Information In Clinical Settings Research Articles

Fast and accurate T2 mapping using Bloch simulations and low-rank plus sparse matrix decomposition

PurposeMRI's T2 relaxation time is one of the key contrast mechanisms for clinical diagnosis and prognosis of pathologies. Mapping this relaxation time, however, involves extensive scan times, which are needed to collect quantitative data, thereby impeding its integration into clinical routine. This study employs a low-rank plus sparse (L + S) signal decomposition approach in order to reconstruct accurate T2-maps from highly undersampled multi-echo spin-echo (MESE) MRI data. MethodsTwo new algorithms are presented: the first uses standard L + S approach, where both L and S are iteratively updated. The second technique, dubbed SPArse and fixed RanK (SPARK), uses a fixed-rank L, under the assumption that most MESE information is found in the L component and that this rank can be pre-calculated. The utility of these new techniques is demonstrated on in vivo brain and calf data at x2 to x6 acceleration factors. ResultsAccelerated T2 maps showed improved accuracy compared to fully sampled ground truth maps, when using L + S and SPARK techniques vis-à-vis standard GRAPPA acceleration. ConclusionSPARK provides accurate T2 maps with increased robustness to the selection of reconstruction parameters making it suitable to a wide range of applications and facilitating the use of quantitative T2 information in clinical settings.

Breast arterial calcification rates in a diverse, urban group of screening mammography patients

Breast arterial calcifications (BAC), detected by digital mammography are a potential marker of coronary artery disease (CAD). Past BAC research has been limited by having primarily racially and ethnically homogeneous samples, samples at higher risk for CAD, and neglecting to explore the influence of women's health factors. The purpose of this study was to evaluate the prevalence of, and factors associated with, BAC in an ethnically and racially diverse group. We conducted a retrospective chart review on 17,237 screening mammography patients. Mammography results and patient responses to a demographic and medical history questionnaire were abstracted. Logistic regression was used. BAC prevalence was 12.3%. Age was a significant risk factor, with the odds of BAC approximately doubling every decade. Age-adjusted analyses showed: 1) higher BAC prevalence among Hispanic and Black women; 2) lower BAC prevalence among Ashkenazi women, nulliparous and pre-menopausal women, those with dense breasts and breast implants, and those currently using HRT; and, 3) no association between BAC prevalence and BMI or age at menarche. BAC prevalence differs according to age, ethnicity, race, women's health, and breast-specific factors. Communication of BAC information in clinical settings could potentially prompt women to engage in preventive care.

Inference from Imprecisely Measured Exposures: Caution Is Needed When Using Health Insurance Data for Clinical Research: Commentary on an article by Karch M. Smith, BA, et al.: "The Effect of Sex Hormone Deficiency on the Incidence of Rotator Cuff Repair. Analysis of a Large Insurance Database".

