Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma.

A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.

Impact of Propofol Exposure on Neurocognitive Outcomes in Children With High-Risk B ALL: A Children's Oncology Group Study.

PURPOSE: Many children treated for ALL develop long-term neurocognitive impairments. Increased risk of these impairments is associated with treatment and demographic factors. Exposure to anesthesia is an additional possible risk factor. This study evaluated the impact of cumulative exposure to anesthesia on neurocognitive outcomes among a multicenter cohort of children with ALL. METHODS: This study was embedded in AALL1131, a Children's Oncology Group phase III trial for patients with high-risk B-ALL. In consenting patients age 6-12 years, prospective uniform assessments of neurocognitive function were performed during and at 1 year after completion of therapy. Exposure to all episodes of anesthetic agents was abstracted. Multivariable linear regression models determined associations of cumulative anesthetic agents with the primary neurocognitive outcome reaction time/processing speed (age-normed) at 1 year off therapy, adjusting for baseline neurocognitive score, age, sex, race/ethnicity, insurance status (as a proxy for socioeconomic status), and leukemia risk group. RESULTS: One hundred and forty-four children, 76 (52.8%) males, mean age of 9.1 (min-max, 6.0-12.0) years at diagnosis, underwent a median of 27 anesthetic episodes (min-max, 1-37). Almost all patients were exposed to propofol (140/144, 97.2%), with a mean cumulative dose of 112.3 mg/kg. One year after therapy, the proportion of children with impairment (Z-score ≤-1.5) was significantly higher compared with a normative sample. In covariate-adjusted multivariable analysis, cumulative exposure to propofol was associated with a 0.05 Z-score decrease in reaction time/processing speed per each 10 mg/kg propofol exposure (P = .03). CONCLUSION: In a multicenter and uniformly treated cohort of children with B-ALL, cumulative exposure to propofol was an independent risk factor for impairment in reaction time/processing speed 1 year after therapy. Anesthesia exposure is a modifiable risk, and opportunities to minimize propofol use should be considered.

Assessing Diversity, Equity, and Inclusion in Patient-Facing Websites in Neurosurgical Departments in the United States.

BACKGROUND: Patient-facing websites serve as essential platforms for disseminating information, engaging with patients, and increasing access to neurosurgical resources and services. Diversity, Equity, and Inclusion are at the forefront of issues facing the field of neurosurgery, especially concerning race and gender disparities in regards to providers in the field. METHODS: Data were collected in regards to the race and gender of patients and providers displayed on the neurosurgery department's patient-facing website in addition to accommodations for disabilities, decreased ability to pay, and language. RESULTS: Patients who were White were depicted more commonly than those of color (69% vs. 31%, P < 0.00001). White patients also were over-represented when compared with the average demographics of the communities in which the hospitals served (P = 0.03846). Neurosurgical providers who were White outnumbered those of color (70% vs. 30%, P < 0.00001). The racial depiction of providers was comparable with racial disparities currently observed in neurosurgery (P = 0.59612). Female neurosurgery providers were seen less than male providers on patient-facing websites (P < 0.00001) but were seen more commonly on patient-facing websites than the percentage of practicing neurosurgeons they currently comprise (28% vs. 8%, P < 0.00001). CONCLUSIONS: The results of this study suggest that patient-facing websites of neurosurgical departments are an area of improvement in regards to Diversity, Equity, and Inclusion in the field of neurosurgery. Disparities are noted in regards to the racial depiction of patients and further call to attention racial and gender disparities in the field of neurosurgery.

Impaired neurocognitive functioning 3 months following diagnosis of high-risk acute lymphoblastic leukemia: A report from the Children's Oncology Group.

PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer diagnosis. Cognitive late effects develop in 20%-40% of ALL survivors, but the course of declines is unclear. The aim of this paper is to characterize cognitive functioning, and its association with patient-reported outcomes, early in treatment. PATIENTS AND METHODS: A total of 483 children with high-risk ALL, aged 6-12 years at diagnosis, consented to the neurocognitive study embedded in a prospective therapeutic trial, Children's Oncology Group (COG) AALL1131. A computerized neurocognitive battery (Cogstate) was administered 3 months post diagnosis assessing reaction time, visual attention, working memory, visual learning, and executive functioning. Parent-reported executive functioning and patient-reported physical symptoms were also collected. RESULTS: Data from 390 participants (mean age at diagnosis = 9.2 years, 55.4% male) were obtained. Relatively few patients reported pain (16.0%) or nausea (22.6%), but a majority (68.5%) reported feeling at least some fatigue at testing. Mean Cogstate Z-scores were within normal limits across tasks; however, rates of impairment (Z-scores ≤ -1.5) for reaction time, working memory, visual learning, and visual attention were all higher than expected compared to the standardization sample. Patients reporting fatigue were significantly more likely to have impaired reaction time and visual attention compared to those reporting no fatigue. CONCLUSION: Findings support feasibility of computerized cognitive assessments and suggest higher-than-expected rates of impaired cognitive performance early during treatment for pediatric ALL, notably within 3 months of diagnosis, suggesting intervention efforts may be indicated. These results also highlight acute factors that may impact reliability of "baseline" assessments conducted soon after diagnosis.

