Pediatric acquired brain injury resources for educators: a multi-year scan of Canadian-relevant internet resources.

BACKGROUND: Acquired Brain Injury (ABI) is the leading cause of death and disability in children, yet educators report a lack of knowledge about ABI and supporting students with ABI. With no formal learning about ABI, education professionals may turn to the internet for information. OBJECTIVES: To find online resources about supporting students with ABI, in any format, available freely and publicly, aimed toward elementary educators and that could be applied in a Canadian context. METHODS: We performed an environmental scan using keyword Google searches, key websites, and expert recommendations. The search was performed twice: 2018 and 2021. RESULTS: 96 resources were included after screening. The resources were published by organizations in the United States (n = 57), Canada (n = 19), United Kingdom (n = 16), Australia (n = 3) and New Zealand (n = 1). Traumatic brain injury and concussion were the most commonly addressed type of ABI, and Short Fact/Information sheets were the most common resource format. Between 2018 and 2021, 13 previously included resource links were no longer accessible. CONCLUSIONS: This scan suggests that there are many online resources available to educators in a variety of formats, and that information online can be transient. Future studies should evaluate the accuracy and quality of the resources available.

Social Perspective Taking and Empathy in Children with Fetal Alcohol Spectrum Disorders.

Children with fetal alcohol spectrum disorders (FASD) show sociobehavioral impairments; however, the social cognitive profile contributing to these impairments is poorly understood. This study compared social perspective taking and empathy in children with FASD versus typically developing controls (TDC). Thirty-seven children with FASD and 21 TDC participated. Measures included parent-rated CBCL and SSIS, and NEPSY-II Theory of Mind, Test of Social Cognition and Index of Empathy. Parents rated the FASD group higher than TDC on indices of behavior problems and lower on indices of social skills and empathy. Children with FASD scored significantly below TDC on tasks requiring complex social cognition. The majority of correlations between social cognition and parent-ratings were not significant in FASD and TDC, with the exception of a negative correlation between self-reported empathy and parent-rated behavior difficulties in TDC. FASD subgroup analyses revealed lower theory of mind and empathy scores among children with ARND than pFAS/FAS. With regard to sex, males with FASD were rated as having more behavior difficulties than females, whereas TDC females obtained higher empathy ratings than males. In both groups, females scored higher on theory of mind and empathy indices. On theory of mind tasks, older children with FASD performed below younger, whereas younger TDC children performed more poorly than older. Children with FASD show reduced functioning on indices of sociobehavioral and social cognition, and the effects are influenced by sex and age. These findings provide insight into the clinical and social profile of children with FASD.

The Teach-ABI Professional Development Module for Educators About Pediatric Acquired Brain Injury: Mixed Method Usability Study.