Commentary Rotator cuff injuries are common and can lead to disability and pain1,2. Smith et al. utilized health-care billing data to explore whether sex hormone deficiency (SHD) was associated with rotator cuff repair (RCR). Their work builds on several studies that have assessed the relationship between SHD and postoperative recovery. Understanding the possible link between SHD and rotator cuff disease could point to strategies for preventing the need for RCRs and improving outcomes following treatment. As the availability and use of billing data for research increase, the importance of understanding their strengths and limitations cannot be overemphasized. The longitudinal, large-scale, and comprehensive nature of health-care claims databases make the data particularly appealing for answering questions such as the one posed by Smith et al. The MarketScan database includes all services paid by a variety of health insurers across multiple care settings and over time. Billing data also include clinical information relevant to payment decisions, including diagnoses and procedure codes; however, it is important to bear in mind that billing data are requests for payment of services rather than a record of patient health. Many of the challenges associated with the use of administrative data arise because of their origin as payment claims. A diagnosis is recorded on a bill when it explains the need for the service or how its presence complicates the service delivery. Therefore, it is much easier to measure services in administrative billing data than diagnoses. In the case of tobacco use, a diagnosis code reporting a history of tobacco use may be recorded to explain a bill for services such as tobacco cessation treatment or counseling. Not all people who use tobacco will have claims-based evidence of tobacco use, only those whose tobacco use is important for payment. Administrative data do not detect the absence of a condition, and it is not possible to add a claims-based code for “never used tobacco,” which results in claims-based measures of tobacco use having high specificity but low sensitivity3. When interpreting an SHD diagnosis in the claims, we must remember that it will typically have been recorded for use explaining or informing the use of services. The challenge, then, is interpreting analyses performed with use of these imprecisely measured exposures. If the exposure is mismeasured in both the RCR and non-RCR groups, the bias is in favor of finding no association. We are most concerned if the measurement of the condition may be related to the measurement of the outcome. If surgeons use the opportunity of rotator cuff disease or recurrence to counsel their patients on tobacco use, a tobacco use diagnosis may appear at a higher rate for those receiving RCR. This same challenge may be seen with SHD if some part of the RCR work-up led to the diagnosis and treatment of SHD or if the diagnosis and work-up of SHD led to the recognition of a need for RCR. In this case, the association is identified but the underlying mechanism would be misinterpreted. It is encouraging to note, as the authors do, that the measured rate is similar to a non-claims-based estimate, but the differential between the RCR and non-RCR groups was previously not known. As Smith et al. note, there are limitations to measuring health conditions in administrative data. Spending time thinking about the proposed relationship and the factors associated with observing the exposure and outcome of interest in administrative billing data can be helpful. The strengths of administrative data—e.g., the number of patients, availability of controls, and data provided from a variety of health-care settings—seem to support the validity of the reported association between SHD and RCR. Further prospective studies are needed to determine if the relationship remains with direct measurement. If this association is confirmed, we will need to determine how to use this information in clinical settings for the prevention and treatment of rotator cuff injury.

Combination of Bone Marrow Biopsy and Flow Cytometric Analysis: The Prognostically Relevant Central Approach for Detecting Bone Marrow Invasion in Diffuse Large B-Cell Lymphoma.

Bone marrow (BM) involvement is associated with prognosis in diffuse large B-cell lymphoma (DLBCL), the most prevalent disease subtype of malignant lymphoma. We conducted this multi-institutional retrospective study to investigate the functional association and prognostic values of four BM tests (BM biopsy, BM clot, flow cytometry (FCM), and BM smear). A total of 221 DLBCL patients were enrolled. BM involvement was detected in 17 (7.7%), 16 (7.2%), 27 (12.2%), and 34 (15.4%) patients by BM biopsy, BM clot, FCM, and BM smear, respectively. The consistency between BM biopsy and clot examination was favorable, with a κ coefficient of 0.705, whereas the consistencies among other modalities were poor. In 184 patients treated with the first-line R-CHOP (-like) regimen, BM involvement was associated with shorter progression-free survival (PFS) irrespective of the type of modality for a positive result. Intriguingly, among various single and combinatory modalities, the combination of BM biopsy and FCM had the highest hazard ratio of 3.33 and a c-index of 0.712. In conclusion, our study suggested that the combination of BM biopsy and FCM is the prognostically relevant central approach for BM involvement detection. The other BM examinations also may provide complementary information in clinical settings.

Self-Reported and Parental Assessments of Internet Gaming Disorder, and Their Accordance with DSM-5 Criteria in a Clinical Relevant Population.

Internet gaming disorder (IGD) is of growing importance as a research field and in clinical settings, as documented by the inclusion of the diagnosis in Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the preliminary International Classification of Diseases. Studies using screening tools to assess IGD and comparison with expert evaluations in clinical relevant populations are rare. Furthermore, concerned parents are often the first source of information in clinical practice, and their assessment of addictive behavior often differs widely from their child's self-evaluation. In two studies (N = 95) we investigated the usefulness of the Internet Addiction Test (IAT) and the Compulsive Internet Use Scale (CIUS) with adolescents at risk of IGD, either in parental company (Study 1) or alone (Study 2). Self-reported assessments on the scales were compared with parental ratings (only Study 1) and an expert face-to-face evaluation according to DSM-5 (both studies). We found higher correlations between expert evaluations of IGD criteria and screening scores for self-reported compared with parental ratings. Quality of categorization into persons with and without IGD confirmed that parental assessments were not conclusive in this setting. In this context, different cutoff values, sensitivity, and specificity for the screening instruments are discussed. We conclude that IAT and CIUS provide tentative usefulness for self-evaluation of adolescents at risk of IGD, and suggestions for using different cutoff scores for varying purposes are provided. In our study, parental assessments on the screening tools lead to an overestimation of IGD and are, therefore, not recommended as a sole source of information in clinical settings.

