with a hazard ratio (HR) of 2.62 (P < .001) during cross validation of the training set. In an independent validation set of 144 samples, the signature identified high-risk patients with an HR of 2.53 (P < .001) for recurrence and an HR of 2.21 (P = .0084) for cancer-related death. Additionally, the signature was shown to perform independently from known prognostic factors (P < .001). CONCLUSION: This gene signature represents a novel prognostic biomarker for patients with stage II colon cancer that can be applied to FFPE tumor samples.
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Neoplasias del Colon/patología , Recurrencia Local de Neoplasia/patología , Adhesión en Parafina/métodos , Anciano , Neoplasias del Colon/genética , Femenino , Formaldehído , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Estadificación de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Adhesión en Parafina/normas , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Fijación del TejidoRESUMEN
OBJECTIVES: We investigated the relationship between BRCA1 protein expression by immunohistochemistry (IHC) and clinical outcome following platinum and platinum/taxane chemotherapy in sporadic epithelial ovarian cancer (EOC). METHODS: BRCA1 IHC was performed on a cohort of 292 ovarian tumours from two UK oncology centres. BRCA1 protein expression levels were correlated with overall survival (OS), progression free survival (PFS) and clinical response to chemotherapy by multivariate analysis. RESULTS: EOC patients with absent/low BRCA1 protein expression (41%) had a better chance of clinical response following chemotherapy as compared to patients with high BRCA1 expression (odds ratio 2.47: 95%CI 1.10-5.55, p=0.029). Patients with absent/low BRCA1 had a higher probability of clinical response following single agent platinum compared to high BRCA1 expressing patients (68.5% vs. 46.8%), while addition of a taxane increased response rates independent of BRCA1. Overall, patients with absent/low BRCA1 had a better clinical outcome compared to patients with high BRCA1 protein expression in terms of both OS (HR=0.65: 95%CI 0.48-0.88, p=0.006) and PFS (HR=0.74, 95%CI 0.55-0.98, p=0.040). CONCLUSIONS: We confirm that absent/low BRCA1 protein expression is a favourable prognostic marker. However, we also provide the first evidence that absent/low BRCA1 protein expression in sporadic EOC patients predicts for an improved clinical response to chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteína BRCA1/genética , Biomarcadores de Tumor/genética , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/genética , Compuestos Organoplatinos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Proteína BRCA1/biosíntesis , Biomarcadores de Tumor/biosíntesis , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Carcinoma Epitelial de Ovario , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Glandulares y Epiteliales/metabolismo , Compuestos Organoplatinos/administración & dosificación , Neoplasias Ováricas/metabolismo , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Tasa de Supervivencia , Taxoides/administración & dosificaciónRESUMEN
UNLABELLED: BMD values in approximately 3000 perimenopausal Scottish women were adjusted by regression to identify and account for nongenetic factors. Adjusted BMD values were not associated with simple tandem repeat (STR) markers or single nucleotide polymorphisms (SNPs) at the Cathepsin K (CTSK) locus. We present a thorough analysis of common CTSK polymorphisms and genetic relatedness among CTSK haplotypes. INTRODUCTION: CTSK is a cysteine protease of the papain family and is thought to play a critical role in osteoclast-mediated bone degradation. Rare, inactivating mutations in CTSK cause pychodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature. However, there have been no studies of common genetic variants in CTSK and their possible association with bone density in the general population. MATERIALS AND METHODS: To identify common single nucleotide polymorphisms (SNPs) and simple tandem repeat (STR) polymorphisms in and around CTSK, we screened all CTSK exons, intron A, all intron-exon boundaries, and the putative CTSK promoter region in 130 random whites using both high-performance liquid chromatography (HPLC) and DNA sequencing. CTSK markers were genotyped in approximately 3000 perimenopausal Scottish women whose hip and spine bone mineral density (BMD) had been measured by DXA. We performed linear regression analysis to identify and adjust for nongenetic predictors of BMD, and adjusted BMD values (regression residuals) were tested for association with individual CTSK markers and haplotypes by ANOVA and the composite haplotype method of Zaykin et al. RESULTS AND CONCLUSIONS: We discovered two intronic SNPs (8% and 9% frequency), but no common exonic SNPs (> 1% frequency), and found that three STRs at the immediate 5' end of the CTSK locus are highly polymorphic. The population frequencies of haplotypes defined by these five polymorphisms were estimated, and a cladogram was derived showing proximity of relationship and likely descent of the 30 most common CTSK haplotypes. Regression analyses revealed that approximately 39% of spine and 19% of hip rate of change in BMD was accounted for by nongenetic factors. For baseline BMD values in premenopausal women, nongenetic predictors explained 11% of the variance at the spine and 13% at the hip. Adjusted BMD values showed no statistically significant association with any of the individual CTSK polymorphisms or CTSK haplotypes.
