Abstract
PURPOSE
Brain metastases (BM) are common in patients with anaplastic lymphoma kinase fusion-positive NSCLC (ALK+ NSCLC). We characterized the genomics of patients with ALK+ NSCLC BM treated ...with alectinib with or without local therapy to identify correlations of co-mutations with CNS-specific outcomes.
METHODS
We retrospectively reviewed ALK+ NSCLC patients with BMs who received alectinib for the definitive treatment of BM from 1/2012 and 5/2021. Genomic characteristics of 27 specimens from 27 patients were assessed with MSK-IMPACT, a 505-gene next-generation sequencing (NGS)-based tumor sequencing assay with >700x coverage. Intracranial progression-free survival (iPFS) and overall survival (OS) from BM diagnosis were analyzed using standard statistical methods.
RESULTS
The median age at BM diagnosis was 57 years (range 25-83). Median iPFS was 1.94 years (95%CI: 1.58- not reached) and median OS was 6.08 years (95%CI: 1.7– not reached). All patients received alectinib for the treatment of brain metastases (78% as 1st-line TKI) and 22% received local therapy. The most frequently altered co- alterations were CDKN2A (48%), TP53 (22%), MAP2K4 (15%), SMARCA4 (11%), CREBBP (11%), and ATM (7%). CDKN2A alterations were more common in patients with intracranial progression (64% vs 31%). MAP2K4 alterations were enriched in metastatic samples (p = 0.028, q = 0.113). SMARCA4 co- alterations were associated with inferior OS (HR: 8.76, 95%CI = 1.74-44.2, p= 0.009) and trended toward association with iPFS but was insignificant (HR: 3.25, 95%CI = 0.83-12.4, p=0.089). We identified missense ALK alterations in CSF from a patient who acquired resistance to alectinib and had leptomeningeal progression (G1269A, I1171T, L1108P).
CONCLUSION
This study is the first analysis of CNS specific outcomes with detailed genomic annotation for ALK+ NSCLC patients who received definitive alectinib for BM. Further investigation into the role of CNS-penetrant TKIs and the genomic alterations predictive of CNS failure are needed.
Few studies have examined whether familiarity of partner affects social responses in children with autism. This study investigated heart rate regulation (respiratory sinus arrhythmia RSA: The ...myelinated vagus nerve's regulation of heart rate) and temporal-parietal electroencephalogram (EEG) activity while nineteen 8- to 12-year-old children with autism and 14 controls viewed videos of a familiar and an unfamiliar person reading a story. Children with autism had lower overall RSA levels and exhibited decreased RSA to the unfamiliar person, versus control children. Both groups decreased temporal-parietal EEG activity to the unfamiliar person. Higher RSA was related to higher social skill ratings and fewer problem behaviors. Thus, the social difficulties of children with autism may be characterized by specific mobilization to unfamiliar people.
This article details the development and methodological characteristics of the Systemic Therapy Inventory of Change (STIC), the first measurement system designed to assess change in family, couple, ...and individual therapy from a multisystemic and multidimensional perspective. The article focuses specifically on the developmental process that resulted in the five valid and reliable scales that comprise the core measure of the system, the INITIAL STIC, which is administered to clients just before beginning therapy. The scales focus on five systemic domains: individual adult, family of origin, couple, family, and individual child. This article describes the five system scales, the results of the factor analytic process that created them, as well as data on their convergent and discriminant validity.
Abstract Although heart rate and temperature are continuously monitored in patients during recovery following surgery, measures that extract direct manifestations of neural regulation of autonomic ...circuits from the beat-to-beat heart rate may be more sensitive to outcome. We explore the relationship between features of autonomic regulation and survival in the prairie vole, a small mammal, with features of vagal regulation of the heart similar to humans. Cardiac vagal regulation is manifested in the beat-to-beat heart rate variability (HRV) pattern and can be quantified by extracting measures of the amplitude of periodic oscillations associated with spontaneous breathing. Thus, monitoring beat-to-beat heart rate patterns post-surgery in the prairie vole may provide an opportunity to dynamically assess autonomic adjustments during recovery. Surgeries to implant telemetry devices to monitor body temperature and continuous ECG in prairie voles are routinely performed in our laboratory. Ten of these implanted prairie voles died within 48 h post-surgery. To compare the post-surgery autonomic trajectories with typical surviving prairie voles, the post-surgery data from 17 surviving prairie voles were randomly selected. The data are reported hourly for 27 prairie voles between 6 and 14 h (1 h before the demise of the first subject) post-surgery. Receiver operator curves were calculated hourly for each variable to evaluate sensitivity in discriminating survival. The data illustrate that measures of HRV are the most sensitive indicators. These findings provide a foundation for investigating further neural mechanisms of cardiovascular function.
The ancient Greek historian Thucydides has had an enormous impact on modern historiography, political theory, international relations and strategic studies, but this influence has never been properly ...studied. This book brings together leading scholars from a range of disciplines to explore the different facets of Thucydides' modern reception and influence, from the birth of political theory in Renaissance Europe to the rise of scientific history in nineteenth-century Germany and the triumph of 'realism' in twentieth-century international relations theory. Its chapters consider the different national and disciplinary traditions of reading and citing Thucydides, but also highlight common themes and questions; in particular, the variety of images of the historian produced by his modern readers: the scientific historian or the artful rhetorician, the brilliant analyst of society and politics or the great narrator of political and military events, the man of experience and affairs or the man of contemplation and reflection.
The purpose of this study was to obtain validity evidence for the Physical Activity and Healthy Food Efficacy Scale for Children (PAHFE). Construct validity evidence identifies four subscales: ...Goal-Setting for Physical Activity, Goal-Setting for Healthy Food Choices, Decision-Making for Physical Activity, and Decision-Making for Healthy Food Choices. The scores on each of these subscales show a moderate to high degree of internal consistency (0.59 ≤ α ≤ 0.87). The Decision-Making for Healthy Food Choice subscale and the Decision-Making for Physical Activity subscale scores show significant convergent validity evidence. These results provide support for using this self-efficacy scale to measure children's perceived confidence to make decisions about healthy eating and physical activity. The PAHFE may be considered to be a useful predictor of both physical activity and eating behaviors.
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