The difference in knowledge and concerns between healthcare professionals and patients about genetic-related issues: A questionnaire-based study.

Effective adoption of genetics in clinical practice requires the support of and interaction between the different partners of healthcare system; healthcare professionals (HCPs) and patients. The study aimed to assess and compare the knowledge, factors affecting the knowledge, and concerns of HCPs and patients regarding genetic-related issues such as lack of knowledge about genetics and genetic conditions, awareness of the importance of genetics in clinical practice and genetic services and resources deficits. A cross sectional study was conducted in different areas of Jordan using a convenient sampling approach. An English questionnaire was self-administered to HCPs. Face-to-face interviews were conducted with patients in Arabic by trained researcher. A total of 1000 HCPs and 1448 patients were recruited. There was a significant difference (p<0.001) in the knowledge between HCPs and patients. Among HCPs, physicians (OR = 2.278, 95%CI = 1.410–3.680, p = 0.001) and pharmacists (OR = 2.163, 95%CI = 1.362–3.436, p = 0.001) were more knowledgeable than nurses. In addition, females were more knowledgeable than males (OR = 1.717, 95%CI = 1.203–2.451, p = 0.003). Among patients, participants who had a bachelor degree (OR = 1.579, 95%CI = 1.231–2.025, p<0.001) were more knowledgeable compared to those who only had school education. HCPs appeared to have more concerns than patients (p<0.001) regarding all genetic-related issues. These findings suggested a positive association between education and genetic knowledge as well as concerns; as HCPs were more knowledgeable and concerned than patients. Appropriate integration and expansion of basic genetic knowledge courses and clinical genetic training in the curriculum should be adopted to prepare HCPs to enhance the integration of genetic information in clinical settings.

The need of information in clinical settings

No abstract available

Identifying Schizophrenia Using Structural MRI With a Deep Learning Algorithm.

ObjectiveAlthough distinctive structural abnormalities occur in patients with schizophrenia, detecting schizophrenia with magnetic resonance imaging (MRI) remains challenging. This study aimed to detect schizophrenia in structural MRI data sets using a trained deep learning algorithm.MethodFive public MRI data sets (BrainGluSchi, COBRE, MCICShare, NMorphCH, and NUSDAST) from schizophrenia patients and normal subjects, for a total of 873 structural MRI data sets, were used to train a deep convolutional neural network.ResultsThe deep learning algorithm trained with structural MR images detected schizophrenia in randomly selected images with reliable performance (area under the receiver operating characteristic curve [AUC] of 0.96). The algorithm could also identify MR images from schizophrenia patients in a previously unencountered data set with an AUC of 0.71 to 0.90. The deep learning algorithm’s classification performance degraded to an AUC of 0.71 when a new data set with younger patients and a shorter duration of illness than the training data sets was presented. The brain region contributing the most to the performance of the algorithm was the right temporal area, followed by the right parietal area. Semitrained clinical specialists hardly discriminated schizophrenia patients from healthy controls (AUC: 0.61) in the set of 100 randomly selected brain images.ConclusionsThe deep learning algorithm showed good performance in detecting schizophrenia and identified relevant structural features from structural brain MRI data; it had an acceptable classification performance in a separate group of patients at an earlier stage of the disease. Deep learning can be used to delineate the structural characteristics of schizophrenia and to provide supplementary diagnostic information in clinical settings.

Deciphering the total RNA content of extracellular vesicles.

Extracellular vesicles (EVs) have been recognized as relevant players in cell-cell communication. To fully explore their potential as carriers of biological information in clinical settings, protocols capable of dealing with minute amounts of proteins, lipids, and nucleic acids present in their cargo are a requirement. Here we delve into a protocol to decipher the total transcriptome of EVs, from undetectable amounts of EVs-derived RNA from clinical samples.