BACKGROUND: Acquired brain injury (ABI) is a leading cause of death and disability in children and can lead to lasting cognitive, physical, and psychosocial outcomes that affect school performance. Students with an ABI experience challenges returning to school due in part to lack of educator support and ABI awareness. A lack of knowledge and training contribute to educators feeling unprepared to support students with ABI. Teach-ABI, an online professional development module, was created to enhance educators' ABI knowledge and awareness to best support students. Using a case-based approach, Teach-ABI explains what an ABI is, identifies challenges for students with ABI in the classroom, discusses the importance of an individualized approach to supporting students with ABI, and describes how to support a student with an ABI in the classroom. OBJECTIVE: This study aims to assess the usability of and satisfaction with Teach-ABI by elementary school educators. The following questions were explored: (1) Can elementary school teachers use and navigate Teach-ABI?, (2) Are the content and features of Teach-ABI satisfactory?, and (3) What modifications are needed to improve Teach-ABI? METHODS: Elementary school educators currently employed or in training to be employed in Ontario elementary schools were recruited. Using Zoom, individual online meetings with a research team member were held, where educators actively reviewed Teach-ABI. Module usability was evaluated through qualitative analysis of think-aloud data and semistructured interviews, direct observation, user success rate during task completion, and the System Usability Scale (SUS) scores. The usability benchmark selected was 70% of participants performing more than half of module tasks independently. RESULTS: A total of 8 female educators participated in the study. Educators were classroom (n=7) and preservice (n=1) teachers from public (n=7) and private (n=1) school boards. In terms of task performance, more than 85% of participants (ie, 7/8) independently completed 10 out of 11 tasks and 100% of participants independently completed 7 out of 11 tasks, demonstrating achievement of the module usability goal. The average overall SUS score was 86.25, suggesting a high satisfaction level with the perceived usability of Teach-ABI. Overall, participants found Teach-ABI content valuable, useful, and aligned with the realities of their profession. Participants appreciated the visual design, organization, and varying use of education strategies within Teach-ABI. Opportunities for enhancement included broadening content case examples of students with ABI and enhancing the accessibility of the content. CONCLUSIONS: Validated usability measures combined with qualitative methodology revealed educators' high level of satisfaction with the design, content, and navigation of Teach-ABI. Educators engaged with the module as active participants in knowledge construction, as they reflected, questioned, and connected content to their experiences and knowledge. This study established strong usability and satisfaction with Teach-ABI and demonstrated the importance of usability testing in building online professional development modules.

Understanding the Needs of Ontario Educators in Supporting Students With Acquired Brain Injury in the Classroom.

BACKGROUND: When a child sustains an acquired brain injury (ABI), the impact extends to significant environments in their life, including school. Educator knowledge of ABI can influence a child's success with academic and social reintegration. An assessment of educator ABI knowledge was conducted to determine what information they require to support school reintegration. METHODS: A mixed-methods approach included a sampling of educators in a needs assessment survey and workshop. The survey determined levels of educator knowledge regarding ABI in the classroom, and the workshop scoped educator views in the development of a user-driven ABI learning program to enrich their expertise. RESULTS: Our sample reported being somewhat knowledgeable about ABI and the impact on students. There were no differences based on respondents' educational role. Teachers reported having minimal and inadequate supports for students following ABI during school transitions, feeling unprepared to assist students during these transitions, and that families also appeared unprepared for school reintegration following ABI. The workshop identified the need for a 2-part educational course. CONCLUSIONS: Supportive school environments are essential for the reintegration of students following ABI. This study identified educators' needs for ABI knowledge and resources to support their existing expertise.

A Phase 2 Study of Capmatinib in Patients With MET-Altered Lung Cancer Previously Treated With a MET Inhibitor.

INTRODUCTION: Capmatinib is approved for MET exon 14-altered NSCLC on the basis of activity in targeted therapy-naive patients. We conducted a phase 2 study to assess the efficacy of capmatinib in patients previously treated with a MET inhibitor. METHODS: Patients with advanced NSCLC harboring MET amplification or MET exon 14 skipping alterations received capmatinib 400 mg twice daily. The primary end point was the objective response rate. Secondary end points included progression-free survival, disease control rate (DCR), intracranial response rate, and overall survival. Circulating tumor DNA was analyzed to identify capmatinib resistance mechanisms. RESULTS: A total of 20 patients were enrolled between May 2016 and November 2019, including 15 patients with MET skipping alterations and five patients with MET amplification. All patients had received crizotinib; three had also received other MET-directed therapies. The median interval between crizotinib and capmatinib was 22 days (range: 4-374). Two patients (10%) achieved an objective response to capmatinib and 14 had stable disease, yielding a DCR of 80%. Among five patients who discontinued crizotinib for intolerance, the DCR was 83%, including two patients with the best tumor shrinkage of -25% and -28%. Intracranial DCR among four patients with measurable brain metastases was 100%, with no observed intracranial objective responses. Overall, the median progression-free survival and overall survival were 5.5 (95% confidence interval: 1.3-11.0) and 11.3 (95% confidence interval: 5.5-not reached) months, respectively. MET D1228 and Y1230 mutations and MAPK alterations were recurrently detected in postcrizotinib, precapmatinib plasma. New and persistent MET mutations and MAPK pathway alterations were detected in plasma at progression on capmatinib. CONCLUSIONS: Capmatinib has modest activity in crizotinib-pretreated MET-altered NSCLC, potentially owing to overlapping resistance mechanisms.