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Densidad Ósea , Catepsinas/genética , Climaterio/metabolismo , Polimorfismo Genético/genética , Análisis de Varianza , Estatura , Índice de Masa Corporal , Peso Corporal , Catepsina K , Climaterio/genética , Estudios de Cohortes , Repeticiones de Dinucleótido/genética , Femenino , Cuello Femoral/química , Frecuencia de los Genes , Genotipo , Haplotipos/genética , Terapia de Reemplazo de Hormonas , Humanos , Desequilibrio de Ligamiento/genética , Vértebras Lumbares/química , Persona de Mediana Edad , Polimorfismo Genético/fisiología , Polimorfismo de Nucleótido Simple/genética , Estudios Prospectivos , Análisis de Regresión , Escocia , Factores de TiempoRESUMEN
We have developed a new method using the Qbead system for high-throughput genotyping of single nucleotide polymorphisms (SNPs). The Qbead system employs fluorescent Qdot semiconductor nanocrystals, also known as quantum dots, to encode microspheres that subsequently can be used as a platform for multiplexed assays. By combining mixtures of quantum dots with distinct emission wavelengths and intensities, unique spectral 'barcodes' are created that enable the high levels of multiplexing required for complex genetic analyses. Here, we applied the Qbead system to SNP genotyping by encoding microspheres conjugated to allele-specific oligonucleotides. After hybridization of oligonucleotides to amplicons produced by multiplexed PCR of genomic DNA, individual microspheres are analyzed by flow cytometry and each SNP is distinguished by its unique spectral barcode. Using 10 model SNPs, we validated the Qbead system as an accurate and reliable technique for multiplexed SNP genotyping. By modifying the types of probes conjugated to microspheres, the Qbead system can easily be adapted to other assay chemistries for SNP genotyping as well as to other applications such as analysis of gene expression and protein-protein interactions. With its capability for high-throughput automation, the Qbead system has the potential to be a robust and cost-effective platform for a number of applications.
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Análisis Mutacional de ADN/métodos , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo de Nucleótido Simple/genética , ADN/química , ADN/genética , Análisis Mutacional de ADN/instrumentación , Femenino , Genotipo , Humanos , Masculino , Microesferas , Reacción en Cadena de la Polimerasa/instrumentación , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: Studies in mice have shown that genetic disruption of monocyte chemotactic protein-1 or its receptor, the C-C chemokine receptor 2 (CCR2), inhibits atherosclerosis, but few data exist in humans to suggest that the monocyte chemotactic protein-1-CCR2 interaction is important in atherogenesis. A common polymorphism in the human CCR2 gene resulting in a substitution of isoleucine for valine (Val64Ile) has been associated with other disease phenotypes in humans. METHODS AND RESULTS: A cohort of first-degree relatives of persons with premature coronary artery disease was recruited and quantitatively phenotyped for the extent of CAC, a marker of coronary atherosclerosis, by using electron beam CT. The extent of CAC was significantly lower in subjects with the CCR2-Ile64 variant (Val/Ile and Ile/Ile genotypes) than in subjects carrying 2 Val64 alleles, even after adjustment for traditional risk factors. CONCLUSIONS: This study provides genetic evidence linking CCR2 with coronary atherosclerosis in humans.