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INTRODUCTION: Further evidence is needed to support the use of plasma amyloid ß (Aß) biomarkers as Alzheimer's disease prescreening tools. This study evaluated the clinical performance and robustness of plasma Aß42 /Aß40 for amyloid positivity prescreening. METHODS: Data were collected from 333 BioFINDER and 121 Alzheimer's Disease Neuroimaging Initiative study participants. Risk and predictive values versus percentile of plasma Aß42 /Aß40 evaluated the actionability of plasma Aß42 /Aß40 , and simulations modeled the impact of potential uncertainties and biases. Amyloid PET was the brain amyloidosis reference standard. RESULTS: Elecsys plasma Aß42 /Aß40 could potentially rule out amyloid pathology in populations with low-to-moderate amyloid positivity prevalence. However, simulations showed small measurement or pre-analytical errors in Aß42 and/or Aß40 cause misclassifications, impacting sensitivity or specificity. The minor fold change between amyloid PET positive and negative cases explains the biomarkers low robustness. DISCUSSION: Implementing plasma Aß42 /Aß40 for routine clinical use may pose significant challenges, with misclassification risks. HIGHLIGHTS: Plasma Aß42 /Aß40 ruled out amyloid PET positivity in a setting of low amyloid-positive prevalence. Including (pre-) analytical errors or measurement biases caused misclassifications. Plasma Aß42 /Aß40 had a low inherent dynamic range, independent of analytical method. Other blood biomarkers may be easier to implement as robust prescreening tools.
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Doença de Alzheimer , Amiloidose , Humanos , Peptídeos beta-Amiloides , Doença de Alzheimer/diagnóstico por imagem , Encéfalo/metabolismo , Biomarcadores , Amiloide/metabolismo , Fragmentos de PeptídeosRESUMO
OBJECTIVE: Oligomeric forms of amyloid ß protein (oAß) are believed to be principally responsible for neurotoxicity in Alzheimer disease (AD), but it is not known whether anti-Aß antibodies are capable of lowering oAß levels in humans. METHODS: We developed an ultrasensitive immunoassay and used it to measure oAß in cerebrospinal fluid (CSF) from 104 AD subjects participating in the ABBY and BLAZE phase 2 trials of the anti-Aß antibody crenezumab. Patients received subcutaneous (SC) crenezumab (300mg) or placebo every 2 weeks, or intravenous (IV) crenezumab (15mg/kg) or placebo every 4 weeks for 68 weeks. Ninety-eight of the 104 patients had measurable baseline oAß levels, and these were compared to levels at week 69 in placebo (n = 28), SC (n = 35), and IV (n = 35) treated patients. RESULTS: Among those receiving crenezumab, 89% of SC and 86% of IV patients had lower levels of oAß at week 69 versus baseline. The difference in the proportion of patients with decreasing levels was significant for both treatment arms: p = 0.0035 for SC and p = 0.01 for IV crenezumab versus placebo. The median percentage change was -48% in the SC arm and -43% in the IV arm. No systematic change was observed in the placebo group, with a median change of -13% and equivalent portions with negative and positive change. INTERPRETATION: Crenezumab lowered CSF oAß levels in the large majority of treated patients tested. These results support engagement of the principal pathobiological target in AD and identify CSF oAß as a novel pharmacodynamic biomarker for use in trials of anti-Aß agents. ANN NEUROL 2019;86:215-224.
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Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Anticorpos Monoclonais Humanizados/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: We studied whether fully automated Elecsys cerebrospinal fluid (CSF) immunoassay results were concordant with positron emission tomography (PET) and predicted clinical progression, even with cutoffs established in an independent cohort. METHODS: Cutoffs for Elecsys amyloid-ß1-42 (Aß), total tau/Aß(1-42), and phosphorylated tau/Aß(1-42) were defined against [18F]flutemetamol PET in Swedish BioFINDER (n = 277) and validated against [18F]florbetapir PET in Alzheimer's Disease Neuroimaging Initiative (n = 646). Clinical progression in patients with mild cognitive impairment (n = 619) was studied. RESULTS: CSF total tau/Aß(1-42) and phosphorylated tau/Aß(1-42) ratios were highly concordant with PET classification in BioFINDER (overall percent agreement: 90%; area under the curve: 94%). The CSF biomarker statuses established by predefined cutoffs were highly concordant with PET classification in Alzheimer's Disease Neuroimaging Initiative (overall percent agreement: 89%-90%; area under the curves: 96%) and predicted greater 2-year clinical decline in patients with mild cognitive impairment. Strikingly, tau/Aß ratios were as accurate as semiquantitative PET image assessment in predicting visual read-based outcomes. DISCUSSION: Elecsys CSF biomarker assays may provide reliable alternatives to PET in Alzheimer's disease diagnosis.