Neurocognitive and emotional factors predict pain-related healthcare utilization in children with sickle cell disease.

BACKGROUND: Youth with sickle cell disease (SCD) experience increased rates of neurocognitive and emotional difficulties. Cross-sectional studies suggest neurocognitive and emotional functioning are associated with health outcomes in SCD. We investigated whether neurocognitive and emotional factors predicted future pain-related healthcare utilization in children with SCD. PROCEDURE: Total 112 youth with SCD between ages 7 and 16 years reported sociodemographics and completed measures of neurocognitive functioning and emotional well-being. The number of emergency department (ED) visits and hospitalizations for pain 1 and 3 years after enrollment were determined by chart review. RESULTS: The mean age of participants was 10.61 years (standard deviation = 2.91), with most being female (n = 65; 58%). Eighty-three (74%) participants had either HbSS or HbSß0 thalassemia. Regression analyses showed that attention significantly predicted ED visits and hospitalizations for pain at 1 and 3 years after enrollment (all p-values ≤ .017), such that poorer attention was associated with higher healthcare utilization. Lower emotional quality of life also predicted more ED visits for pain at 3 years (b = -.009, p = .013) and hospitalizations for pain at 3 years (b = -.008, p = .020). CONCLUSIONS: Neurocognitive and emotional factors are associated with subsequent healthcare use in youth with SCD. Poor attentional control might limit implementation of strategies to distract from pain or could make disease self-management behaviors more challenging. Results also highlight the potential impact of stress on pain onset, perception, and management. Clinicians should consider neurocognitive and emotional factors when developing strategies to optimize pain-related outcomes in SCD.

Realistic Assessment of Research Publications by Neurosurgery Residency Applicants.

OBJECTIVE: Neurosurgical residency applicants' prior research experience can amplify their ability to stand out to prospective neurosurgery programs. We attempted to accurately quantify the number of research publications coauthored by applicants by analyzing the publications of applicants who matched into neurosurgery in the 2021 Match. METHODS: Scopus, a peer-reviewed literature database, was queried for publications by applicants who matched into neurosurgery in the 2021 Match before the finalization of rank lists. Conference papers, abstracts, and book chapters were excluded to determine an accurate average of actual publications. Descriptive statistics for resident publication data were used, with a Mann-Whitney U test used to compare research productivity between male and female residents. RESULTS: There were 234 positions filled by the 2021 Match, and 233 neurosurgical residents were identifiable in this study. A total of 187 residents matching from U.S. Doctor of Medicine and Doctor of Osteopathic Medicine programs were identified with 946 total publications-an average of 5.1 publications per resident. Analysis of descriptive statistics revealed type of research conducted, authorship information, most published journals, and citation data. Significant differences were found in the number of publications between male and female applicants with averages of 5.6 and 3.8 publications, respectively. CONCLUSIONS: Students matriculating to neurosurgery residency programs display a wide range of research productivity. Typical U.S. Doctor of Medicine and Doctor of Osteopathic Medicine applicants have coauthored a mean of 5.1 and a median of 4.0 publications. This information may assist program directors in weighing applicants' research background and give medical students interested in the field reasonable research expectations.

Suicidal ideation and executive functioning in pediatric cancer.

