Citations

AbstractThe last decade has seen a substantial increase in research focused on the identification of blood‐based biomarkers that have utility in Alzheimer's disease (AD). Blood‐based biomarkers have significant advantages of being time‐ and cost‐efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility and an unclear path for moving basic discovery toward clinical utilization. Here we reviewed the recent literature on blood‐based biomarkers in AD to provide a current state of the art. In addition, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and toward clinical use. Key resources are provided. This new public‐private partnership model is intended to circumvent the traditional handoff model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases.

Goals/Background: Data on acute variceal hemorrhage (AVH) in the United States is limited and the best method to stratify risk is not clear. Taking advantage of a prospective US cohort study, we aimed to (1) describe clinical outcomes of AVH and their predictors; (2) compare predictors of 6-week mortality. Study: Prospective 15-center US cohort of patients with cirrhosis presenting with endoscopically proven AVH, all of whom received antibiotics, vapreotide (a somatostain analog) infusion and endoscopic band ligation. Patients were enrolled between August 2006 and April 2008. Primary outcome was 6-week mortality. Secondary outcome was 5-day treatment failure. The prognostic value of Child-Turcotte-Pugh (CTP) class, Model for End-stage Liver Disease (MELD) score and a recent recalibrated MELD were compared. Results: Seventy eligible patient were enrolled; 18 (26%) patients died within 6-weeks of index bleed. Demographic, clinical, and laboratory data were compared between survivors and nonsurvivors. Multivariate models showed that admission CTP or the MELD score (separately) were independent predictors of survival. The discriminative values of CTP (area under receiver operating characteristic: 0.75) and MELD (area under receiver operating characteristic: 0.79) were good and not significantly different (P=0.27). However, calibration (correlation between observed and predicted mortality) test was significantly better for CTP than for MELD, with the recently described recalibrated MELD model having the worst agreement. Predicted mortality for CTP-A was <10%, CTP-B 10% to 30%; and CTP-C >33%. Conclusions: AVH mortality of 26% in the United States is in the upper range limit compared with recent series but may be due to inclusion of patients with more advanced cirrhosis. CTP score has the best overall performance in the prediction of 6-week mortality and is best at stratifying risk.

Freely available software, derived from the past 2 decades of neuroimaging research, is significantly more flexible for research purposes than presently available clinical tools. Here, we describe and demonstrate the utility of rapidly deployable analysis software to facilitate trainee-driven translational neuroimaging research. A recipe and video tutorial were created to guide the creation of a NeuroDebian-based virtual computer that conforms to current neuroimaging research standards and can exist within a HIPAA-compliant system. This allows for retrieval of clinical imaging data, conversion to standard file formats, and rapid visualization and quantification of individual patients’ cortical and subcortical anatomy. As an example, we apply this pipeline to a pediatric patient’s data to illustrate the advantages of research-derived neuroimaging tools in asking quantitative questions “at the bedside.” Our goal is to provide a path of entry for trainees to become familiar with common neuroimaging tools and foster an increased interest in translational research.

Purpose Extramedullary disease (EMD) at diagnosis in patients with acute myeloid leukemia (AML) has been recognized for decades. Reported herein are results from a large study of patients with AML who were treated in consecutive ECOG-ACRIN Cancer Research Group frontline clinical trials in an attempt to define the incidence and clinical implications of EMD. Methods Patients with newly diagnosed AML, age 15 years and older, who were treated in 11 clinical trials, were studied to identify EMD, as defined by physical examination, laboratory findings, and imaging results. Results Of the 3,522 patients enrolled, 282 were excluded, including patients with acute promyelocytic leukemia, incorrect diagnosis, or no adequate assessment of EMD at baseline. The overall incidence of EMD was 23.7%. The sites involved were: lymph nodes (11.5%), spleen (7.3%), liver (5.3%), skin (4.5%), gingiva (4.4%), and CNS (1.1%). Most patients (65.3%) had only one site of EMD, 20.9% had two sites, 9.5% had three sites, and 3.4% had four sites. The median overall survival was 1.035 years. In univariable analysis, the presence of any EMD ( P = .005), skin involvement ( P = .002), spleen ( P < .001), and liver ( P < .001), but not CNS ( P = .34), nodal involvement ( P = .94), and gingival hypertrophy ( P = .24), was associated with a shorter overall survival. In contrast, in multivariable analysis, adjusted for known prognostic factors such as cytogenetic risk and WBC count, neither the presence of EMD nor the number of specific sites of EMD were independently prognostic. Conclusion This large study demonstrates that EMD at any site is common but is not an independent prognostic factor. Treatment decisions for patients with EMD should be made on the basis of recognized AML prognostic factors, irrespective of the presence of EMD.