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Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/diagnóstico , Imunoensaio , Tomografia por Emissão de Pósitrons , Idoso , Compostos de Anilina , Automação Laboratorial , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Progressão da Doença , Etilenoglicóis , Feminino , Humanos , Imunoensaio/métodos , Masculino , Compostos Radiofarmacêuticos , Proteínas tau/líquido cefalorraquidianoRESUMO
INTRODUCTION: Available assays for quantitation of the Alzheimer's disease (AD) biomarker amyloid-beta 1-42 (Aß [1-42]) in cerebrospinal fluid demonstrate significant variability and lack of standardization to reference measurement procedures (RMPs). We report analytical performance data for the novel Elecsys ß-amyloid (1-42) assay (Roche Diagnostics). METHODS: Lot-to-lot comparability was tested using method comparison. Performance parameters were measured according to Clinical & Laboratory Standards Institute (CLSI) guidelines. The assay was standardized to a Joint Committee for Traceability in Laboratory Medicine (JCTLM) approved RMP. RESULTS: Limit of quantitation was <11.28 pg/mL, and the assay was linear throughout the measuring range (200-1700 pg/mL). Excellent lot-to-lot comparability was observed (correlation coefficients [Pearson's r] >0.995; bias in medical decision area <2%). Repeatability coefficients of variation (CVs) were 1.0%-1.6%, intermediate CVs were 1.9%-4.0%, and intermodule CVs were 1.1%-3.9%. Estimated total reproducibility was 2.0%-5.1%. Correlation with the RMP was good (Pearson's r, 0.93). DISCUSSION: The Elecsys ß-amyloid (1-42) assay has high analytical performance that may improve biomarker-based AD diagnosis.
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Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides , Biomarcadores/líquido cefalorraquidiano , Imunoensaio/normas , Luminescência , Fragmentos de Peptídeos , Biomarcadores/análise , Humanos , Imunoensaio/instrumentação , Imunoensaio/métodos , Padrões de Referência , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Biomarkers can be subtle tools to aid the diagnosis, prognosis and monitoring of therapy and disease progression. The validation of biomarkers is a cumbersome process involving many steps. Serum samples from lung cancer patients were collected in the framework of a larger study for evaluation of biomarkers for early detection of lung cancer. The analysis of biomarker levels measured revealed a noticeable difference in certain biomarker values that exhibited a dependence of the time point and setting of the sampling. Biomarker concentrations differed significantly if taken before or after the induction of anesthesia and if sampled via venipuncture or arterial catheter. METHODS: To investigate this observation, blood samples from 13 patients were drawn 1-2 days prior to surgery (T1), on the same day by venipuncture (T2) and after induction of anesthesia via arterial catheter (T3). The biomarkers Squamous Cell Carcinoma antigen (CanAG SCC EIA, Fujirebio Diagnostics, Malvern, USA), Carcinoembrionic Antigen (CEA), and CYFRA 21-1 (Roche Diagnostics GmbH, Mannheim, Germany) were analyzed. RESULTS: SCC showed a very strong effect in relation to the sampling time and procedure. While the first two points in time (T1; T2) were highly comparable (median fold-change: 0.84; p = 0.7354; correlation ρ = 0.883), patients showed a significant increase (median fold-change: 4.96; p = 0.0017; correlation ρ = -0.036) in concentration when comparing T1 with the sample time subsequent to anesthesia induction (T3). A much weaker increase was found for CYFRA 21-1 at T3 (median fold-change: 1.40; p = 0.0479). The concentration of CEA showed a very small, but systematic decrease (median fold-change: 0.72; p = 0.0039). CONCLUSIONS: In this study we show the unexpectedly marked influence of blood withdrawal timing (before vs. after anesthesia) and procedure (venous versus arterial vessel puncture) has on the concentration of the protein biomarker SCC and to a less extent upon CYFRA21-1. The potential causes for these effects remain to be elucidated in subsequent studies, however these findings highlight the importance of a standardized, controlled blood collection protocol for biomarker detection.