OBJECTIVE: Neurocognitive impairments and psychological distress are among the most common difficulties experienced by children treated for cancer. Elevated rates of suicidal ideation (SI) are documented among cancer survivors, and a link between neurocognitive deficits and SI is evident, yet the relationship between SI and pediatric cancer-related neurocognitive effects has not yet been studied. PARTICIPANTS AND METHODS: Participants were 166 pediatric cancer patients (57.8% Brain Tumor, 31.3% leukemia, 10.8% other cancers) aged 6-23 (M = 11.57, SD = 3.82; 45.8% female) referred for neuropsychological surveillance. SI prevalence was measured by parent, teacher, or patient endorsement of self-harm related items on informant-report measures (e.g., the Child Behavior Checklist). Executive functioning (Behavior Rating Inventory of Executive Function), ADHD symptoms (ADHD Rating Scale), and performance-based measures were compared between those with SI and those without. RESULTS: 17.5% of pediatric cancer patients experienced SI, of which 44.7% had self-endorsement only, 58.5% parent-endorsement only, 20.6% teacher-endorsement only, and 24.1% had two endorsements. Those with SI had significantly greater impairments in global executive composite scores by both parent- and teacher-report (ps < 0.05). Parents of children with SI endorsed significantly more inattention symptoms (M = 6.10, SD = 15.48) than those without SI (M = 50.56, SD = 8.70; p < 0.01), but hyperactivity symptoms did not differ. Intellectual and executive function performance did not differ between those with and without SI (ps > 0.1). CONCLUSIONS: An elevated number of children treated for cancer experience SI and related neurocognitive problems. Screening for SI and further assessment of the connection between executive functioning and SI in pediatric cancer populations is needed.

Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states.

Single-cell RNA sequencing has revealed extensive transcriptional cell state diversity in cancer, often observed independently of genetic heterogeneity, raising the central question of how malignant cell states are encoded epigenetically. To address this, here we performed multiomics single-cell profiling-integrating DNA methylation, transcriptome and genotype within the same cells-of diffuse gliomas, tumors characterized by defined transcriptional cell state diversity. Direct comparison of the epigenetic profiles of distinct cell states revealed key switches for state transitions recapitulating neurodevelopmental trajectories and highlighted dysregulated epigenetic mechanisms underlying gliomagenesis. We further developed a quantitative framework to directly measure cell state heritability and transition dynamics based on high-resolution lineage trees in human samples. We demonstrated heritability of malignant cell states, with key differences in hierarchal and plastic cell state architectures in IDH-mutant glioma versus IDH-wild-type glioblastoma, respectively. This work provides a framework anchoring transcriptional cancer cell states in their epigenetic encoding, inheritance and transition dynamics.

Computerized Working Memory Training for Children With Neurofibromatosis Type 1 (NF1): A Pilot Study.

INTRODUCTION: The present study aimed to evaluate the feasibility and efficacy of CogmedRM, a computerized, home-based working memory (WM) training program, in children with NF1. METHOD: A pre-post design was used to evaluate changes in performance-based measures of attention and WM, and parent-completed ratings of executive functioning. Children meeting eligibility criteria completed CogmedRM over 9 weeks. Primary outcomes included compliance statistics and change in attention and WM scores. RESULTS: Thirty-one children (52% male; M age = 10.97 ± 2.51), aged 8-15, were screened for participation; 27 children (87%) evidenced WM difficulties and participated in CogmedRM training. On average, participants completed 19.7 out of 25 prescribed sessions, with an adherence rate of 69%. Participants demonstrated improvements in short-term memory, attention, and executive functioning (all Ps < .05). CONCLUSION: Results suggest that computerized, home-based WM training programs may be both feasible and efficacious for children with NF1 and cognitive deficits.

Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma.

Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18-SSX fusion, and is characterized by low T cell infiltration. Here, we studied the cancer-immune interplay in SyS using an integrative approach that combines single-cell RNA sequencing (scRNA-seq), spatial profiling and genetic and pharmacological perturbations. scRNA-seq of 16,872 cells from 12 human SyS tumors uncovered a malignant subpopulation that marks immune-deprived niches in situ and is predictive of poor clinical outcomes in two independent cohorts. Functional analyses revealed that this malignant cell state is controlled by the SS18-SSX fusion, is repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/CDK6 inhibitors. This drug combination enhanced malignant-cell immunogenicity in SyS models, leading to induced T cell reactivity and T cell-mediated killing. Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.

Resolving medulloblastoma cellular architecture by single-cell genomics.

Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.

A screening tool for detecting eating disorder risk and diagnostic symptoms among college-age women.

Objective: As eating disorders (EDs) often emerge during college, managing EDs would ideally integrate prevention and treatment. To achieve this goal, an efficient tool is needed that detects clinical symptoms and level of risk. This study evaluated the performance of a screen designed to identify individuals at risk for or with an ED. Participants: Five hundred forty-nine college-age women. Methods: Participants completed a screen and diagnostic interview. Results: Using parsimonious thresholds for ED diagnoses, screen sensitivity ranged from 0.90 (anorexia nervosa) to 0.55 (purging disorder). Specificity ranged from 0.99 (anorexia nervosa) to 0.78 (subthreshold binge eating disorder) compared to diagnostic interview. Moderate to high area under the curve values were observed. The screen had high sensitivity for detecting high risk. Conclusions: The screen identifies students at risk and has acceptable sensitivity and specificity for identifying most ED diagnoses. This tool is critical for establishing stepped care models for ED intervention.