A review on the biomechanics of coronary arteries

Globally, cardiovascular diseases are seen as one of the largest economic burdens on society and the single largest cause of death, with atherosclerosis the leading cause of myocardial infarction (heart attack). Due to the complex interactions in the coronary vasculature, medical imaging technology is unable to recognise correlations between artery and fluid mechanics and disease initiation and progression, hence, biomechanical analysis of coronary arteries in patient-specific models is necessary to provide critical information in clinical settings; large variability in modelling approaches, parameters and results still, however, hamper accurate and reliable model development. This review aims to assist in filling that gap by presenting an overview of research efforts to date, from both theoretical and experimental perspectives, to assist in addressing the challenge of developing a reliable and accurate biomechanical model of human coronary arteries. Studies have been categorised primarily on their approach, either purely theoretical, purely experimental/clinical or a combined theoretical and experimental/clinical approach as well as then divided into structural, fluid, and fluid–structure interaction (FSI) analysis. From research efforts to date it is clear that the development of FSI models to incorporate the effects of shear-thinning, non-Newtonian flows in viscoelastic, realistic artery and plaque morphologies developed from in vivo, high resolution imaging is critical for accurate determination of disease initiation/progression, including atherosclerosis, plaque formation, and failure mechanisms. The inclusion of micro-constituents such as micro-calcification, endothelial cell layer, collagen cross-linking, vascular smooth muscle cell contractility and constitutive blood equations also affects stress magnitude, distribution and failure mechanisms and should be adequately accounted for. A set of appendices are also provided where studies are summarised and assessed based on their approach to modelling and are categorised by considering the imaging modality used, methodology, material and blood properties, type of coronary artery, approach to the study (theoretical, experimental, in vitro & in vivo), number of patients/specimens and a general description. It is hoped this review will assist in furthering the field of coronary artery biomechanics and contribute to developing accurate and reliable patient-specific models capable of improving our understanding of cardiovascular biomechanics and hence, the initiation/progression of related diseases to address the growing global morbidity, mortality and economic challenge of cardiovascular disease and myocardial infarction.

How Uncertainty Influences Lay People's Attitudes and Risk Perceptions Concerning Predictive Genetic Testing and Risk Communication.

The interpretation of genetic information in clinical settings raises moral issues about adequate risk communication and individual responsibility about one’s health behavior. However, it is not well-known what role numeric probabilities and/or the conception of disease and genetics play in the lay understanding of predictive genetic diagnostics. This is an important question because lay understanding of genetic risk information might have particular implications for self-responsibility of the patients.Aim: Analysis of lay attitudes and risk perceptions of German lay people on genetic testing with a special focus on how they deal with the numerical information.Methods: We conducted and analyzed seven focus group discussions (FG) with lay people (n = 43).Results: Our participants showed a positive attitude toward predictive genetic testing. We identified four main topics: (1) Anumeric risk instead of statistical information; (2) Treatment options as a factor for risk evaluation; (3) Epistemic and aleatory uncertainty as moral criticism; (4) Ambivalence as a sign of uncertainty.Conclusion: For lay people, risk information, including the statistical numeric part, is perceived as highly normatively charged, often as an emotionally significant threat. It seems necessary to provide lay people with a deeper understanding of risk information and of the limitations of genetic knowledge with respect to one’s own health responsibility.

Respiratory Waveform Estimation From Multiple Accelerometers: An Optimal Sensor Number and Placement Analysis.