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Purpose: To explore the contributions of fundus autofluorescence (FAF) topographic imaging features to the performance of convolutional neural network-based deep learning (DL) algorithms in predicting geographic atrophy (GA) growth rate. Methods: Retrospective study with data from study eyes from three clinical trials (NCT02247479, NCT02247531, NCT02479386) in GA. The algorithm was initially trained with full FAF images, and its performance was considered benchmark. Ablation experiments investigated the contribution of imaging features to the performance of the algorithms. Three FAF image regions were defined relative to GA: Lesion, Rim, and Background. For No Lesion, No Rim, and No Background datasets, a single region of interest was removed at a time. For Lesion, Rim, and Background Shuffled datasets, individual region pixels were randomly shuffled. For Lesion, Rim, and Background Mask datasets, masks of the regions were used. A Convex Hull dataset was generated to evaluate the importance of lesion size. Squared Pearson correlation (r2) was used to compare the predictive performance of ablated datasets relative to the benchmark. Results: The Rim region influenced r2 more than the other two regions in all experiments, indicating the most relevant contribution of this region to the performance of the algorithms. In addition, similar performance was observed for all regions when pixels were shuffled or only a mask was used, indicating intensity information was not independently informative without textural context. Conclusions: These ablation experiments enabled topographic clinical insights on FAF images from a DL-based GA progression prediction algorithm. Translational Relevance: Results from this study may lead to new insights on GA progression prediction.
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Aprendizado Profundo , Progressão da Doença , Atrofia Geográfica , Humanos , Atrofia Geográfica/diagnóstico , Atrofia Geográfica/patologia , Estudos Retrospectivos , Feminino , Masculino , Idoso , Algoritmos , Pessoa de Meia-Idade , Angiofluoresceinografia/métodos , Redes Neurais de Computação , Imagem Óptica/métodosRESUMO
The partial area under the receiver operating characteristic curve (PAUC) is a well-established performance measure to evaluate biomarker combinations for disease classification. Because the PAUC is defined as the area under the ROC curve within a restricted interval of false positive rates, it enables practitioners to quantify sensitivity rates within pre-specified specificity ranges. This issue is of considerable importance for the development of medical screening tests. Although many authors have highlighted the importance of PAUC, there exist only few methods that use the PAUC as an objective function for finding optimal combinations of biomarkers. In this paper, we introduce a boosting method for deriving marker combinations that is explicitly based on the PAUC criterion. The proposed method can be applied in high-dimensional settings where the number of biomarkers exceeds the number of observations. Additionally, the proposed method incorporates a recently proposed variable selection technique (stability selection) that results in sparse prediction rules incorporating only those biomarkers that make relevant contributions to predicting the outcome of interest. Using both simulated data and real data, we demonstrate that our method performs well with respect to both variable selection and prediction accuracy. Specifically, if the focus is on a limited range of specificity values, the new method results in better predictions than other established techniques for disease classification.
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Biomarcadores/análise , Neoplasias Colorretais/diagnóstico , Algoritmos , Detecção Precoce de Câncer/métodos , Humanos , Modelos Lineares , Modelos Teóricos , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Alzheimer's disease (AD) is a complex and heterogeneous disease, which requires reliable biomarkers for diagnosis and monitoring disease activity. Preanalytical protocol and technical variability associated with biomarker immunoassays makes comparability of biomarker data across multiple cohorts difficult. This study aimed to compare cerebrospinal fluid (CSF) biomarker results across independent cohorts, including participants spanning the AD continuum. METHODS: Measured on the NeuroToolKit (NTK) prototype panel of immunoassays, 12 CSF biomarkers were evaluated from three cohorts (ALFA+, Wisconsin, and Abby/Blaze). A correction factor was applied to biomarkers found to be affected by preanalytical procedures (amyloid-ß1-42, amyloid-ß1-40, and alpha-synuclein), and results between cohorts for each disease stage were compared. The relationship between CSF biomarker concentration and cognitive scores was evaluated. RESULTS: Biomarker distributions were comparable across cohorts following correction. Correlations of biomarker values were consistent across cohorts, regardless of disease stage. Disease stage differentiation was highest for neurofilament light (NfL), phosphorylated tau, and total tau, regardless of the cohort. Correlation between biomarker concentration and cognitive scores was comparable across cohorts, and strongest for NfL, chitinase-3-like protein-1 (YKL40), and glial fibrillary acidic protein. DISCUSSION: The precision of the NTK enables merging of biomarker datasets, after correction for preanalytical confounders. Assessment of multiple cohorts is crucial to increase power in future studies into AD pathogenesis.
