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At least 19 recordsLinked to original sources
PubMed2006

Imaging biomarkers as surrogate endpoints for drug development.

The employment of biomarkers (including imaging biomarkers, especially PET) in drug development has gained increasing attention during recent years. This has been partly stimulated by the hope that the integration of biomarkers into drug development programmes may be a means to increase the efficiency and effectiveness of the drug development process by early identification of promising drug candidates--thereby counteracting the rising costs of drug development. More importantly, however, the interest in biomarkers for drug development is the logical consequence of recent advances in biosciences and medicine which are leading to target-specific treatments in the framework of "personalized medicine". A considerable proportion of target-specific drugs will show effects in subgroups of patients only. Biomarkers are a means to identify potential responders, or patient subgroups at risk for specific side-effects. Biomarkers are used in early drug development in the context of translational medicine to gain information about the drug's potential in different patient groups and disease states. The information obtained at this stage is mainly important for designing subsequent clinical trials and to identify promising drug candidates. Biomarkers in later phases of clinical development may--if properly validated--serve as surrogate endpoints for clinical outcomes. Regulatory agencies in the EU and the USA have facilitated the use of biomarkers early in the development process. The validation of biomarkers as surrogate endpoints is part of FDA's "critical path initiative".

Biomarkers↗
PubMed2006

Dynamic contrast-enhanced magnetic resonance imaging as an imaging biomarker.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is being used in oncology as a noninvasive method for measuring properties of the tumor microvasculature. There is potential for DCE-MRI to be used as an imaging biomarker to measure antiangiogenic effects of cancer treatments. This article reviews the general methodology for performing DCE-MRI and discusses existing data and challenges to applying DCE-MRI for treatment response assessment in clinical trials.

Angiogenesis Inhibitors↗
PubMed2006

The functional diffusion map: an imaging biomarker for the early prediction of cancer treatment outcome.

Functional diffusion map (fDM) has been recently reported as an early and quantitative biomarker of clinical brain tumor treatment outcome. This approach spatially maps and quantifies treatment-induced changes in tumor water diffusion values resulting from alterations in cell density/cell membrane function and microenvironment. This current study was designed to evaluate the capability of fDM for preclinical evaluation of dose escalation studies and to determine if these changes were correlated with outcome measures (cell kill and overall survival). Serial T2-weighted were carried out on rodents with orthotopically implanted 9L brain tumors receiving three doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (6.65, 13.3, and 26.6 mg/kg, i.p.). All images were coregistered to baseline T2-weighted images for fDM analysis. Analysis of tumor fDM data on day 4 posttreatment detected dose-dependent changes in tumor diffusion values, which were also found to be spatially dependent. Histologic analysis of treated tumors confirmed spatial changes in cellularity as observed by fDM. Early changes in tumor diffusion values were found to be highly correlative with drug dose and independent biologic outcome measures (cell kill and survival). Therefore, The fDM imaging biomarker for early prediction of treatment efficacy can be used in the drug development process.

Animals↗
PubMed2004

Noninvasive magnetic resonance spectroscopic imaging biomarkers to predict the clinical grade of pediatric brain tumors.

The diagnosis and therapy of childhood brain tumors, most of which are low grade, can be complicated because of their frequent adjacent location to crucial structures, which limits diagnostic biopsy. Also, although new prognostic biomarkers identified by molecular analysis or DNA microarray gene profiling are promising, they too depend on invasive biopsy. Here, we test the hypothesis that combining information from biologically important intracellular molecules (biomarkers), noninvasively obtained by proton magnetic resonance spectroscopic imaging, will increase the diagnostic accuracy in determining the clinical grade of pediatric brain tumors. We evaluate the proton magnetic resonance spectroscopic imaging exams for 66 children with brain tumors. The intracellular biomarkers for choline-containing compounds (Cho), N-acetylaspartate, total creatine, and lipids and/or lactate were measured at the highest Cho region and normalized to the surrounding healthy tissue total creatine. Neuropathological grading was done with WHO criteria. Normalized Cho and lipids and/or lactate were elevated in high-grade (n = 23) versus low-grade (n = 43) tumors, which multiple logistic regression confirmed are independent predictors of tumor grade (for Cho, odds ratio 24.8, P < 0.001; and for lipids and/or lactate, odds ratio 4.4, P < 0.001). A linear combination of normalized Cho and lipids and/or lactate that maximizes diagnostic accuracy was calculated by maximizing the area under the receiver operating characteristic curve. Proton magnetic resonance spectroscopic imaging, although not a proxy for histology, provides noninvasive, in vivo biomarkers for predicting clinical grades of pediatric brain tumors.