Respiratory patterns are commonly measured to monitor and diagnose cardiovascular, metabolic, and sleep disorders. Electronic devices such as masks used to record respiratory waveforms usually require medical staff support and obstruct the patients' breathing, causing discomfort. New techniques are being investigated to overcome such limitations. An emerging approach involves accelerometers to estimate the respiratory waveform based on chest motion. However, most of the existing techniques employ a single accelerometer placed on an arbitrary thorax position. The present work investigates the use and optimal placement of multiple accelerometers located on the thorax and the abdomen. The study population is composed of 30 healthy volunteers in three different postures. By means of a custom-made microcontrolled system, data are acquired from an array of ten accelerometers located on predefined positions and a pneumotachograph used as reference. The best sensor locations are identified by optimal linear reconstruction of the reference waveform from the accelerometer data in the minimum mean square error sense. The analysis shows that right-hand side locations contribute more often to optimal respiratory waveform estimates, a sound finding given that the right lung has a larger volume than the left lung. In addition, we show that the respiratory waveform can be blindly extracted from the recorded accelerometer data by means of independent component analysis. In conclusion, linear processing of multiple accelerometers in optimal positions can successfully recover respiratory information in clinical settings, where the use of masks may be contraindicated.

Clinical usefulness of library and information services in Japan: The detailed use and value of information in clinical settings.

ObjectivesConsidering that there is a lack of evidence regarding the contribution of library and information services to evidence-based medicine in actual clinical practice in Japan, the purpose of the study is to explore the current status of use and value of library and information services in clinical settings to examine the usefulness of information in implementing evidence-based medicine (EBM) into practice.MethodsA Web-based survey was conducted at seven sites (hospitals with 300–1,200 beds) and interviews conducted at five sites to investigate information behavior among health professionals (physicians, residents, and nurses) in 2016, replicating the Value Study carried out in the United States in 2010 and 2011. Using a critical incident technique, respondents answered questions about their information topics, information resources used, search location, access points, and evaluation of the information.ResultsAnalysis from 598 valid responses (275 physicians, 55 residents, and 268 nurses) revealed the characteristics of information use and recognition of the value of information. Physicians and residents showed their information needs regarding clinical care using PubMed (80.4%, 65.5%), Ichushi-Web (61.8%, 63.6%), and UpToDate (40.4%, 65.5%). While physicians rely more on electronic journals (37.8%), residents use more hybrid resources including Japanese print books (38.2%) and online books (30.9% for Japanese, 32.7% for English) to confirm their knowledge. Nurses need more information close to patients and explore a wider variety of information resources such as Japanese print books (60.4%), Ichushi -Web (40.3%), Japanese online books (20.5%), and websites of academic organizations (19.0%). Although the overall recognition of the value of information was relatively modest, concrete changes in clinical practice were found in some areas. Environments with insufficient information and availability of electronic resources should be improved to increase the use of library and information services for implementing EBM.

New insights into the epigenetics of inflammatory rheumatic diseases.

Over the past decade, awareness of the importance of epigenetic alterations in the pathogenesis of rheumatic diseases has grown in parallel with a general recognition of the fundamental role of epigenetics in the regulation of gene expression. Large-scale efforts to generate genome-wide maps of epigenetic modifications in different cell types, as well as in physiological and pathological contexts, illustrate the increasing recognition of the relevance of epigenetics. To date, although several reports have demonstrated the occurrence of epigenetic alterations in a wide range of inflammatory rheumatic conditions, epigenomic information is rarely used in a clinical setting. By contrast, several epigenetic biomarkers and treatments are currently in use for personalized therapies in patients with cancer. This Review highlights advances from the past 5 years in the field of epigenetics and their application to inflammatory rheumatic diseases, delineating the future lines of development for a rational use of epigenetic information in clinical settings and in personalized medicine. These advances include the identification of epipolymorphisms associated with clinical outcomes, DNA methylation as a contributor to disease susceptibility in rheumatic conditions, the discovery of novel epigenetic mechanisms that modulate disease susceptibility and the development of new epigenetic therapies.