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Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Proteínas tau/líquido cefalorraquidiano , Doenças Neurodegenerativas/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidianoRESUMO
OBJECTIVE: To develop deep learning models for annualized geographic atrophy (GA) growth rate prediction using fundus autofluorescence (FAF) images and spectral-domain OCT volumes from baseline visits, which can be used for prognostic covariate adjustment to increase power of clinical trials. DESIGN: This retrospective analysis estimated GA growth rate as the slope of a linear fit on all available measurements of lesion area over a 2-year period. Three multitask deep learning models-FAF-only, OCT-only, and multimodal (FAF and OCT)-were developed to predict concurrent GA area and annualized growth rate. PARTICIPANTS: Patients were from prospective and observational lampalizumab clinical trials. METHODS: The 3 models were trained on the development data set, tested on the holdout set, and further evaluated on the independent test sets. Baseline FAF images and OCT volumes from study eyes of patients with bilateral GA (NCT02247479; NCT02247531; and NCT02479386) were split into development (1279 patients/eyes) and holdout (443 patients/eyes) sets. Baseline FAF images from study eyes of NCT01229215 (106 patients/eyes) and NCT02399072 (169 patients/eyes) were used as independent test sets. MAIN OUTCOME MEASURES: Model performance was evaluated using squared Pearson correlation coefficient (r2) between observed and predicted lesion areas/growth rates. Confidence intervals were calculated by bootstrap resampling (B = 10 000). RESULTS: On the holdout data set, r2 (95% confidence interval) of the FAF-only, OCT-only, and multimodal models for GA lesion area prediction was 0.96 (0.95-0.97), 0.91 (0.87-0.95), and 0.94 (0.92-0.96), respectively, and for GA growth rate prediction was 0.48 (0.41-0.55), 0.36 (0.29-0.43), and 0.47 (0.40-0.54), respectively. On the 2 independent test sets, r2 of the FAF-only model for GA lesion area was 0.98 (0.97-0.99) and 0.95 (0.93-0.96), and for GA growth rate was 0.65 (0.52-0.75) and 0.47 (0.34-0.60). CONCLUSIONS: We show the feasibility of using baseline FAF images and OCT volumes to predict individual GA area and growth rates using a multitask deep learning approach. The deep learning-based growth rate predictions could be used for covariate adjustment to increase power of clinical trials. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
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Aprendizado Profundo , Atrofia Geográfica , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Angiofluoresceinografia/métodos , Imagem MultimodalRESUMO
Purpose: To examine deep learning (DL)-based methods for accurate segmentation of geographic atrophy (GA) lesions using fundus autofluorescence (FAF) and near-infrared (NIR) images. Methods: This retrospective analysis utilized imaging data from study eyes of patients enrolled in Proxima A and B (NCT02479386; NCT02399072) natural history studies of GA. Two multimodal DL networks (UNet and YNet) were used to automatically segment GA lesions on FAF; segmentation accuracy was compared with annotations by experienced graders. The training data set comprised 940 image pairs (FAF and NIR) from 183 patients in Proxima B; the test data set comprised 497 image pairs from 154 patients in Proxima A. Dice coefficient scores, Bland-Altman plots, and Pearson correlation coefficient (r) were used to assess performance. Results: On the test set, Dice scores for the DL network to grader comparison ranged from 0.89 to 0.92 for screening visit; Dice score between graders was 0.94. GA lesion area correlations (r) for YNet versus grader, UNet versus grader, and between graders were 0.981, 0.959, and 0.995, respectively. Longitudinal GA lesion area enlargement correlations (r) for screening to 12 months (n = 53) were lower (0.741, 0.622, and 0.890, respectively) compared with the cross-sectional results at screening. Longitudinal correlations (r) from screening to 6 months (n = 77) were even lower (0.294, 0.248, and 0.686, respectively). Conclusions: Multimodal DL networks to segment GA lesions can produce accurate results comparable with expert graders. Translational Relevance: DL-based tools may support efficient and individualized assessment of patients with GA in clinical research and practice.
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Aprendizado Profundo , Atrofia Geográfica , Humanos , Estudos Transversais , Fundo de Olho , Atrofia Geográfica/diagnóstico por imagem , Estudos Retrospectivos , Estudos Clínicos como AssuntoRESUMO
Importance: Alzheimer disease (AD), a neurodegenerative disease characterized by ß-amyloid plaques and τ tangles in the brain, represents an unmet medical need with no fully approved therapeutics to modify disease progression. Objective: To investigate the safety and efficacy of crenezumab, a humanized monoclonal immunoglobulin G4 antibody targeting ß-amyloid oligomers, in participants with prodromal to mild (early) AD. Design, Setting, and Participants: Two phase 3 multicenter randomized double-blind placebo-controlled parallel-group efficacy and safety studies of crenezumab in participants with early AD, CREAD and CREAD2, were initiated in 2016 and 2017, respectively, and were designed to evaluate the efficacy and safety of crenezumab in participants with early AD. CREAD (194 sites in 30 countries) and CREAD2 (209 sites in 27 countries) were global multicenter studies. