Clinical Realm Research Articles

Abstract 4260: Standardized decision support in next-generation sequencing (NGS) reports of somatic cancer variants

Abstract Introduction: Of hundreds to thousands of somatic mutations that exist in each cancer genome, a large number are unique and non-recurrent variants. Many such variants occur in tumor genes that have well-established biological and clinical relevance and are putative targets of molecular therapy, however, most variants are still of unknown significance. Prioritizing and reporting genetic variants identified via NGS technologies remains a major challenge. Methods: Based on a systematic framework for cancer variant annotation/prioritization, we propose a structured molecular pathology report using standardized terminology in order to best inform oncology clinical practice. In parallel with the variant interpretation pipeline, we developed a comprehensive knowledge database (Kdb) that integrates tumor types, genes, variants, response/resistance patterns to approved and experimental agents and PubMed identifiers. Results: As physicians rely heavily on limited subsets of data and frequently apply rules based on strength of evidence in the decision-making process, NGS results are presented in a very discrete manner, avoiding detailed descriptions of each genomic aberration. Reportable variants are grouped in three categories: (i) actionable, which support treatment recommendation, enrollment in clinical trials and/or have prognostic or diagnostic implications; (ii) biologically relevant but not clearly actionable, including novel variants lacking functional preclinical validation in known cancer genes; and (iii) variants of unknown significance. Predictive associations are reported according to tumor type and classified in a hierarchical way based on the strength of evidence: (i) late trials; (ii) early trials; (iii) case reports; and (iv) preclinical data being explored in clinical trials. In our internal Kdb, tumor types with the largest number of emerging predictive associations are acute leukemias, non-small cell lung cancer, brain tumors, melanoma, colorectal, ovarian and breast cancers, comprising more than 100 unique gene - drug interactions. Further interpretation of gene variants requires a team with strong background in cancer biology, careful evaluation of the published literature and ability to match a patient's tumor genotype to clinical trials in the context of multiple aberrations. Conclusions: With large amounts of data being generated as high throughput sequencing assays enter the clinical realm, there is a growing need to better communicate relevant findings in a timely manner while remaining cognizant of the potential consequences of misuse or overinterpretation of genomic information. The scientific knowledge on actionable events should be presented the report, so that physicians can make evidence-based decisions and patients may benefit from treatment with matched targeted agents. We hope that our experience in this process will help other institutions implement similar programs. Citation Format: Rodrigo Dienstmann, Fei Dong, Darrell Borger, Dora Dias Santagata, Leif W. Ellisen, Long P. Le, A. John Iafrate. Standardized decision support in next-generation sequencing (NGS) reports of somatic cancer variants. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4260. doi:10.1158/1538-7445.AM2014-4260

Animal models of Huntington's disease for translation to the clinic: best practices.

Mouse models of Huntington's disease (HD) recapitulate many aspects of the human disease. These genetically modified mice are powerful tools that are used not only to examine the pathogenesis of the disease, but also to assess the efficacy of potential new treatments. Disappointingly, in the past few years we have seen the success of potential therapies in animal studies, subsequently followed by failure in clinical trials. We discuss here a number of factors that influence the translatability of findings from the preclinical to the clinical realm. In particular, we discuss issues related to sample size, reporting of information regarding experimental protocols and mouse models, assignment to experimental groups, incorporation of cognitive measures for early phases of the disease, environmental enrichment, surrogate measures for survival, and the use of more than one HD mouse model. Although it is reasonable to question the appropriateness of the animal models used, we argue that it is more parsimonious to assume that improvements in experimental design and publication of negative results will lead to improved translatability to the clinic and insights about HD pathophysiology.