Intimate partner violence screening and the comparative effects of screening mode on disclosure of sensitive health behaviours and exposures in clinical settings

ObjectiveDetecting sensitive health information in clinical settings is of scientific and practical importance. The purpose of this study was to determine whether mode of screening influenced disclosure of intimate partner violence (IPV) in patterns similar to other forms of sensitive information. Study designThis cross sectional study was designed to compare effects of face-to-face vs computer self-assessment for sensitive health information on disclosure rates. Multivariate logistic regression was used for the analysis. MethodsData were collected in 2012 from 639 eligible African American consenting women receiving services in women, infants and children (WIC) clinics. Women were randomized to complete assessments of sensitive exposures via computer-assisted self-interview (CASI) or face-to-face interview (FTFI). Those with complete information were included in the analysis (n = 616). ResultsOf 39 sensitive health exposures, reporting was higher for FTFI than CASI for exposure to IPV (7 of 7 outcomes), tobacco use (2 of 3 outcomes) and reproductive health care (2 of 3 outcomes). For example, face-to-face improved disclosure of IPV in the last year (adjusted odds ratios [aOR] = 2.27; 95% CI = 1.60–3.21) and any drug, tobacco or alcohol in the last week (aOR = 1.39; 95% CI = 1.00–1.93). ConclusionTrained personnel may enhance disclosure above computer-based assessments for IPV for African American women receiving public assistance through The Special Supplemental Nutrition Program for Women, Infants and Children (WIC) Propensities to disclose sexual health behaviour and drug use by CASI may not apply to IPV in this population. The context and personal motivations influence women's decision to disclose IPV.

Characteristics of safety information obtained from postmarketing observational studies for re-examination in Japan.

BackgroundIn Japan, postmarketing surveillance (PMS) studies are required for newly approved drug products to further collect safety information in clinical settings. “PMS study” is a general term encompassing both postmarketing observational (PMO) studies and postmarketing intervention studies for re-examination. Each PMS study is conducted under contracts between the pharmaceutical company and medical institutions in accordance with Good Postmarketing Study Practice. It has been reported that the safety information collected postmarketing is limited because of underreporting. The objective of this investigation was to identify differences among profiles of the drug product safety information collected through intervention studies and observational studies before and after approval. Our study addressed whether the issue of underreporting, generally considered as associated with observational studies, occurs in PMO studies for re-examination. In addition, we considered potential causes of such underreporting.ResultsThe overall adverse reaction rate was lower in PMO studies than in intervention studies before approval in almost all cases. The adverse reaction rate in intervention studies exhibited similar profiles regardless of whether they were conducted prior to or following approval. In addition, we found that one reason for a lower adverse reaction rate in PMO studies was that the number of reports of adverse reactions that had occurred frequently prior to approval decreased postmarketing.ConclusionsUnderreporting was observed even in PMO studies for re-examination under the Japanese regulation. Although it was suggested that expected and common adverse reactions were more likely to be subject to underreporting, further investigation is warranted to explore the reasons for the under-reporting in PMO studies.

Revision of the Measurement Tool for Patients' Health Information Protection Awareness.

ObjectivesDespite the importance of the protection of patients' health information in clinical settings, little is known about the awareness of this concept in nursing students due to the lack of a suitable measurement tool. Hence, this study attempted to redevelop the Patients' Health Information Protection Awareness Scale, and evaluate its construct validity and reliability for nursing students.MethodsA cross-sectional descriptive study was conducted. Nursing students who were in their 3rd and 4th year were recruited from 10 universities in Korea to assess the construct validity, and 30 experts (27 nurses and 3 faculty members) participated in the content validation process.ResultsThe content validity assessment indicated that 23 items were ideal. The assessment of construct validity using exploratory factor analysis revealed three factors: communication, management, and referrals. They together accounted for 54.1% of the variance in scale scores. The three-factor scale had good fit in the confirmatory factor analysis. Scale reliability was confirmed, with a Cronbach's alpha of 0.94 for all items.ConclusionsThis study was the first attempt to redevelop the Patients' Health Information Protection Awareness Scale for student nurses. The 23-item scale was shown to be a reliable and valid tool. It facilitates the assessment of nursing students' awareness of patient information protection. Academic nursing programs and health organizations can use its scores to implement adequate education plans to safeguard information in nursing students.

Commentary: Tractography-Activation Models Applied to Subcallosal Cingulate Deep Brain Stimulation.

Commentary: Tractography-Activation Models Applied to Subcallosal Cingulate Deep Brain Stimulation.

The DTI Challenge: Toward Standardized Evaluation of Diffusion Tensor Imaging Tractography for Neurosurgery.