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. Both trials enrolled individuals aged 50 to 85 years with early AD. Participants with some comorbidities and evidence of cerebral infarction or more than 4 microbleeds or areas of leptomeningeal hemosiderosis on magnetic resonance imaging were excluded. After 2923 and 2858 were excluded, respectively, 813 participants in CREAD and 806 in CREAD2 were randomly assigned in a 1:1 ratio to either placebo or crenezumab. In the final analysis, there were 409 participants in the placebo group and 404 in the crenezumab group in CREAD and 399 in the placebo group and 407 in the crenezumab group in CREAD2. Data were analyzed up until January 2019 and August 2019, respectively. Interventions: Participants received placebo or 60 mg/kg crenezumab intravenously every 4 weeks for up to 100 weeks. Main Outcomes and Measures: The primary outcome was change from baseline to week 105 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. Results: There were 813 participants in CREAD (mean [SD] age, 70.7 [8.2] years; 483 female and 330 male) and 806 in CREAD2 (mean [SD] age, 70.9 [7.7] years; 456 female and 350 male). Baseline characteristics were balanced between both groups. The between-group difference in mean change from baseline in CDR-SB score (placebo minus crenezumab) was -0.17 (95% CI, -0.86 to 0.53; P = .63) at week 105 in the CREAD study (88 placebo; 86 crenezumab). Compared with previous trials, no new safety signals were identified, and amyloid-related imaging abnormalities with edema were rare, mild, and transient. No meaningful changes in AD biomarkers were observed. Both studies were discontinued following a preplanned interim analysis indicating that CREAD was unlikely to meet the primary end point. Conclusions and Relevance: Crenezumab was well tolerated but did not reduce clinical decline in participants with early AD. Trial Registration: ClinicalTrials.gov Identifiers: CREAD, NCT02670083; CREAD2, NCT03114657.
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Doença de Alzheimer , Anticorpos Monoclonais Humanizados , Adulto , Idoso , Feminino , Humanos , Masculino , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Método Duplo-Cego , Placa Amiloide , Resultado do Tratamento , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
BACKGROUND: The pathogenesis of Crohn's disease (CD) is unknown. Besides immunoregulatory, genetic and environmental aspects, a nutritional impact is also encountered. Whether taste perception exerts any influence on an increased consumption of carbohydrates is unknown. OBJECTIVE: To evaluate nutritional habits and taste perception in CD patients, either in active or inactive disease stages. DESIGN: A prospective study was performed with 31 active and 27 inactive CD patients, and 30 age and sex-matched healthy subjects. Nutritional behavior was determined using an extensive optical nutrition questionnaire and taste perception was assessed by a 3-drop method with exceeding dilution tests. RESULTS: Active and inactive CD patients exhibited a significant increased taste threshold for the detection of all solutions (bitter: P=0.0012; salty: P=0.0198; sour: P=0.0021; and sweet: P=0.0208). For recognition, the determination of bitter solution (P=0.0014) was significantly reduced in CD patients compared with healthy subjects. No impact of clinical or objective parameters of inflammation on taste perception could be established. The consumption of refined sugar in CD patients was higher than in healthy subjects, though not significant. CONCLUSIONS: An increased taste threshold for the detection of all 4 taste qualities in active and inactive CD patients suggests a systemic pathogenesis, such as an inflammation of the oral cavity, as a manifestation of CD. In this study, changes in taste threshold were not associated with altered sugar consumption.
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Doença de Crohn/complicações , Preferências Alimentares , Percepção Gustatória , Adulto , Estudos de Casos e Controles , Doença de Crohn/fisiopatologia , Carboidratos da Dieta/administração & dosagem , Sacarose Alimentar/administração & dosagem , Comportamento Alimentar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e Questionários , Limiar Gustativo , Adulto JovemRESUMO
BACKGROUND: Since the 1970s, studies have examined potential risk factors associated with adverse drug reactions (ADRs) in a variety of settings. However, no pharmacoepidemiological study exists that incorporates clinical and laboratory parameters in a multiple regression model in order to consider predictors for ADRs. OBJECTIVES: To characterize risk factors associated with ADRs in patients admitted to university hospital departments of internal medicine. DESIGN AND SETTING: Intensive pharmacovigilance was carried out in departments of internal medicine of two university hospitals. All admissions were followed prospectively for the occurrence of ADRs by members of a pharmacoepidemiological team consisting of physicians, pharmacologists and pharmacists. To identify patients at high risk for experiencing ADRs, patient histories and several clinical and laboratory data, determined at the time of admission, were taken into consideration. In addition to the drug prescribed, 40 parameters defined vital status at admission. These included temperature, heart rate, blood pressure (systolic-diastolic), body mass index, nicotine and alcohol use, and first laboratory test results after admission on nutrition status, inflammation, liver, kidney, pancreas or thyroid status, electrolytes, blood count and coagulation. RESULTS: 907 patients were observed during the study period. The mean age of the study population was 60 +/- 16 years. The median number of different drugs administered per patient during hospitalization was 9.6 +/- 7.7. In 345 patients, 592 ADRs were evaluated: 33.4% possible, 61.5% probable and 4.7% highly probable. Two ADR-related deaths were observed during the study period. Analysing ADR predictors, 17 of 40 parameters reached significance in univariate analysis, but only five in a multivariate binary regression model: raised temperature (odds ratio [OR] 1.609; 95% CI 1.133, 2.285), low erythrocyte levels (OR 0.386; 95% CI 0.194, 0.768), low thrombocyte levels (OR 0.788, 95% CI 0.627, 0.989), high number of drugs (OR 1.117; 95% CI 1.076, 1.159) and female sex (OR 1.562; 95% CI 0.785, 2.013) were independent predictors for ADRs. CONCLUSION: For the patients investigated, of the large number of clinical data available only five independent factors predict ADR occurrence. Taking these results into account, physicians will be able to focus early on patients at risk for ADRs. To minimize ADR occurrence, ADR predictors should be integrated into the clinical pathway.