Comparison of Postinjection Protocols After Intratendinous Achilles Platelet-Rich Plasma Injections: A Cadaveric Study

The purpose of the present investigation was to evaluate the distribution of intratendinous injected platelet-rich plasma (PRP) after 15 minutes of prone resting versus immediate manipulation simulating weightbearing. Ten cadaveric lower limbs were injected under ultrasound guidance with PRP dyed with India blue ink. The dyed PRP was injected into the mid-portion of the Achilles tendon, after which 5 specimens were placed in the prone position for 15 minutes (simulating rest) and the remaining 5 specimens were manipulated through 100 cycles of ankle dorsiflexion and plantarflexion (simulating walking). Thereafter, the specimens were dissected, and the distribution of the India blue dye was ascertained. In the simulated rest group, every specimen showed dyed PRP in the Achilles tendon and in the space between the paratenon and tendon. The median craniocaudal spread of the PRP was 140 (range 125 to 190) mm. In 4 of the simulated rest tendons (80%), the distribution of PRP extended across the entire transverse plane width of the tendon. In the simulated motion group, every specimen showed dyed PRP extending across the entire transverse plane width of the tendon and in the space between the paratenon and tendon. The median craniocaudal spread was 135 (range 115 to 117) mm. No statistically significant difference was found in the amount of craniocaudal spread between the simulated motion and rest groups. In conclusion, it does not appear to matter whether the ankle has been moved through its range of motion or maintained stationary during the first 15 minutes after PRP injection into the mid-portion of the Achilles tendon. The precise meaning of this information in the clinical realm remains to be discerned.

Oral Mucosal Injury in Oncology Patients

The field of oral mucosal injury caused by cancer therapies has strategically matured in the scientific as well as clinical realms over the past decade. Prior to the late 1990s, the condition had been viewed by many healthcare providers as an inevitable consequence of high-dose chemotherapy and other intensive therapies in oncology practice. Fortunately, expanding insights into the pathobiology as well as design strategies for clinical trials in recent years have fostered development of high-quality clinical practice guidelines as well as health professional education relative to prevention and treatment. This report is directed to analysis of this contemporary modeling. Guideline-based management recommendations that have emerged over the past year and controversies in the field are highlighted.

Basic science research in pediatric radiology — how to empower the leading edge of our field

Basic science research aims to explore, understand and predict phenomena in the natural world. It spurs the discovery of fundamentally new principles and leads to new knowledge and new concepts. By comparison, applied research employs basic science knowledge toward practical applications. In the clinical realm, basic science research and applied research should be closely connected. Basic science discoveries can build the foundation for a broad range of practical applications and thereby bring major benefits to human health, education, environment and economy. This article explains how basic science research impacts our field, it describes examples of new research directions in pediatric imaging and it outlines current challenges that we need to overcome in order to enable the next groundbreaking discovery.

Adding Low-Field Magnetic Stimulation to Noninvasive Electromagnetic Neuromodulatory Therapies

Adding Low-Field Magnetic Stimulation to Noninvasive Electromagnetic Neuromodulatory Therapies

The neuroanatomical correlates of anxiety in a healthy population: differences between the State-Trait Anxiety Inventory and the Hamilton Anxiety Rating Scale.

ObjectivesThe State-Trait Anxiety Inventory (STAI) and the Hamilton scale for anxiety (HARS) are two of the most important scales employed in clinical and psychological realms for the evaluation of anxiety. Although the reliability and sensibility of these scales are widely demonstrated there is an open debate on what exactly their scores reflect. Neuroimaging provides the potential to validate the quality and reliability of clinical scales through the identification of specific biomarkers. For this reason, we evaluated the neural correlates of these two scales in a large cohort of healthy individuals using structural neuroimaging methods.Case reportNeuroimaging analysis included thickness/volume estimation of cortical and subcortical limbic structures, which were regressed on anxiety inventory scores with age and gender used for assessing discriminant validity. A total of 121 healthy subjects were evaluated. Despite the two anxiety scales, at a behavioral level, displaying significant correlations among them (HARS with STAI-state (r = 0.24; P = 0.006) and HARS with STAI-trait (r = 0.42; P < 0.001)), multivariate neuroimaging analyses demonstrated that anatomical variability in the anterior cingulate cortex was the best predictor of the HARS scores (all β's ≥ 0.31 and P's ≤ 0.01), whereas STAI-related measures did not show any significant relationship with regions of limbic circuits, but their scores were predicted by gender (all β's ≥ 0.23 and P's ≤ 0.02).ConclusionAlthough the purpose of HARS and STAI is to quantify the degree and characteristics of anxiety-like behaviors, our neuroimaging data indicated that these scales are neurobiologically different, confirming that their scores might reflect different aspects of anxiety: the HARS is more related to subclinical expression of anxiety disorders, whereas the STAI captures sub-dimensions of personality linked to anxiety.