Coronavirus Disease 2019 Infection in a Patient Population with Lung Cancer: Incidence, Presentation, and Alternative Diagnostic Considerations.

INTRODUCTION: Lung cancer is associated with severe coronavirus disease 2019 (COVID-19) infections. Symptom overlap between COVID-19 and lung cancer may complicate diagnostic evaluation. We aimed to investigate the incidence, symptoms, differential diagnosis, and outcomes of COVID-19 in patients with lung cancer. METHODS: To determine an at-risk population for COVID-19, we retrospectively identified patients with lung cancer receiving longitudinal care within a single institution in the 12 months (April 1, 2019 to March 31, 2020) immediately preceding the COVID-19 pandemic, including an "active therapy population" treated within the last 60 days of this period. Among patients subsequently referred for COVID-19 testing, we compared symptoms, laboratory values, radiographic findings, and outcomes of positive versus negative patients. RESULTS: Between April 1, 2019 and March 31, 2020, a total of 696 patients received longitudinal care, including 406 (58%) in the active therapy population. Among 55 patients referred for COVID-19 testing, 24 (44%) were positive for COVID-19, representing a cumulative incidence of 3.4% (longitudinal population) and 1.5% (active therapy population). Compared with patients who were COVID-19 negative, those who were COVID-19 positive were more likely to have a supplemental oxygen requirement (11% versus 54%, p = 0.005) and to have typical COVID-19 pneumonia imaging findings (5 versus 56%, p = 0.001). Otherwise, there were no marked differences in presenting symptoms. Among patients who were COVID-19 negative, alternative etiologies included treatment-related toxicity (26%), atypical pneumonia (22%), and disease progression (22%). A total of 16 patients positive for COVID-19 (67%) required hospitalization, and seven (29%) died from COVID-related complications. CONCLUSIONS: COVID-19 was infrequent in this lung cancer population, but these patients experienced high rates of morbidity and mortality. Oncologists should maintain a low threshold for COVID-19 testing in patients with lung cancer presenting with acute symptoms.

Mental Health Care in Pediatric Rehabilitation Hospitals: A Biopsychosocial, Collaborative, and Agency-based Service Integration Approach.

Background: Canadian hospitals are not currently prepared to meet the psychosocial needs of children with disabilities as services are rooted in a biomedical care model. Objective: To describe a practical and holistic framework for pediatric rehabilitation hospitals to meet the health care needs of children and their families. Method: An environmental scan was conducted of best practice guidelines, policy documents, and models of integrated mental health care. Recommendations from clinical guidelines and national strategy documents were incorporated to develop a service integration approach. Results: An agency-based approach was used to develop a two-phase biopsychosocial framework. In framework Phase I, reactive care is provided to mental health concerns. In Phase II, there is a shift to proactive care and mental health wellbeing. Conclusions: Emphasis is placed on capacity building of clinical staff into best practices for mental health care. Implementation needs and consideration for uptake of the framework are also discussed.

MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer.

PURPOSE: Most ALK-positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed. EXPERIMENTAL DESIGN: We performed FISH and/or next-generation sequencing on 207 posttreatment tissue (n = 101) or plasma (n = 106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance. RESULTS: MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop MET amplification than those who had received next-generation ALK inhibitors after crizotinib (P = 0.019). Two tumor specimens harbored an identical ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved rapid responses to ALK/MET combination therapy. CONCLUSIONS: Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET.

Social cognitive and emotion processing abilities of children with fetal alcohol spectrum disorders: a comparison with attention deficit hyperactivity disorder.