Mental Health Stigma Prevention: Pilot Testing a Novel, Language Arts Curriculum-Based Approach for Youth.

BACKGROUND: Researchers have emphasized the importance of integrating mental health education with academic curriculum. The focus of the current studies was Mental Health Matters (MHM), a mental health curriculum that is integrated with English language arts. It is taught by trained community member volunteers and aims to increase knowledge and decrease stigma toward individuals with mental health disorders. METHODS: In Study 1, 142 sixth graders participated in MHM and completed pre- and postprogram measures of mental health knowledge, stigma, and program acceptability. Teachers also completed ratings of acceptability. Study 2 (N = 120 seventh graders) compared participants who had participated in MHM the previous year with those who had not using the same measures. RESULTS: Sixth grade students and teachers rated the program as highly acceptable. Participants significantly increased their knowledge and decreased their levels of stigma. Seventh graders who had participated in MHM had significantly more mental health knowledge than peers who had not, but there were no differences in stigma. CONCLUSIONS: The model appears to be acceptable to students and teachers. Future research is needed to assess the long-term effectiveness of integrating mental health education with other academic curriculum such as language arts or science.

Reducing eating disorder onset in a very high risk sample with significant comorbid depression: A randomized controlled trial.

OBJECTIVE: Eating disorders (EDs) are serious problems among college-age women and may be preventable. An indicated online eating disorder (ED) intervention, designed to reduce ED and comorbid pathology, was evaluated. METHOD: 206 women (M age = 20 ± 1.8 years; 51% White/Caucasian, 11% African American, 10% Hispanic, 21% Asian/Asian American, 7% other) at very high risk for ED onset (i.e., with high weight/shape concerns plus a history of being teased, current or lifetime depression, and/or nonclinical levels of compensatory behaviors) were randomized to a 10-week, Internet-based, cognitive-behavioral intervention or waitlist control. Assessments included the Eating Disorder Examination (EDE, to assess ED onset), EDE-Questionnaire, Structured Clinical Interview for DSM Disorders, and Beck Depression Inventory-II. RESULTS: ED attitudes and behaviors improved more in the intervention than control group (p = .02, d = 0.31); although ED onset rate was 27% lower, this difference was not significant (p = .28, NNT = 15). In the subgroup with highest shape concerns, ED onset rate was significantly lower in the intervention than control group (20% vs. 42%, p = .025, NNT = 5). For the 27 individuals with depression at baseline, depressive symptomatology improved more in the intervention than control group (p = .016, d = 0.96); although ED onset rate was lower in the intervention than control group, this difference was not significant (25% vs. 57%, NNT = 4). CONCLUSIONS: An inexpensive, easily disseminated intervention might reduce ED onset among those at highest risk. Low adoption rates need to be addressed in future research.

Internet-based preventive intervention for reducing eating disorder risk: A randomized controlled trial comparing guided with unguided self-help.

Student Bodies, an internet-based intervention, has successfully reduced weight/shape concerns and prevented eating disorders in a subset of college-age women at highest risk for an eating disorder. Student Bodies includes an online, guided discussion group; however, the clinical utility of this component is unclear. This study investigated whether the guided discussion group improves program efficacy in reducing weight/shape concerns in women at high risk for an eating disorder. Exploratory analyses examined whether baseline variables predicted who benefitted most. Women with high weight/shape concerns (N = 151) were randomized to Student Bodies with a guided discussion group (n = 74) or no discussion group (n = 77). Regression analyses showed weight/shape concerns were reduced significantly more among guided discussion group than no discussion group participants (p = 0.002; d = 0.52); guided discussion group participants had 67% lower odds of having high-risk weight/shape concerns post-intervention (p = 0.02). There were no differences in binge eating at post-intervention between the two groups, and no moderators emerged as significant. Results suggest the guided discussion group improves the efficacy of Student Bodies in reducing weight/shape concerns in college students at high risk for an eating disorder.

Psychiatric co-morbidity in women presenting across the continuum of disordered eating.

OBJECTIVE: To compare the prevalence and correlates of psychiatric co-morbidity across a large sample of college women without an eating disorder, those at high risk for an eating disorder and women diagnosed using DSM-5 criteria for an eating disorder. PARTICIPANTS: 549 college women aged 18-25. METHODS: Data from the Eating Disorder Examination, the Structured Clinical Interview for DSM-IV Axis I disorders and self-report questionnaires were analyzed using logistic regression for categorical data and ANCOVA for continuous measures. RESULTS: Eating disordered symptomatology was strongly associated with anxiety disorders, mood disorders and insomnia. These co-morbidities (type and severity) tend to increase with eating disorder symptom severity. CONCLUSIONS: Prevention and treatment programs for eating disorders need to address the high levels of mood, anxiety and sleep problems in this population. The findings on insomnia are novel and suggest that sleep disturbance may play an integral role in eating-related difficulties.