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Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Plaquetas/metabolismo , Temperatura Corporal , Eritrócitos/metabolismo , Feminino , Alemanha , Hospitais Universitários/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Polimedicação , Estudos Prospectivos , Análise de Regressão , Fatores de Risco , Fatores Sexuais , Adulto JovemRESUMO
OBJECTIVE: To evaluate the safety and efficacy of crenezumab in patients with mild to moderate Alzheimer disease (AD). METHODS: In this phase 2 trial, 431 patients with mild to moderate AD 50 to 80 years of age were randomized 2:1 (crenezumab:placebo). Patients received low-dose subcutaneous crenezumab 300 mg or placebo every 2 weeks (n = 184) or high-dose intravenous crenezumab 15 mg/kg or placebo every 4 weeks (n = 247) for 68 weeks. Primary outcome measures were change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) and Clinical Dementia Rating-Sum of Boxes scores from baseline to week 73. RESULTS: The primary and secondary endpoints were not met. In an exploratory post hoc analysis, a reduction in decline on the ADAS-Cog12 was observed in the high-dose group. Separation from the placebo group on the ADAS-Cog12 was greatest in the milder subsets of AD patients and reached statistical significance in the group with Mini-Mental State Examination scores of 22 to 26. In both groups, there was a significant increase in CSF ß-amyloid1-42 levels that correlated with crenezumab CSF levels. The overall rate of adverse events was balanced between groups. One case of amyloid-related imaging abnormalities indicative of vasogenic edema or effusions was reported. CONCLUSIONS: Although prespecified criteria for testing treatment effects were not met, these data suggest a potential treatment effect in patients with mild AD treated with high-dose crenezumab. Together with the safety profile for crenezumab, these data support the exploration of crenezumab treatment at even higher doses in patients with early AD. CLINICALTRIALSGOV IDENTIFIER: NCT 01343966. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, for people with AD, crenezumab does not significantly improve cognition or function at 18 months. The study is rated Class II because <80% of enrolled patients completed the study.
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Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Anticorpos Monoclonais/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Resultado do TratamentoRESUMO
BACKGROUND: We investigated the effect of crenezumab, a humanized anti-amyloid-beta (Aß) immunoglobulin (Ig)G4 monoclonal antibody, on biomarkers of amyloid pathology, neurodegeneration, and disease progression in patients with mild-to-moderate Alzheimer's disease (AD). METHODS: This double-blind, placebo-controlled, randomized phase II study enrolled patients with mild-to-moderate AD and a Mini-Mental State Examination (MMSE) score of 18-26. In part 1 of the study, patients were 2:1 randomized to receive low-dose subcutaneous (SC) 300 mg crenezumab every 2 weeks (q2w) or placebo for 68 weeks; in part 2, patients were 2:1 randomized to receive high-dose intravenous (IV) 15 mg/kg crenezumab every 4 weeks (q4w) or placebo for 68 weeks. The primary endpoint was change in amyloid burden from baseline to week 69 assessed by florbetapir positron emission tomography (PET) in the modified intent-to-treat population. Secondary endpoints were change from baseline to week 69 in cerebrospinal fluid (CSF) biomarkers and fluorodeoxyglucose PET, and change from baseline to week 73 in 12-point Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog12) and Clinical Dementia Rating Sum of Boxes (CDR-SB). Safety was assessed in patients who received at least one dose of study treatment. RESULTS: From August 2011 to September 2012, 91 patients were enrolled and randomized (low-dose SC cohort: crenezumab (n = 26) or placebo (n = 13); high-dose IV cohort: crenezumab (n = 36) or placebo (n = 16)). The primary endpoint was not met using a prespecified cerebellar reference region to calculate standard uptake value ratios (SUVRs) from florbetapir PET. Exploratory analyses using subcortical white matter reference regions showed nonsignificant trends toward slower accumulation of plaque amyloid in the high-dose IV cohort. In both cohorts, a significant mean increase from baseline in CSF Aß(1-42) levels versus placebo was observed. Nonsignificant trends toward ADAS-Cog12 and CDR-SB benefits were identified in a mild (MMSE 20-26) subset of the high-dose IV cohort. No amyloid-related imaging abnormalities due to edema/effusion were observed. CONCLUSION: The primary endpoint was not met. Exploratory findings suggest potential Aß target engagement with crenezumab and possible slower accumulation of plaque amyloid. Studies investigating the effects of higher doses of crenezumab on amyloid load and disease progression are ongoing. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01397578 . Registered on 18 July 2011.