Pharmacogenetics of antidepressant treatment in obsessive-compulsive disorder: an update and implications for clinicians.

Obsessive-compulsive disorder (OCD) is a chronic neuropsychiatric disorder with high genetic influence. Antidepressants such as serotonin reuptake inhibitors, are widely accepted as the first-line medications for OCD; however, approximately 50% of OCD patients show poor response. Personalized medicine utilizing genetic testing has recently received much attention because the variability of antidepressant response and tolerability are partly due to an individual's genetic variations. This has led to researchers investigating the role of specific genetic factors on antidepressant response and utility of testing in the clinical realm. Genetic test panels are showing promise for guiding antidepressant treatment to improve outcomes in depression. This article will review the most recent findings in the pharmacogenetics of OCD and its related disorders. Promising results have been reported for several serotonergic and glutamatergic system genes and the cytochrome CYP450 liver enzyme genes, which appear to play an important role in OCD and antidepressant response.

Borderline personality disorder: treatment approaches and perspectives

Borderline personality disorder is a disorder associated with significant morbidity, mortality and imparts a significant societal toll. The field of research into the pathophysiology, conceptualization and treatment approaches for borderline personality disorder is rapidly expanding. Once considered by many to be a diagnosis consisting of fixed and untreatable patient characteristics, our current understanding had lead to a more hopeful prognosis and a set of therapeutic approaches to accelerate patient recovery. These approaches include evidence-based psychotherapy, domain-targeted medication treatment and combined strategies. Despite this growth in the literature and improvement in patient care, significant opportunities exist to further our understanding and implement best practices in the clinical realm, research and physician education.

Found in Translation

Stroke presents a major global burden to patients, their relatives, and whole economies.1 Worldwide intense efforts are being undertaken to understand the pathobiology of stroke and to develop novel, effective treatments. This has led to the discovery of a plethora of preclinically promising treatment strategies,2 but intravenous thrombolysis remains the only specific pharmacological treatment with proven efficacy in acute ischemic stroke.3 Apparently, of several hundred controlled clinical trials4 aiming to protect the brain against ischemia (neuroprotection) with compounds previously found effective in animal experiments, not a single one has led to the regulatory approval of a drug for this indication. Many pharmaceutical companies have, therefore, stopped developing treatments for this devastating disease, and nihilism is spreading in the field. A roadblock seems to exist between bench and bedside, preventing the translation of highly effective preclinical neuroprotectants into the clinical realm.5 Despite the prevailing mantra of translational medicine,6 other fields report similar problems when making the preclinical-to-clinical transition. Much has been speculated about the reasons underlying the translational roadblock, and the phrase lost in translation has entered the titles of numerous biomedical publications. In this article, we propose that contrary to current opinion, preclinical stroke research can indeed predict clinical outcomes and phenotypes. Numerous neuroprotectants were reported as lost in translation (Figure 1A), but there is reason to argue that the clinical trials were based on rather weak preclinical evidence, and that many pathophysiological principles and therapies were actually discovered in translation (Figure 1B). We propose that there is little reason for nihilism. We present a concise list of potential improvements that may help to reduce the current attrition rate of bench-to-bedside translation, even in neuroprotection. Stroke may even serve as a model disease because our analysis may apply to other fields where development of …

Conflict Prevention, Conflict Mitigation, and Manifestations of Conflict During Emergency Department Consultations

The objective was to determine the causes of and mitigating factors for conflict between emergency physicians and other colleagues during consultations. From March to September 2010, a total of 61 physicians (31 residents and 30 attendings from emergency medicine [EM], internal medicine, and general surgery) were interviewed about how junior learners should be taught about emergency department (ED) consultations. During these interviews, they were asked if and how conflict manifests during the ED consultation process. Two investigators reviewed the transcripts independently to generate themes related to conflict until saturation was reached. Disagreements were resolved by consensus. The trustworthiness of the analysis was ensured by generating an audit trail, which was subsequently audited by an investigator not involved with the initial analysis. This analysis was compared to previously proposed models of trust and conflict from the sociology and business literature. All participants recalled some manifestation of conflict. There were 12 negative conflict-producing themes and 10 protective conflict-mitigating themes. When comparing these themes to a previously developed model of the domains of trust, each theme mapped to domains of the model. Conflict affects the ED consultation process. Areas that lead to conflict are identified that map to previous models of trust and conflict. This work extends the current understanding about intradisciplinary conflict in the clinical realm. These new findings may improve the understanding of the nature of conflicts that occur and form the foundation for interventions that may decrease conflict during ED consultations.