Aspartic Acid↗
PubMed2005

Using imaging biomarkers to accelerate drug development and clinical trials.

There is increasing evidence that human medical imaging can help answer key questions that arise during the drug development process. Imaging modalities such as magnetic resonance imaging, computed tomography and positron emission tomography can offer significant insights into the bioactivity, pharmacokinetics and dosing of drugs, in addition to supporting registration applications. In this review, examples from oncology, neurology, psychiatry, infectious diseases and inflammatory diseases are used to illustrate the role imaging can play. We conclude with some remarks concerning new developments that will be required to significantly advance the field of pharmaco-imaging.

Animals↗
PubMed2005

Rationale and methods of the integrated biomarker and imaging study (IBIS): combining invasive and non-invasive imaging with biomarkers to detect subclinical atherosclerosis and assess coronary lesion biology.

Death or myocardial infarction, the most serious clinical consequences of atherosclerosis, often result from plaque rupture at non-flow limiting lesions. Current diagnostic imaging with coronary angiography only detects large plaques that already impinge on the lumen and cannot accurately identify those that have a propensity to cause unheralded events. Accurate evaluation of the composition or of the biomechanical characteristics of plaques with invasive or non-invasive methods, alone or in conjunction with assessment of circulating biomarkers, could help identify high-risk patients, thus providing the rationale for aggressive treatments in order to reduce future clinical events. The IBIS (Integrated Biomarker and Imaging Study) study is a prospective, single-center, non-randomized, observational study conducted in Rotterdam. The aim of the IBIS study is to evaluate both invasive (quantitative coronary angiography, intravascular ultrasound (IVUS) and palpography) and non-invasive (multislice spiral computed tomography) imaging techniques to characterize non-flow limiting coronary lesions. In addition, multiple classical and novel biomarkers will be measured and their levels correlated with the results of the different imaging techniques. A minimum of 85 patients up to a maximum of 120 patients will be included. This paper describes the study protocol and methodological solutions that have been devised for the purpose of comparisons among several imaging modalities. It outlines the analyses that will be performed to compare invasive and non-invasive imaging techniques in conjunction with multiple biomarkers to characterize non-flow limiting subclinical coronary lesions.

Adult↗
PubMed2006

Magnetic resonance as a cancer imaging biomarker.

Cancer is a diverse disease with many manifestations. Magnetic resonance (MR) has a wide range of sensitivities, and therefore has often been used to study cancer in humans in numerous different ways, most typically with MR spectroscopy and MR imaging. This article is not an exhaustive catalog of the use of MR in cancer, but will briefly highlight some of the many promising MR methods that have been developed, proposed, or used to focus on the problem of detecting and characterizing cancer, its treatments, and adverse effects.

Biomarkers, Tumor↗
PubMed2004

Toward imaging biomarkers for osteoarthritis.