Diffusion tensor imaging (DTI) tractography reconstruction of white matter pathways can help guide brain tumor resection. However, DTI tracts are complex mathematical objects and the validity of tractography-derived information in clinical settings has yet to be fully established. To address this issue, we initiated the DTI Challenge, an international working group of clinicians and scientists whose goal was to provide standardized evaluation of tractography methods for neurosurgery. The purpose of this empirical study was to evaluate different tractography techniques in the first DTI Challenge workshop. Eight international teams from leading institutions reconstructed the pyramidal tract in four neurosurgical cases presenting with a glioma near the motor cortex. Tractography methods included deterministic, probabilistic, filtered, and global approaches. Standardized evaluation of the tracts consisted in the qualitative review of the pyramidal pathways by a panel of neurosurgeons and DTI experts and the quantitative evaluation of the degree of agreement among methods. The evaluation of tractography reconstructions showed a great interalgorithm variability. Although most methods found projections of the pyramidal tract from the medial portion of the motor strip, only a few algorithms could trace the lateral projections from the hand, face, and tongue area. In addition, the structure of disagreement among methods was similar across hemispheres despite the anatomical distortions caused by pathological tissues. The DTI Challenge provides a benchmark for the standardized evaluation of tractography methods on neurosurgical data. This study suggests that there are still limitations to the clinical use of tractography for neurosurgical decision making.

Abstract 3350: Plucked hair as a biomarker platform for monitoring transcriptional consequences of clinical exposure to antagonism of the HDM2/P53 interaction in tumors.

Abstract The ability to assess and monitor target engagement is crucial for informing early drug development decisions. High vascularisation of the hair follicle, frequent epithelial origin of tumors, and high degree of congruence of expression in hair of pathways dysregulated in cancers, makes the cellular bulb on plucked human scalp hair an excellent surrogate tissue for non-invasive monitoring of PD effects in clinical trials. Disruption of the p53-HDM2 interaction with small molecules has demonstrated single agent anti-tumor activity in preclinical models and represents an attractive treatment strategy in oncology. Development of a peripheral tissue based gene expression signature of inhibition of the p53-HDM2 interaction could facilitate the early development of these compounds. To develop a peripheral PD biomarker of antagonism of this interaction, we used two selective p53-HDM2 antagonists, Nutlin-3 and Sanofi's SAR405838 and applied our plucked hair biomarker platform to develop a gene expression signature indicative of compound exposure. SAR405838 displays potent activity in vitro and in vivo against p53 WT cell lines / xenograft models, but not in the p53 mutant context. Three hairs from each of four healthy donors were exposed to either SAR405838 or Nutlin-3 over a range of compound concentrations for 6hr or 24hr in our proprietary ex vivo cultures. We extracted RNA from the cellular bulb of individual hairs and assessed the transcriptome by microarray analysis. Biological enrichment analysis of genes differentially expressed revealed strong correlation to activated P53 signaling pathways. Further analysis revealed a core set of congruent genes as candidate PD biomarkers of p53-HDM2 antagonism, one of which was MIC-1, a secreted plasma protein that demonstrates a strong PK/PD relationship in patients treated with p53-MDM2 antagonists in Phase 1 trials. In ex vivo plucked hair, we have demonstrated biologically relevant differential expression of a panel of transcriptional markers exhibiting common response to Nutlin-3 and SAR405838. These reflect compound mechanism of action, and can provide further evidence of target engagement in addition to plasma MIC-1 levels. While the temporal and kinetic relationship between gene expression changes, toxicity, and clinical efficacy remains to be determined, the genes identified in this study may be used to provide further MOA information in clinical settings to monitor PD responses in plucked scalp hair obtained from patients exposed to SAR405838. Citation Format: Gino Miele, Elliot Harrison, Tim Mefo, Jo Read, Lydia Meyer Turkson, Alan Murdoch, Michael Teufel, Laurent Debussche, Donald Bergstrom, James Watters. Plucked hair as a biomarker platform for monitoring transcriptional consequences of clinical exposure to antagonism of the HDM2/P53 interaction in tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3350. doi:10.1158/1538-7445.AM2013-3350