Personalized Medicine Without the “Omics”

Few concepts in health care have stirred the popular imagination like personalized medicine. However, finding cures and identifying best treatments based on genetics and genomics has been much more challenging than early proponents hoped. A broader view of personalization, one based on phenotypes and patient preferences, seems much more promising—at least for the immediate future. Society of General Internal Medicine (SGIM) members have been at the forefront of this work. For example, former SGIM President Shelly Greenfield has performed a series of studies over decades that greatly clarifies our understanding of how patient complexity and comorbidity influence prognosis, treatment responsiveness, and vulnerability to adverse treatment effects. University of California, San Francisco (UCSF) geriatricians Louise Walter, Ken Covinsky, and Sei Lee have shown how applying preventive care guidelines indiscriminately to elders with multiple chronic conditions can result in more harm than good. And general internists Rod Hayward, Tim Hofer, Eve Kerr and Sandeep Vijan (all at the University of Michigan and/or its affiliated VA) have demonstrated, with mathematical precision, the importance of treatment effect heterogeneity and how to navigate between the shoals of over-treatment and under-treatment. In this issue of JGIM, a Special Symposium focuses much-needed attention on multimorbidity and its consequences for patient health, population measurement, and clinical policymaking. As described in an editorial by Symposium editors Cynthia Boyd and David Kent, three articles, each by a group of national experts, take on the challenges of evidence generation, evidence synthesis, and guideline development for patients affected by multiple chronic conditions.1 Whether or not the ideas in these papers lead immediately to new scientific paradigms, they make for provocative reading and will stimulate the field. Three other articles in JGIM take up the theme of individualization of care. The article by Michaelidis et al. considers whether treatment of outpatient respiratory infections can be improved through collection of more precise clinical data—in this case, the use of procalcitonin as a marker of bacterial infection.2 They conclude that procalcitonin testing can reduce antibiotic use, but is not cost-effective unless societal costs owing to antibiotic resistance are considered. In an entirely different clinical realm, Stephens et al. ask similar questions about alcoholic detoxification, specifically evaluating a new, more patient-specific, protocol.3 Finally, the paper by Singh et al. applies the “individualization principle” at the policy level. In their analysis of hospital readmission rates, only a small amount of between-hospital variation could be ascribed to the hospitals themselves; patient characteristics were far more important.4 The genomics revolution continues to stir high hopes. In the meantime, techniques to identify and explore heterogeneity of treatment effects across patient subgroups may offer prospects for more immediate progress. Over the next several years, this new science of clinical care—“personalized medicine without the omics”—will move us closer to the holy grail of clinical medicine, providing the right care to the right patient at the right time. JGIM plans to be there as it happens.

Supervision and the art of baseball.