Many new therapeutic strategies have been and are being developed to correct, prevent, or slow the progression of osteoarthritis. Our ability to evaluate the efficacy of these techniques, or to determine the situations for which they might provide the most benefit, critically depends on diagnostic measures that can serve as proxies for the present or predicted state of the cartilage. Many of the magnetic resonance imaging techniques that have been emerging over the past decades appear promising in that they have shown technical validity in measuring the morphologic and molecular state of cartilage. With continued development and added insight from pilot clinical studies, these or related methods may soon be in customary use. These techniques are part of a paradigm shift where therapeutic strategies are developed hand-in-hand with diagnostic approaches-a shift that offers the promise of speeding development of effective therapies, and focusing their use in areas where they can be most successful.

Biomarkers↗
PubMed2006

Positron emission tomography as an imaging biomarker.

Positron emission tomography (PET) allows noninvasive, quantitative studies of various biologic processes in the tumor tissue. By using PET, investigators can study the pharmacokinetics of anticancer drugs, identify various therapeutic targets and monitor the inhibition of these targets during therapy. Furthermore, PET provides various markers to assess tumor response early in the course of therapy. A significant number of studies have now shown that changes in tumor glucose utilization during the first weeks of chemotherapy are significantly correlated with patient outcome. These data suggest that PET may be used as a sensitive test to assess the activity of new cytotoxic agents in phase II studies. Furthermore, early identification of nonresponding tumors provides the opportunity to adjust treatment regimens according to the individual chemosensitivity of the tumor tissue. However, further prospective and randomized validation of PET is still required before PET controlled chemotherapy can be used in clinical practice.

Antineoplastic Agents↗
PubMed2003

Biomarkers in imaging: realizing radiology's future.

Modern pharmaceuticals and medical devices have provided substantial benefits to patients throughout the world. These benefits come at a high and increasing cost, with development of the typical pharmaceutical requiring 12 years and hundreds of millions of dollars before gaining U.S. Food and Drug Administration marketing approval. Appropriate use of imaging biomarkers--defined as anatomic, physiologic, biochemical, or molecular parameters detectable with imaging methods used to establish the presence or severity of disease--offer the prospect of smaller, less expensive, and more efficient preclinical studies and clinical trials. Scientists, government regulators, and industry have all recognized the potential of biomarkers in imaging. Although real, this promise can only be realized with the rigorous application of science to their use. Success is most likely when (a) the presence of an imaging marker is closely linked with the presence of a target disease; (b) detection and/or measurement of the biomarker is accurate, reproducible, and feasible over time; and (c) measured changes are closely linked to success or failure of the therapeutic effect of the product being evaluated. By applying this paradigm to the array of imaging modalities, the radiology community is poised to become a major force in preclinical and clinical evaluations of new medical treatments.

Biomarkers↗
PubMed2006

Noninvasive detection of subclinical coronary atherosclerosis coupled with assessment of changes in plaque characteristics using novel invasive imaging modalities: the Integrated Biomarker and Imaging Study (IBIS).

OBJECTIVES: Our purpose was to assess noninvasive imaging in detection of subclinical atherosclerosis and to examine novel invasive modalities to describe prevalence and temporal changes in putative characteristics of "high-risk" plaques. BACKGROUND: Conventional coronary imaging cannot identify "high-risk" lesions. METHODS: Conventional (quantitative angiography and intravascular ultrasound [IVUS]) and novel imaging (IVUS-based palpography and gray scale echogenicity) were performed at baseline and 6 months later in 67 patients with diverse clinical presentations. Different imaging techniques were compared within a common segment defined by multislice computed tomography (MSCT). RESULTS: Compared with IVUS, the sensitivity, specificity, and positive and negative predictive value of MSCT for detecting significant plaque was 86%, 69%, 90%, and 61%, respectively. In coronary arteries with <50% stenosis, there were no temporal changes in luminal and plaque dimensions measured by quantitative coronary angiography or IVUS; however, a significant reduction in abnormal strain pattern was detected on palpography (density high strain spots/cm: 1.6 +/- 1.5 vs. 1.2 +/- 1.4, p = 0.0123. These changes were mainly related to significant changes in patients who presented with ST-segment elevation myocardial infarction. The assessment of plaque echogenicity showed no temporal changes. There were no correlations between circulating biomarkers and quantifiable imaging parameters. CONCLUSIONS: Mild angiographic disease is associated with large atherosclerotic plaques on MSCT. Conventional invasive coronary imaging reveals static luminal and plaque dimensions on standard medical therapy with plaque hypoechogenicity remaining unchanged over the 6-month period. By contrast, palpography measurements of strain correlate with clinical presentation and significantly decrease on standard medical therapy. Novel imaging modalities, such as palpography, might provide insights into plaque biology and might eventually serve as intermediate end points in interventional trials.