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Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Anticorpos Monoclonais/uso terapêutico , Encéfalo/diagnóstico por imagem , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Método Duplo-Cego , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Resultado do TratamentoRESUMO
OBJECTIVE: To clarify the properties of different approaches to estimate the contribution of single-risk factors to the disease load in a population. STUDY DESIGN AND SETTING: Three methods of partitioning attributable risks are reviewed and two additional procedures as modifications of the existing algorithms are introduced. Basis properties of the approaches are outlined in the simplest setting with two exposure variables. The extension to more complex settings is illustrated by an example involving three risk factors. RESULTS: The quantification of the impact of single-risk factors can vary considerably according to the method used. Different orderings of the risk factors with respect to their impact can occur. Approaches can be classified according to two features: (i) inclusion or exclusion of partial interactions between risk factors, (ii) equal or proportional distribution of the surplus resulting from the combined action of risk factors. Practical applications have to carefully consider intrinsic limitations of all partitioning approaches. CONCLUSION: The decision on which concept to use when partitioning attributable risks on the population level should be based on the desired properties the solution ought to have. Arguments from game-theoretical reasoning can help to guide further research in this area, especially in exploring the methods using proportional division rules that are not yet fully understood.
Assuntos
Interpretação Estatística de Dados , Doença/etiologia , Medição de Risco/métodos , Algoritmos , Projetos de Pesquisa Epidemiológica , Humanos , Modelos Biológicos , Modelos Estatísticos , Fatores de RiscoRESUMO
Several criteria in B-scan and colour-coded Doppler ultrasound have been shown to discriminate malignant transformation of cervical lymph nodes. All these parameters tend to be operator dependent. We describe the first use of computer-assisted analysis of contrast-enhanced ultrasound images evaluating cervical lymphadenopathy in differentiation between benign and malignant lesions. The results from sonography were compared with the histologic findings in 60 patients. Subjective sonomorphologic parameters were evaluated and compared with quantitative criteria obtained from computer analysis after intravenous contrast medium (SonoVue) application to estimate diagnostic impact. Our results confirm that malignant lymph nodes are round in shape (p < 0.001) and show peripheral perfusion (p = 0.0089). Dynamic parameters revealed that malignant nodes were characterized by contrast medium wash-in time (p = 0.0487). However, the contrast-related criteria did not improve the pretherapeutic prediction of malignancy. Although contrast medium kinetics provided statistically significant new criteria for identifying malignant lymph nodes, differentiating between malignant and inflammatory changes in lymph nodes remains a diagnostic challenge.
Assuntos
Carcinoma de Células Escamosas/secundário , Neoplasias de Cabeça e Pescoço/secundário , Linfadenite/diagnóstico por imagem , Pescoço/diagnóstico por imagem , Fosfolipídeos , Hexafluoreto de Enxofre , Ultrassonografia Doppler em Cores/métodos , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/patologia , Diagnóstico por Computador , Diagnóstico Diferencial , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Aumento da Imagem/métodos , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Linfadenite/patologia , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Microbolhas , Pescoço/patologia , Estudos Prospectivos , Sensibilidade e EspecificidadeRESUMO
RATIONALE AND OBJECTIVES: To evaluate the ability of dynamic contrast-enhanced magnetic resonance imaging (MRI) to differentiate several tumor entities of the parotid gland in a prospective clinical trial. MATERIALS AND METHODS: A total of 112 patients with parotid tumors were examined with dynamic contrast-enhanced 1.5 T MRI. Precontrast axial T1-weighted imaging was used to select five slices for the dynamic study. Subsequently, a T1-weighted FLASH sequence was used for the dynamic contrast study (0.2 ml Gd/kg x body weight). Contrast agent application and the FLASH sequence were started simultaneously. Ten acquisitions of 10 seconds' scan time each were performed (total acquisition time 1:40 minutes). Signal intensity versus time (SIvT) curves was obtained for all tumors. After correlation of the categorized SIvT curves, these were compared with histopathology. Finally, all MRIs together with the tumor specific SIvT curves were re-read and correlated with histopathologic diagnosis. All reading sessions were done by three experienced radiologists. RESULTS: Four characteristic intensity-time curves were observed: pleomorphic adenoma showed a gradual increase in signal intensity, followed by a plateau phase on a low intensity level. Cysts showed a vacillating course at a low signal intensity level. Adenolymphomas as well as carcinomas showed a rapid increase in signal intensity followed by a plateau phase. Statistic significance was found for the time-to-peak values for adenolymphomas and pleomorphic adenomas and for the maximum peak signal intensity values for carcinomas. Together with other morphologic MRI criteria (contrast enhancement, border characteristics) and clinical features, a differentiation between adenolymphoma and carcinoma was possible. CONCLUSIONS: With additional dynamic contrast-enhanced MRI, a more reliable differentiation between common parotid tumors is possible before surgery.