BACKGROUND: Although children with Fetal Alcohol Spectrum Disorders (FASDs) are at high risk of attention deficit hyperactivity disorder (ADHD), direct comparisons show distinct cognitive phenotypes in the 2 diagnoses. However, these groups have not been directly compared for social problems or social cognition, nor has social cognition been directly examined in FASDs. OBJECTIVES: To compare FASDs and ADHD groups on social cognition tasks and determine whether deficient social cognition and emotion processing predict behavioral problems and social skills. METHODS: Studied were 33 children with FASDs, 30 with ADHD, and 34 normal controls (NC). All received tasks of social cognition and emotion processing. Parents and teachers rated children on measures of completed questionnaires assessing child's behavioral problems and social skills using the Child Behavior Checklist, Teacher Report Form, and Social Skills Rating Scale. Children received 3 subtests from the Saltzman-Benaiah and Lalonde (2007) Theory of Mind Task as a measure of social cognition and 4 subtests from the Minnesota Test of Affective Processing (Lai et al., 1991) to assess emotion processing. RESULTS: Parents and teachers reported more behavior problems and poorer social skills in children in FASD and ADHD than NC groups. FASDs demonstrated significantly weaker social cognition and facial emotion processing ability than ADHD and NC groups. Regression analyses identified social cognition as a significant predictor of behavior problems and emotion processing as a significant predictor of social skills. CONCLUSIONS: Children with FASDs show a distinct behavioral profile from children with ADHD. Difficulties in social cognition and emotion processing in children with FASDs may contribute to their high incidence of social behavioral problems.

Testing whether gaze cues and arrow cues produce reflexive or volitional shifts of attention.

It has been suggested that two types of uninformative central cues produce reflexive orienting: gaze and arrow cues. Using the criterion that voluntary shifts of attention facilitate both response speed and perceptual accuracy, whereas reflexive shifts of attention facilitate only response speed (Prinzmetal, McCool, & Park, 2005), we tested whether these cues produce reflexive or volitional shifts of attention. A cued letter discrimination task was used with both gaze (Experiments 1A and 1B) and arrow (Experiments 2A and 2B) cues, in which participants responded to the identity of the target letter. In the response time (respond speed) tasks, participants were asked to respond as quickly as possible to the target; in the accuracy (perceptual quality) tasks, participants were asked to respond as accurately as possible. For both cue types, compatible cues were found to facilitate response speed but not perceptual accuracy, indicating that both gaze and arrow cues generate reflexive shifts in attention.

Visuospatial experience modulates attentional capture: evidence from action video game players.

Visuospatial experience, the prolonged engagement in a demanding visual task, obtained through action video game play enhances several visual and cognitive processes. The underlying mechanisms involved in these processes, however, remain unclear. Here we demonstrate that experience with action video games modulates early sensory processing, resulting in increases sensitivity to salient visual events that capture attention. In two experiments, we show using a Temporal Order Judgment (TOJ) and a Signal Detection Paradigm (d') that action video game players show greater sensitivity to exogenous sensory events in the visual array. These results suggest that visuospatial experience modulates the earliest sensory aspects of visual processing.

Informing pediatric rehabilitation: Language-based neuropsychological profile following traumatic brain injury and stroke secondary to arteriovenous malformation.

PURPOSE: To describe language-based neuropsychological outcomes following brain injury in two pediatric populations commonly treated in rehabilitation settings, namely severe traumatic brain injury (sTBI) and stroke secondary to arteriovenous malformation (AVM). METHODS: Investigated were children between the ages of 6 and 16 who were admitted to a brain injury rehabilitation program in a pediatric rehabilitation hospital and who were diagnosed with a left-sided sTBI (n= 16; mean age = 13.2) or a left-hemispheric stroke secondary to AVM (n= 16, mean age = 10.7). Groups were compared on demographic information, as well as general cognitive and language-based neuropsychological measures, controlling for age. RESULTS: Children in the AVM group presented with greater deficits, at trend levels, relative to the sTBI group on measures of working memory, verbal fluency, and an aphasia screening tool. CONCLUSIONS: This study represents an initial step in understanding the language-based neuropsychological outcomes of children diagnosed with sTBI compared to those with stroke secondary to AVM, which will help inform the rehabilitation process. With this knowledge, clinicians, families, and educators will be better equipped to provide informed individual rehabilitation programs, recommendations, and education for children and adolescents with brain injuries.

Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors through Longitudinal Analysis of Circulating Tumor DNA.

PURPOSE: ALK rearrangements predict for sensitivity to ALK tyrosine kinase inhibitors (TKIs). However, responses to ALK TKIs are generally short-lived. Serial molecular analysis is an informative strategy for identifying genetic mediators of resistance. Although multiple studies support the clinical benefits of repeat tissue sampling, the clinical utility of longitudinal circulating tumor DNA analysis has not been established in ALK-positive lung cancer. METHODS: Using a 566-gene hybrid-capture next-generation sequencing (NGS) assay, we performed longitudinal analysis of plasma specimens from 22 ALK-positive patients with acquired resistance to ALK TKIs to track the evolution of resistance during treatment. To determine tissue-plasma concordance, we compared plasma findings to results of repeat biopsies. RESULTS: At progression, we detected an ALK fusion in plasma from 19 (86%) of 22 patients, and identified ALK resistance mutations in plasma specimens from 11 (50%) patients. There was 100% agreement between tissue- and plasma-detected ALK fusions. Among 16 cases where contemporaneous plasma and tissue specimens were available, we observed 100% concordance between ALK mutation calls. ALK mutations emerged and disappeared during treatment with sequential ALK TKIs, suggesting that plasma mutation profiles were dependent on the specific TKI administered. ALK G1202R, the most frequent plasma mutation detected after progression on a second-generation TKI, was consistently suppressed during treatment with lorlatinib. CONCLUSIONS: Plasma genotyping by NGS is an effective method for detecting ALK fusions and ALK mutations in patients progressing on ALK TKIs. The correlation between plasma ALK mutations and response to distinct ALK TKIs highlights the potential for plasma analysis to guide selection of ALK-directed therapies.

[Formula: see text]Social perception in children with fetal alcohol spectrum disorder.

Although the profile of social cognitive difficulties is well recognized in children with certain neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), this profile is not as well established in other clinical pediatric populations. The objective of the present study is to examine patterns of social perception in children with fetal alcohol spectrum disorder (FASD) compared to typically-developing (TD) control children. A total of 56 children between 8 and 12 years of age-35 with FASD and 21 TD-completed the Reading the Mind in the Eyes Task - Children's Version (RMET-C). The RMET-C accuracy scores were compared between groups and also by item difficulty and emotional valence. The relation between cognitive functioning, age, FASD severity, and RMET-C performance was also investigated. The children in the FASD group did not perform as well as the children in the TD group on the RMET-C Total score and Easy items, as well as the Positive, Negative, and Neutral emotional valence items. When age and IQ were investigated, there was a significant effect of age on the Positive items in the TD group, with scores increasing with age. With regard to FASD severity, children with alcohol-related neurodevelopmental disorder were outperformed by children with full/partial fetal alcohol syndrome on the Positive and Negative items. Overall, these results further the understanding of the social cognitive profile in children with FASD and how this profile relates to other childhood-onset neurodevelopmental disorders.

Preliminary Findings that a Targeted Intervention Leads to Altered Brain Function in Children with Fetal Alcohol Spectrum Disorder.