Coronary Angiography↗
PubMed2005

Medical imaging in pharmaceutical clinical trials: what radiologists should know.

The role of medical imaging in pharmaceutical clinical trials includes identification of likely responders; detection and diagnosis of lesions and evaluation of their severity; and therapy monitoring and follow-up. Nuclear imaging techniques such as PET can be used to monitor drug pharmacokinetics and distribution and study specific molecular endpoints. In assessing drug efficacy, imaging biomarkers and imaging surrogate endpoints can not only be more objective and faster to measure than clinical outcomes, but also allow small group sizes, quick results and good statistical power. In this article some basic principles of drug clinical development are explained. Study design, image reading and quantitative image processing in clinical trials with imaging components are discussed.

Clinical Trials as Topic↗
PubMed2004

Improved small volume lung cancer detection with computer-aided detection: database characteristics and imaging of response to breast cancer risk reduction strategies.

Computer-aided detection (CAD) and diagnosis (CADx) of in vivo imaging studies are important tools based on bioinformatics. Currently, there are two diseases for which the United States Food and Drug Administration (FDA) has given premarket approval (PMA): the detection of signs consistent with lung cancer on chest radiographs and breast cancer on mammograms. There are systems for other diseases and other types of images under development; however, this process depends on the availability of an accurate database. The author helped in the development of the databases for such systems and management of the clinical trial that resulted in the FDA-PMA of the system that detects findings consistent with lung cancer. The characteristics of the database used will be described. Further, a woman's risk of developing breast cancer differs from those of other women. Risk can be high, average, or low. There are now pharmaceuticals that decrease the risk that women, as a group, will develop breast cancer and it has been suggested that dietary changes could have similar effects. The pharmaceutical agents, though, have some associated side effects, and it is clinically important to determine whether these agents have decreased an individual woman's risk of breast cancer. In vivo imaging biomarkers of risk and successful risk reduction are therefore sought, but the information on possible in vivo imaging biomarkers is less mature than activities in CAD. Bioinformatics will be an important contributor to this in vivo imaging biomarker development.

Breast Neoplasms↗
PubMed2005

Methodological considerations and approach to cross-technique comparisons using in vivo coronary plaque characterization based on intravascular ultrasound radiofrequency data analysis: insights from the Integrated Biomarker and Imaging Study (IBIS).

Grey scale intravascular ultrasound (IVUS) is a valuable clinical tool to assess the extent and severity of coronary atheroma. However, it cannot reliably identify plaques with a high-risk of future clinical events. Serial IVUS studies to assess the progression and/or regression of atherosclerotic plaques demonstrated only modest effects, of pharmacological intervention on plaque burden, even when clinical efficacy is documented. Spectral analysis of radiofrequency ultrasound data (IVUS-virtual histology (IVUS-VH), Volcano Therapeutics, Rancho Cordova, CA) has the potential to characterize accurately plaque composition. The Integrated Biomarker and Imaging Study (IBIS) evaluated both invasive and non-invasive imaging techniques along with the assessment of novel biomarkers to characterize sub-clinical atherosclerosis. IVUS-VH was not included at the start of the IBIS protocol. The purpose of this paper is to describe the methodology we used to obtain and analyse IVUS-VH images and the approach to cross-correlations with the other techniques.

Biomarkers↗