Assuntos
Adenolinfoma/diagnóstico , Adenoma Pleomorfo/diagnóstico , Carcinoma/diagnóstico , Imageamento por Ressonância Magnética/métodos , Glândula Parótida/patologia , Neoplasias Parotídeas/diagnóstico , Adenolinfoma/cirurgia , Adenoma Pleomorfo/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/cirurgia , Criança , Meios de Contraste/administração & dosagem , Diagnóstico Diferencial , Feminino , Gadolínio , Humanos , Aumento da Imagem/métodos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Glândula Parótida/cirurgia , Neoplasias Parotídeas/cirurgia , Valor Preditivo dos Testes , Estudos Prospectivos , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: Histology of parotid tumors determines the extent of surgery. The aim was to test ultrasound (US) contrast enhancer-kinetics to identify histologic entities, possibly being superior to qualitative morphological parameters. STUDY DESIGN: In a cross-sectional assessment of ultrasound diagnosis, the subjective US-classification was compared with contrast analysis with histology as gold standard. SUBJECTS AND METHODS: A total of 64 male and 61 female patients with a mean age of 54 years were included, with 13 malignant tumors. These were classified with US morphology, then time-dependent contrast medium analysis. RESULTS: A total of 92.8% of tumors were classified correctly as malignant or benign. The sensitivity, specificity, positive- and negative-predictive values were 66.7%, 86.3%, 60.6%, and 89.1% for differentiating Warthin tumors, but only 46.2%, 98.2%, 75%, and 94% for malignant lesions. Contrast parameters yielded significant parameters for benign tumors, not for malignant entities. CONCLUSION: Although contrast medium analysis provided statistical criteria, these, however, do not possess the ability to improve the diagnostic prediction of tumor histology. Neither the morphologic classification nor contrast medium analysis was able to identify a malignant lesion sufficiently.
Assuntos
Neoplasias Parotídeas/diagnóstico por imagem , Adenolinfoma/diagnóstico por imagem , Adenolinfoma/patologia , Adenoma Pleomorfo/diagnóstico por imagem , Adenoma Pleomorfo/patologia , Meios de Contraste , Estudos Transversais , Feminino , Humanos , Aumento da Imagem/métodos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Neoplasias Parotídeas/patologia , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Método Simples-Cego , UltrassonografiaRESUMO
OBJECTIVES: The hepatitis B vaccination policy in Germany was intensified by the implementation of hepatitis B vaccination for adolescents in the vaccination calendar in 1995. To investigate the effect of this measure on the hepatitis B vaccination coverage of healthy adults, we analysed the hepatitis B vaccination status of blood donors. Furthermore, the reasons for vaccination and the relationship between vaccination status and age, sex, and current profession were studied. METHOD: Using a standardised questionnaire, randomly incoming whole blood donors were asked for hepatitis B vaccination status, the reason for vaccination, gender, age and current profession. Multiple logistic regression analysis with vaccination status as dependent variable and age, gender and current profession as explanatory variables was performed. RESULTS: Overall, 1519 (22.3%) of the 6812 interviewed whole blood donors were vaccinated against hepatitis B. Younger age was significantly associated with higher acceptance of hepatitis B vaccination with already 44.1% of whole blood donors aged 18-29 years being hepatitis B immunised. Beside health care workers, teaching professions and students showed the highest hepatitis B vaccination rate. Foreign travel was nearly an equivalently important reason for hepatitis B vaccination as occupational risks. CONCLUSION: The high hepatitis B vaccination coverage among young and healthy adults indicates the success of the intensified hepatitis B vaccination policy since 1995. However, concentrating education measures on individuals with lower educational level and intensifying hepatitis B vaccination in the context of foreign travel could further increase the acceptance of hepatitis B vaccination.