AbstractSupervision of psychotherapy consists of a three-person matrix: supervisor, student, and patient. My approach to supervision is to work within a student's natural personality and not to attempt to change it. A comparison is made to baseball wherein a player's natural approach may be modified but not significantly altered. In both cases uncertainty is normative. Supervision requires a learning which may develop into a facsimile of therapy in order for the student to reinforce positive aspects.Keywords: psychodynamic, psychotherapy, supervision, trainingResumeLa supervision en psychotherapie repose sur une matrice de trois personnes : le superviseur, l'etudiant et le patient. Mon approche en matiere de supervision est de travailler avec la personnalite naturelle de l'etudiant et de ne pas chercher a la changer. On pourrait comparer cette notion avec le baseball : on ne peut que modifier legerement l'approche naturelle d'un joueur. Dans les deux domaines, l'incertitude est normative. La supervision requiert une « alliance d'apprentissage » qui peut evoluer en un genre de therapie afin que l'etudiant puisse renforcer ses aspects positifs.Mots-cles : psychodynamique, psychotherapie, supervision, formation.When I entered graduate school in the middle of the last century, I was told in no uncertain terms that research in psychology was extremely difficult and required a rather lengthy apprenticeship leading to a PhD and then a career requiring continuing dedication and effort. Clinical work, on the other hand was considered to be somewhat easier and mastered in practicum placements and in- ternships. Reality, in the form of years in both the clinical and academic realm has convinced me of the complexity and difficulty of clinical work. The research paradigm conforms to a set of well-established rules both in terms of design, analysis of data, conclusions and so on. This applies to both clinical experimental research (randomized controlled trials, etc.) and grounded theory research. On the other hand, clinical work can be viewed as a unique experiment with each patient as an N of 1. It becomes even more complex in that the clinician must be part of that experiment with each patient and cannot be a constant fixed variable. Clinical work in diagnosis and psychotherapy includes, indeed depends, on personality variables of the psychologist interacting with the unique- ness of the patient's personality and presenting problems. The unique- ness of the psychologist interacts with the patient's personality and presenting problems. Supervision of clinical work is even more com- plex, as I will try to explicate in the article because it involves a three person interaction: supervisor, student, and patient.1My approach to supervision starts with my assessment of the student's natural clinical tendencies. In this regard, I will use professional baseball, especially hitting (batting) as an analogy. It is said and is received wisdom in the sports world that the most difficult act is that of hitting a baseball. It requires enormous skill to hit a hard round ball with a wooden cylindrical bat travelling at upward of 100 mph from a distance of 60 feet, 6 in. The most proficient players may do this successfully three out of 10 at- tempts. I have probably witnessed about 2,000 major league base- ball games and countless games on TV and what has always struck me apart from the complexity of the game are the various ap- proaches to hitting, and the stance each player has. As Yogi Berra, the baseball philosopher said, You can see a lot by observing. Some players have an open stance (more facing the pitcher), some have a more closed stance, some hold the bat low, some high, some close to the home plate, some more distant, some crouch, some stand upright. They use individual trigger mechanisms. Batters vary in terms of how they hold the bat and so on. Professional players have natural tendencies which they have adopted as youngsters. …

Evidence-Based Medicine and the Hard Problem of Multimorbidity

Evidence-based medicine (EBM) rests on the proposition that questions in clinical medicine can be formalized, or reduced, into statistical questions. In the reductionist tradition, these statistical questions can then be addressed by studies designed to isolate the effect of a single exposure (typically an intervention) on a single disease outcome. While the results directly address the statistical question, inferences derived from the results are applied back to the complex clinical realm—where generalists live.

The Four-Function Model of Nonsuicidal Self-Injury

Nonsuicidal self-injury is receiving increasing attention in empirical and clinical realms. Indeed, the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders designated nonsuicidal self-injury as a condition that requires further study, which signals possible future official adoption. Despite growing interest in this perplexing phenomenon, much remains unknown about why nonsuicidal self-injury occurs, including fundamental features of its etiology and underlying mechanisms. In addition, no evidence-based interventions that directly target this maladaptive behavior currently exist. The recently developed, empirically supported four-function model posits that nonsuicidal self-injury is maintained by four distinct reinforcement processes. In this review, we used the four-function model to guide the understanding of important unanswered questions and suggest much-needed studies for future research in the field of self-injury.

Diffusion tensor imaging and tractography of the human language pathways: Moving into the clinical realm

The functional correlates of anatomical derangements are of interest to the neurological clinician. Diffusion tensor tractography (DTT) is a relatively new tool in the arsenal of functional neuroimaging, by which to assess white matter tracts in the brain. While much import has been given to tracking corticospinal tracts in neurological disease, studying language pathway interconnections using DTT has largely remained in the research realm. Hardware and software advances have allowed this tool to ease into clinical practice, with several radiologists, neurologists, and neurosurgeons now familiar with its applications. DTT images, although visually appealing, are founded in mathematical equations and assumptions, and require a more than basic understanding of principles and limitations before they can be integrated into routine clinical practice. Cognitive pathways like that of language, that are normally hard to assess and especially more so when pathologically affected, have been at the receiving end of several opposing and often controversial hypotheses, and the past decade has seen the clarification, validation or rejection of several of these by the in vivo charting of functional connectivity using DTT. The focus of this review is to illustrate DTT of the language pathways with emphasis on practical considerations, clinical applications, and limitations.