Children with fetal alcohol spectrum disorder (FASD) exhibit behavioral dysregulation, executive dysfunction, and atypical function in associated brain regions. Previous research shows early intervention mitigates these outcomes but corresponding brain changes were not studied. Given the Alert® Program for Self-Regulation improves behavioral regulation and executive function in children with FASD, we asked if this therapy also improves their neural functioning in associated regions. Twenty-one children with FASD aged 8-12 years were randomized to the Alert®-treatment (TXT; n = 10) or waitlist-control (WL; n = 11) conditions. They were assessed with a Go-NoGo functional magnetic resonance imaging (fMRI) paradigm before and after training or the wait-out period. Groups initially performed equivalently and showed no fMRI differences. At post-test, TXT outperformed WL on NoGo trials while fMRI in uncorrected results with a small-volume correction showed less activation in prefrontal, temporal, and cingulate regions. Groups also demonstrated different patterns of change over time reflecting reduced signal at post-test in selective prefrontal and parietal regions in TXT and increased in WL. In light of previous evidence indicating TXT at post-test perform similar to non-exposed children on the Go-NoGo fMRI paradigm, our findings suggest Alert® does improve functional integrity in the neural circuitry for behavioral regulation in children with FASD.

Catathrenia, a REM predominant disorder of arousal?

OBJECTIVES: Catathrenia is an uncommon and poorly understood disorder, characterized by groaning during sleep occurring in tandem with prolonged expiration. Its classification, pathogenesis, and clinical relevance remain debated, substantially due to the limited number of cases reported to date. We report a series of consecutive cases of catathrenia, their clinical and polysomnographic characteristics, and their subsequent management. METHODS: Consecutive patients with catathrenia who had undergone full polysomnography in our institution over a 5.5-year period were included. Catathrenia events (CEs) were examined in clusters, which formulated catathrenia periods (CPs). The relationships between CPs, sleep stage distribution, electroencephalogram (EEG) arousals, and other sleep parameters were assessed, along with the clinical presentation and management of catathrenic patients. RESULTS: A total of 427 CPs were identified in 38 patients, 81% arising from rapid eye movement (REM) sleep. EEG arousals preceded or coincided with the onset of 84% of CPs, which were of longer duration than those not associated with an arousal (57.3 ± 56.8 vs. 32.2 ± 29.4 s, p < 0.001). Each CE had a characteristic airflow signal, with inspiration preceding a protracted expiration and a brief more rapid exhalation, followed by deep inspiration. Although the majority of patients were referred on the basis of bed partner complaints, 44.7% complained of daytime sleepiness. Continuous positive airway pressure therapy and sleep-consolidating pharmacotherapy led to subjective improvement, but were limited by poor long-term adherence. CONCLUSIONS: In the largest series of catathrenia patients reported to date, we found that this rare disorder is characterized by a distinct breathing pattern and arises predominantly from REM sleep, with arousals almost uniformly preceding or coinciding with the onset of CPs.

Clinicopathologic Features of NSCLC Diagnosed During Pregnancy or the Peripartum Period in the Era of Molecular Genotyping.

INTRODUCTION: Cancer will be diagnosed in one in 1000 women during pregnancy. The outcomes of NSCLC diagnosed during pregnancy are dismal, with most patients dying within 1 year. Actionable mutations are more likely to be found among younger patients with NSCLC. However, most previous reports of NSCLC diagnosed during pregnancy did not include molecular genotyping. METHODS: We performed a retrospective analysis of patients seen at our institution between 2009 and 2015 to identify women in whom NSCLC was diagnosed during pregnancy or the peripartum period and determined clinicopathologic features, including molecular genotype. RESULTS: We identified 2422 women with NSCLC, including 160 women of reproductive age. Among the women of reproductive age, eight cases of NSCLC diagnosed during pregnancy or the peripartum period were identified; all were diagnosed in minimal or never-smokers with metastatic adenocarcinoma. Six of these patients were found to have anaplastic lymphoma kinase gene (ALK) rearrangements, whereas the remaining two were EGFR mutation positive. We observed a borderline significant association between a diagnosis of NSCLC during pregnancy or the peripartum period and ALK positivity (p = 0.053). All eight women in whom NSCLC was diagnosed during pregnancy or the peripartum period received treatment with genotype-directed therapies after delivery. The median overall survival has not been reached at a median follow-up of 30 months. CONCLUSIONS: Although a diagnosis of NSCLC during pregnancy or the peripartum period is rare, diagnostic evaluation should not be delayed in pregnant women presenting with symptoms worrisome for lung cancer. Evaluation should include testing for targetable molecular alterations.

