Dynamic Contrast-Enhanced Magnetic Resonance Imaging for the Prediction of Monoclonal Antibody Tumor Disposition

The prediction of monoclonal antibody (mAb) disposition within solid tumors for individual patients is difficult due to inter-patient variability in tumor physiology. Improved a priori prediction of mAb pharmacokinetics in tumors may facilitate the development of patient-specific dosing protocols and facilitate improved selection of patients for treatment with anti-cancer mAb. Here, we report the use of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), with tumor penetration of the contrast agent gadobutrol used as a surrogate, to improve physiologically based pharmacokinetic model (PBPK) predictions of cetuximab pharmacokinetics in epidermal growth factor receptor (EGFR) positive xenografts. In the initial investigations, mice bearing Panc-1, NCI-N87, and LS174T xenografts underwent DCE-MRI imaging with the contrast agent gadobutrol, followed by intravenous dosing of an ¹²⁵Iodine-labeled, non-binding mAb (8C2). Tumor concentrations of 8C2 were determined following the euthanasia of mice (3 h–6 days after 8C2 dosing). Potential predictor relationships between DCE-MRI kinetic parameters and 8C2 PBPK parameters were evaluated through covariate modeling. The addition of the DCE-MRI parameter K^trans alone or K^trans in combination with the DCE-MRI parameter Vp on the PBPK parameters for tumor blood flow (QTU) and tumor vasculature permeability (σ_TU^V) led to the most significant improvement in the characterization of 8C2 pharmacokinetics in individual tumors. To test the utility of the DCE-MRI covariates on a priori prediction of the disposition of mAb with high-affinity tumor binding, a second group of tumor-bearing mice underwent DCE-MRI imaging with gadobutrol, followed by the administration of ¹²⁵Iodine-labeled cetuximab (a high-affinity anti-EGFR mAb). The MRI-PBPK covariate relationships, which were established with the untargeted antibody 8C2, were implemented into the PBPK model with considerations for EGFR expression and cetuximab-EGFR interaction to predict the disposition of cetuximab in individual tumors (a priori). The incorporation of the K^trans MRI parameter as a covariate on the PBPK parameters QTU and σ_TU^V decreased the PBPK model prediction error for cetuximab tumor pharmacokinetics from 223.71 to 65.02%. DCE-MRI may be a useful clinical tool in improving the prediction of antibody pharmacokinetics in solid tumors. Further studies are warranted to evaluate the utility of the DCE-MRI approach to additional mAbs and additional drug modalities.     

Outpatient behavioral treatment for cocaine dependence: One-year outcome.

This article describes outcomes observed during the year after treatment entry from two controlled trials in which cocaine-dependent outpatients were randomly assigned to either a multicomponent behavioral treatment or to one of two control treatments. The behavioral treatment integrated the community reinforcement approach (CRA) with an incentive program in which cocaine abstinence was reinforced with vouchers exchangeable for retail items. The two control treatments were drug abuse counseling and CRA without the incentive program. All treatment groups improved significantly compared to intake, and those changes were maintained through the follow-up period. When efficacy differences were observed during treatment and follow-up, they supported CRA with vouchers over control treatments. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Human drug self-administration in a medium of exchange.

In a laboratory setting, a medium of exchange procedure was used to study factors relevant to drug taking. Participants could earn an income, respond to obtain cigarette puffs, and purchase puffs. Across sessions, either the work required for money increased while the work required for puffs remained constant, or vice versa (puffs always cost $0.25 each). Each manipulation was conducted twice, once when they could keep income not spent on puffs, and once when they could not. The two manipulations had equivalent effects on drug taking when income could be spent only on puffs; both manipulations decreased drug taking in equal magnitudes. When participants could keep income not spent on puffs, however, the two manipulations had different effects. Participants spent less on puffs and consumed less when it was the work required for puffs that increased. These and other results show the utility of the medium-of-exchange procedure and the unit-price metric for evaluating basic features of the drug-taking environment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Full-scale aircraft impact test for evaluation of impact force

Previously, estimates of the force caused by aircraft impact into rigid structures have been determined using theoretical methods based on the aircraft's calculated mass and strength distribution. However, these methods required many assumptions to be made and they left many questions unanswered. Because of the uncertainty involved in these analytical predictions of impact force, a full-scale aircraft impact test was performed and an extensive set of response measurements was analyzed to evaluate the impact force against a rigid target. The analysis and evaluation gave an accurate impact force-time curve under the test condition and confirmed the practical use of an existing analytical method. An analysis with a lumped mass spring model also provided good agreement with the test results.     

Clinical and translational research: Introduction to the special issue.

This special issue represents an effort by the journal Experimental and Clinical Psychopharmacology to emphasize its interdisciplinary mission by encouraging the writing of articles on clinical research and the interchange between basic and clinical research on mental illness and the addictions. This special issue opens with a commentary from A. I. Leshner (2002), retired director of the National Institute on Drug Abuse, which emphasizes the importance of translating research findings into clinical practice. Four review articles and 12 original research reports provide a broad sampling of contemporary clinical research, including behavioral therapy, pharmacotherapy, psychiatric comorbidity, and special populations, and also illustrate linkages between clinical research and basic fields of inquiry, including behavioral theory, neuropsychology, neuropharmacology, and statistics. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cross-national interrater reliability of dementia diagnosis in the elderly and factors associated with disagreement

Thirteen researchers from five centers in Australia, Germany, the Netherlands, United Kingdom, and United States applied DSM-III-R and Clinical Dementia Rating (CDR) syndrome-level dementia criteria to written vignettes of 100 elderly people identified in clinics or community surveys. Subjects ranged in type from cognitively intact to severely demented and many were also frail, partially sighted, or deaf. This paper concerns reliability within and between centers, and the relationship between reliability and factors such as diagnostic criteria, dementia severity, and respondents' clinical characteristics. Within-center interrater reliability was high, more so for "yes-no" DSM-III-R diagnoses than the multi-level CDR. Between-center rates were lower but still moderate to good. Concordance was lower for intermediate dementia levels than for no dementia and severe dementia. Physical disability made an additional contribution to uncertainty but deafness, poor vision, anxiety, and depression had no discernible effects. Reliability levels are likely to be lower in representative aged populations than in carefully selected clinical groups.     

Active evaluation of ranking functions based on graded relevance

Evaluating the quality of ranking functions is a core task in web search and other information retrieval domains. Because query distributions and item relevance change over time, ranking models often cannot be evaluated accurately on held-out training data. Instead, considerable effort is spent on manually labeling the relevance of query results for test queries in order to track ranking performance. We address the problem of estimating ranking performance as accurately as possible on a fixed labeling budget. Estimates are based on a set of most informative test queries selected by an active sampling distribution. Query labeling costs depend on the number of result items as well as item-specific attributes such as document length. We derive cost-optimal sampling distributions for the commonly used performance measures Discounted Cumulative Gain and Expected Reciprocal Rank. Experiments on web search engine data illustrate significant reductions in labeling costs.     

Zur Rezeption von Hallers medizinischem und medizinhistorischem Werk im 19. und 20. Jahrhundert

A survey of the secondary literature of Albrecht Haller’s medical work after his death (1777) reveals that already in the 19th century most of his topics and his method were discussed and appreciated. Within physiology his doctrine of irritability and sensibility received most attention. The 20th century shows a considerable expansion of the secondary literature. However, there is still a lack of monographs dealing with Haller’s medical work in a comprehensive way. Not only was the appreciation of Haller’s medical work in the more than 200 years since his death constantly high but, for whatever reasons, it is even characterized by an increasing interest of researchers from many fields.