Comparison of 2f1-f2 DPOAE and 2f2-f1 DPOAE fine structure in young and middle-aged adults

Objective: The 2f2-f1 DPOAE is not as popular as the 2f1-f2 DPOAE in the clinical realm as it is not as robust. However, it does have an advantage of being a predominantly reflection emission. The reflection component has been found to be sensitive to cochlear damage. Our objective was to compare the two types of DPOAE to track subtle changes due to aging. Design: We used the most suitable stimulus parameters to record the fine structures of 2f2-f1 DPOAE and 2f1-f2 DPOAE for comparison in two groups of individuals. Study sample: Young adults and middle-aged adults with normal hearing sensitivity participated in the experiment. Both ears of all participants were tested. Results: Although reductions were noted in the both types of DPOAE in the middle-aged participants compared with the young adults, the decrease in amplitude of the 2f2-f1 DPOAE was found to be statistically significant. This corresponded with statistically significant reductions in the reflection component of the 2f1-f2 DPOAE. Reductions in the 2f2-f1 DPOAE were found with both, high-level and low-level primaries. Conclusions: These results highlight the advantages of analysing fine structure data of the 2f2-f1 DPOAE to track subtle cochlear changes in response to aging.

Posttraumatic Elbow Joint Contractures: Defining Pathologic Capsular Mechanisms and Potential Future Treatment Paradigms

The Andrew J. Weiland Medal is presented by the American Society for Surgery of the Hand to a midcareer researcher who is dedicated to advancing patient care in the field of hand surgery. This essay, awarded the Weiland Medal in 2012, focuses on posttraumatic elbow joint contractures. Joint contractures are well known to hand surgeons because they limit function of our patients. There is a thorough understanding of the pathoanatomy underlying joint contractures. However, the mechanisms leading to the pathoanatomy are either unknown or partially understood, depending on the etiology of the particular clinical condition. This review describes our research over the past 14 years on posttraumatic elbow joint contractures. It defines pathologic cellular, matrix, and growth factor changes in the joint capsule, elaborates on the development of an animal model of posttraumatic joint contractures, presents an evaluation of a potential prevention strategy based on our research, and outlines future plans to bring this work to the clinical realm for the benefit of patients.

The real informatics challenges of personalized medicine: not just about the number of central processing units.

Personalized medicine has the potential to revolutionize patient care. In order to do so, it requires a re-engineering of many life sciences and healthcare processes, the most significant being the integration of the complete biomarker lifecycle from discovery to targeted treatment of patients. Individual patient omic profiles have become a reality owing to the diminishing cost of DNA sequencing. However, managing these data has created a bottleneck due to: the limitations in storage, computing power and information access; the lack of biologist-friendly software to replace the user-unfriendly custom scripts, which are crippling collaboration; the urgency for standardizing data across omics and clinical data realms for cross-study comparisons; undermining innovations of enterprise and open-source software, which saps innovations of open-source and reliability and support of enterprise software; and unavailability of a robust, integrative workflow system, which leads to actionable data at the patient care level.

A role for inflammation in status epilepticus is revealed by a review of current therapeutic approaches

A significant number of patients with epilepsy fail to respond to currently available antiepileptic drugs. This suggests a need for alternative approaches to reduce the occurrence of seizures in these patients. Recent data have shown that in addition to well-known neuronal mechanism, seizures may be a consequence of misguided inflammatory response and blood-brain barrier disruption. Both peripheral and brain proinflammatory events have been demonstrated to govern the onset of status epilepticus. Evidence deriving from the experimental and clinical realms supports the notion that a role for proinflammatory and cerebrovascular events in seizure disorders is broader than previously suspected. As a result, methods to pharmacologically reduce blood-brain barrier permeability and reduce inflammation have emerged as means to reduce seizure burden. For instance, corticosteroids have been shown to be beneficial and the same agents may be able to further reduce seizure burden in conjunction with currently prescribed antiepileptic drugs.