Clinical Activity of Alectinib in Advanced RET-Rearranged Non-Small Cell Lung Cancer.

INTRODUCTION: Chromosomal rearrangements involving rearranged during transfection gene (RET) occur in 1% to 2% of NSCLCs and may confer sensitivity to rearranged during transfection (RET) inhibitors. Alectinib is an anaplastic lymphoma kinase tyrosine kinase inhibitor (TKI) that also has anti-RET activity in vitro. The clinical activity of alectinib in patients with RET-rearranged NSCLC has not yet been reported. METHODS: We have described four patients with advanced RET-rearranged NSCLC who were treated with alectinib (600 mg twice daily [n = 3] or 900 mg twice daily [n = 1]) as part of single-patient compassionate use protocols or off-label use of the commercially available drug. RESULTS: Four patients with metastatic RET-rearranged NSCLC were identified. Three of the four had received prior RET TKIs, including cabozantinib and experimental RET inhibitors. In total, we observed two (50%) objective radiographic responses after treatment with alectinib (one confirmed and one unconfirmed), with durations of therapy of 6 months and more than 5 months (treatment ongoing), respectively. Notably, one of these two patients had his dose of alectinib escalated to 900 mg twice daily and had clinical improvement in central nervous system metastases. In addition, one patient (25%) experienced a best response of stable disease lasting approximately 6 weeks (the drug discontinued for toxicity). A fourth patient who was RET TKI-naive had primary progression while receiving alectinib. CONCLUSIONS: Alectinib demonstrated preliminary antitumor activity in patients with advanced RET-rearranged NSCLC, most of whom had received prior RET inhibitors. Larger prospective studies with longer follow-up are needed to assess the efficacy of alectinib in RET-rearranged NSCLC and other RET-driven malignancies. In parallel, development of more selective, potent RET TKIs is warranted.

Self-regulation therapy increases frontal gray matter in children with fetal alcohol spectrum disorder: evaluation by voxel-based morphometry.

Children with fetal alcohol spectrum disorder show executive function (EF) deficits, particularly in self-regulation skills, and abnormalities in brain regions critical for these skills. None of the validated EF interventions for these children has been evaluated with regards to impacts on brain structure. Twenty-nine children with FASD were assigned to either an immediate-treatment (TX) or delayed-treatment control (DTC) group (DTC). Nineteen typically developing children served as healthy controls (CT). All received a structural MRI scan and baseline neuropsychological testing, following which the TX group underwent 12 weekly 1.5-h sessions of the Alert Program for Self-Regulation(®). After treatment or a period of ~14 weeks, all received a repeat scan and post-intervention testing. Whole-brain and region-of-interest analyses using voxel-based morphometry evaluated group differences and changes over time in gray matter (GM). Exploratory analyses revealed significant group changes: (1) At baseline, combined TX and DTC groups demonstrated global GM reductions compared with the CT group. (2) Region-of-interest analysis using a frontal mask, comparing post-intervention to pre-intervention results, showed significantly increased GM in the left middle frontal gyrus (BA10), right frontal pole (BA11), and right anterior cingulate (BA32) in the TX group. Similar results were not found in the DTC or CT groups. (3) At post-intervention, both TX and CT groups showed larger GM volumes than the DTC group in the left superior frontal gyrus (BA9), which was smaller in the FASD group at baseline. These results suggested that Alert led to improvements in post-intervention testing of self-regulation skills and typical brain development in treated children.