Quantitative computed tomography-based finite-element analysis (QCT/FEA) has become increasingly popular in an attempt to understand and possibly reduce vertebral fracture risk. It is known that scanning acquisition settings affect Hounsfield units (HU) of the CT voxels. Material properties assignments in QCT/FEA, relating HU to Young's modulus, are performed by applying empirical equations. The purpose of this study was to evaluate the effect of QCT scanning protocols on predicted stiffness values from finite-element models. One fresh frozen cadaveric torso and a QCT calibration phantom were scanned six times varying voltage and current and reconstructed to obtain a total of 12 sets of images. Five vertebrae from the torso were experimentally tested to obtain stiffness values. QCT/FEA models of the five vertebrae were developed for the 12 image data resulting in a total of 60 models. Predicted stiffness was compared to the experimental values. The highest percent difference in stiffness was approximately 480% (80 kVp, 110 mAs, U70), while the lowest outcome was ∼1% (80 kVp, 110 mAs, U30). There was a clear distinction between reconstruction kernels in predicted outcomes, whereas voltage did not present a clear influence on results. The potential of QCT/FEA as an improvement to conventional fracture risk prediction tools is well established. However, it is important to establish research protocols that can lead to results that can be translated to the clinical setting.

BACKGROUND. Variable response to chemotherapy in acute myeloid leukemia (AML) represents a major treatment challenge. Clinical and genetic features incompletely predict outcome. The value of clinical epigenetic assays for risk classification has not been extensively explored. We assess the prognostic implications of a clinical assay for multilocus DNA methylation on adult patients with de novo AML. METHODS. We performed multilocus DNA methylation assessment using xMELP on samples and calculated a methylation statistic (M-score) for 166 patients from UPENN with de novo AML who received induction chemotherapy. The association of M-score with complete remission (CR) and overall survival (OS) was evaluated. The optimal M-score cut-point for identifying groups with differing survival was used to define a binary M-score classifier. This classifier was validated in an independent cohort of 383 patients from the Eastern Cooperative Oncology Group Trial 1900 (E1900; NCT00049517). RESULTS. A higher mean M-score was associated with death and failure to achieve CR. Multivariable analysis confirmed that a higher M-score was associated with death ( P = 0.011) and failure to achieve CR ( P = 0.034). Median survival was 26.6 months versus 10.6 months for low and high M-score groups. The ability of the M-score to perform as a classifier was confirmed in patients ≤ 60 years with intermediate cytogenetics and patients who achieved CR, as well as in the E1900 validation cohort. CONCLUSION. The M-score represents a valid binary prognostic classifier for patients with de novo AML. The xMELP assay and associated M-score can be used for prognosis and should be further investigated for clinical decision making in AML patients.

The spine is the most common site for secondary bone metastases, and clinical management for fractures is based on size and geometry of the defect. About 75% of the bone needs to be damaged before lesions are detectable, so clinical tools should measure changes in both geometry and material properties. We have developed an automated, user-friendly, Spine Cancer Assessment (SCA) image-based analysis method that builds on a platform designed for clinical practice providing failure characteristics of vertebrae. The objectives of this study were to (1) validate SCA predictions with experimental failure load outcomes; (2) evaluate the planning capabilities for prophylactic vertebroplasty procedures; and (3) investigate the effect of computed tomography (CT) protocols on predicted failure loads. Twenty-one vertebrae were randomly divided into two groups: (1) simulated defect without treatment (negative control) [ n = 9] and (2) with treatment [ n = 12]. Defects were created and a polymeric biomaterial was injected into the vertebrae in the treated-defect group. Spines were scanned, reconstructed with two algorithms, and analyzed for fracture loads. To virtually plan for prophylactic intervention, vertebrae with empty lesions were simulated to be augmented with either poly(methyl methacrylate) (PMMA) or a novel bone replacement copolymer, poly(propylene fumarate-co-caprolactone) [P(PF-co-CL)]. Axial rigidities were calculated from the CT images. Failure loads, determined from the cross section with the lowest axial rigidity, were compared with experimental values. Predicted loads correlated well with experimental outcomes ( R 2 = 0.73, p < 0.0001). Predictions from negative control specimens highly correlated with measured values ( R 2 = 0.90, p < 0.0001). Although a similar correlation was obtained using both algorithms, the smooth reconstruction (B30) tended to underestimate predicted failure loads by ∼50% compared with the ∼10% underestimate of the sharp reconstruction (B70). Percent increase in failure loads after virtual vertebroplasty showed a higher increase in samples with PMMA compared with those with copolymer. The SCA method developed in this study calculated failure loads from quantitative computed tomography scans in vertebrae with simulated metastatic lytic defects, with or without treatment, facilitating clinical applicability and providing more reliable guidelines for physicians to select appropriate treatment options. Furthermore, the analysis could accommodate augmentation planning procedures that aimed to determine the optimum material that would increase vertebral body failure load.