Validation of a six-item male body image concerns scale (MBICS).

Elevated body image concerns may be a risk factor for eating disorders among males and contribute to a range of other mental health problems. This study tested a 6-item measure of general male body image concerns in two studies with adolescent males ages 14-18 (total N = 122). The measure showed strong convergent validity, scale score reliability, and test-retest reliability, and was significantly correlated with the number of episodes of binge eating in the past month. A short scale will relieve participant burden and provide a useful research tool for studies with males at risk for or with eating disorders.

What constitutes clinically significant binge eating? Association between binge features and clinical validators in college-age women.

OBJECTIVE: To investigate the association between binge features and clinical validators. METHOD: The Eating Disorder Examination assessed binge features in a sample of 549 college-age women: loss of control (LOC) presence, binge frequency, binge size, indicators of impaired control, and LOC severity. Clinical validators were self-reported clinical impairment and current psychiatric comorbidity, as determined via a semistructured interview. RESULTS: Compared with women without LOC, those with LOC had significantly greater odds of reporting clinical impairment and comorbidity (ps < 0.001). Among women with LOC (n = 252), the indicators of impaired control and LOC severity, but not binge size or frequency, were associated with greater odds of reporting clinical impairment and/or comorbidity (ps < 0.05). DICUSSION: Findings confirm that the presence of LOC may be the hallmark feature of binge eating. Further, dimensional ratings about the LOC experience--and possibly the indicators of impaired control--may improve reliable identification of clinically significant binge eating.

Systematic review: pharmacological treatment of tic disorders--efficacy of antipsychotic and alpha-2 adrenergic agonist agents.

We conducted a meta-analysis of randomized, placebo-controlled trials to determine the efficacy of antipsychotic and alpha-2 agonists in the treatment of chronic tic disorders and examine moderators of treatment effect. Meta-analysis demonstrated a significant benefit of antipsychotics compared to placebo (standardized mean difference (SMD)=0.58 (95% confidence interval (CI): 0.36-0.80). Stratified subgroup analysis found no significant difference in the efficacy of the 4 antipsychotic agents tested (risperidone, pimozide, haloperidol and ziprasidone). Meta-analysis also demonstrated a benefit of alpha-2 agonists compared to placebo (SMD=0.31 (95% confidence interval CI: 0.15-0.48). Stratified subgroup analysis and meta-regression demonstrated a significant moderating effect of co-occurring ADHD. Trials which enrolled subjects with tics and ADHD demonstrated a medium-to-large effect (SMD=0.68 (95%CI: 0.36-1.01) whereas trials that excluded subjects with ADHD demonstrated a small, non-significant benefit (SMD=0.15 (95%CI: -0.06 to 0.36). Our findings demonstrated significant benefit of both antipsychotics and alpha-2 agonists in treating tics but suggest alpha-2 agonists may have minimal benefit in tic patients without ADHD.

An examination of the Clinical Impairment Assessment among women at high risk for eating disorder onset.

Identifying measures that reliably and validly assess clinical impairment has important implications for eating disorder (ED) diagnosis and treatment. The current study examined the psychometric properties of the Clinical Impairment Assessment (CIA) in women at high risk for ED onset. Participants were 543 women (20.6 ± 2.0 years) who were classified into one of three ED categories: clinical ED, high risk for ED onset, and low risk control. Among high risk women, the CIA demonstrated high internal consistency (α = 0.93) and good convergent validity with disordered eating attitudes (rs = 0.27-0.68, ps < 0.001). Examination of the CIA's discriminant validity revealed that CIA global scores were highest among women with a clinical ED (17.7 ± 10.7) followed by high risk women (10.6 ± 8.5) and low risk controls (3.0 ± 3.3), respectively (p < 0.001). High risk women reporting behavioral indices of ED psychopathology (objective and/or subjective binge episodes, purging behaviors, driven exercise, and ED treatment history) had higher CIA global scores than those without such indices (ps < 0.05), suggesting good criterion validity. These data establish the first norms for the CIA in a United States sample. The CIA is psychometrically sound among high risk women, and heightened levels of impairment among these individuals as compared to low risk women verify the relevance of early intervention efforts.