Trabectedin Enhances Oncolytic Virotherapy by Reducing Barriers to Virus Spread and Cytotoxic Immunity in Preclinical Pediatric Bone Sarcoma.

We previously reported that the DNA alkylator and transcriptional-blocking chemotherapeutic agent trabectedin enhances oncolytic herpes simplex viroimmunotherapy in human sarcoma xenograft models, though the mechanism remained to be elucidated. Here we report trabectedin disrupts the intrinsic cellular anti-viral response which increases viral transcript spread throughout the human tumor cells. We also extended our synergy findings to syngeneic murine sarcoma models, which are poorly susceptible to virus infection. In the absence of robust virus replication, we found trabectedin enhanced viroimmunotherapy efficacy by reducing immunosuppressive macrophages and stimulating granzyme expression in infiltrating T and NK cells to cause immune-mediated tumor regressions. Thus, trabectedin enhances both the direct virus-mediated killing of tumor cells and the viral-induced activation of cytotoxic effector lymphocytes to cause tumor regressions across models. Our data provide a strong rationale for clinical translation as both mechanisms should be simultaneously active in human patients.

Evaluating appetite/satiety hormones and eating behaviours as predictors of weight loss maintenance with GLP-1RA therapy in adolescents with severe obesity.

INTRODUCTION: Whilst glucagon-like peptide-1 receptor agonists (GLP1-RAs) are effective for treating adolescent obesity, weight loss maintenance (WLM; preventing weight regain) remains a challenge. Our goal was to investigate appetite/satiety hormones and eating behaviours that may predict WLM with exenatide (a GLP1-RA) versus placebo in adolescents with severe obesity. METHODS: Adolescents who had ≥5% body mass index (BMI) reduction with meal replacement therapy were randomized to 52 weeks of once-weekly exenatide extended release or placebo. In this secondary analysis, eating behaviours and appetite/satiety regulation hormones post-meal replacement therapy (pre-randomization to exenatide or placebo) were evaluated as possible predictors of WLM. Percent change in BMI from randomization to 52 weeks served as the primary measure of WLM. RESULTS: The analysis included 66 adolescents (mean age 16.0 years; 47% female). Lower leptin response to meal testing was associated with greater WLM in terms of BMI percent change in those receiving exenatide compared to placebo (p = 0.007) after adjusting for sex, age and BMI. There were no other significant predictors of WLM. CONCLUSIONS: Prior to exenatide, lower leptin response to meals was associated with improved WLM with exenatide compared to placebo. The mostly null findings of this study suggest that GLP1-RA treatment may produce similar WLM for adolescents with obesity regardless of age, BMI, sex and eating behaviours.

Appetitive and psychological phenotypes of pediatric patients with obesity.

BACKGROUND: Obesity is a heterogeneous disease with variable treatment response. Identification of the unique constellation of contributors to obesity may allow for targeted interventions and improved outcomes. OBJECTIVE: Identify empirically derived phenotypes of pediatric patients with obesity based on appetitive and psychological correlates of obesity. METHODS: This cross-sectional study included patients aged 5-12 years who were treated in a weight management clinic and completed standard intake questionnaires including Child Eating Behavior Questionnaire (CEBQ), Vanderbilt ADHD Scale and Pediatric Symptom Checklist. Phenotypes were elicited using latent profile analysis of 12 indicators: eight CEBQ subscales, inattention, hyperactivity/impulsivity, internalizing and externalizing symptoms. RESULTS: Parents/guardians of 384 patients (mean age 9.8 years, mean BMI 30.3 kg/m2 ) completed the intake questionnaires. A 4-phenotype model best fits the data. Hedonic Impulsive phenotype (42.5%) exhibited high food enjoyment and hyperactivity/impulsivity. Inattentive Impulsive phenotype (27.4%) exhibited overall low food approach and high food avoid behaviours, and highest inattention. Hedonic Emotional phenotype (20.8%) scored the highest on food enjoyment, internalizing and externalizing symptoms. Picky Eating phenotype (9.3%) scored the lowest on food approach, inattention, hyperactivity/impulsivity, internalizing and externalizing symptoms. CONCLUSION: Appetitive traits and psychological symptoms appear to cluster in distinct patterns, giving rise to four unique phenotypic profiles, which, if replicated, may help inform the development of tailored treatment plans.

SMART use of medications for the treatment of adolescent severe obesity: A sequential multiple assignment randomized trial protocol.

BACKGROUND: Severe obesity is a complex, chronic disease affecting nearly 9% of adolescents in the U.S. Although the current mainstay of treatment is lifestyle therapy, pediatric clinical practice guidelines recommend the addition of adjunct anti-obesity medication (AOM), such as phentermine and topiramate. However, guidance regarding when adjunct AOM should be started and how AOM should be used is unclear. Furthermore, an inherent limitation of current treatment guidelines is their "one-size-fits-all" approach, which does not account for the heterogeneous nature of obesity and high degree of patient variability in response to all interventions. METHODS: This paper describes the study design and methods of a sequential multiple assignment randomized trial (SMART), "SMART Use of Medications for the Treatment of Adolescent Severe Obesity." The trial will examine 1) when to start AOM (specifically phentermine) in adolescents who are not responding to lifestyle therapy and 2) how to modify AOM when there is a sub-optimal response to the initial pharmacological intervention (specifically, for phentermine non-responders, is it better to add topiramate to phentermine or switch to topiramate monotherapy). Critically, participant characteristics that may differentially affect response to treatment will be assessed and evaluated as potential moderators of intervention efficacy. CONCLUSION: Data from this study will be used to inform the development of an adaptive intervention for the treatment of adolescent severe obesity that includes empirically-derived decision rules regarding when and how to use AOM. Future research will test this adaptive intervention against standard "one-size-fits-all" treatments.

Aberrant activation of wound healing programs within the metastatic niche facilitates lung colonization by osteosarcoma cells.

Purpose: Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. This study delineates how osteosarcoma cells educate the lung microenvironment during metastatic progression. Experimental design: Using single-cell transcriptomics (scRNA-seq), we characterized genome- and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multi-parameter immunofluorescence. We evaluated the ability of nintedanib to impair metastatic colonization and prevent osteosarcoma-induced education of the lung microenvironment in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models. Results: Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. scRNA-seq demonstrated that the surrounding lung stroma adopts a chronic, non-resolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, metastasis-associated lung demonstrated marked fibrosis, likely due to the accumulation of pathogenic, pro-fibrotic, partially-differentiated epithelial intermediates. Inhibition of fibrotic pathways with nintedanib prevented metastatic progression in multiple murine and human xenograft models. Conclusions: Our work demonstrates that osteosarcoma cells co-opt fibrosis to promote metastatic outgrowth. When harmonized with data from adult epithelial cancers, our results support a generalized model wherein aberrant mesenchymal-epithelial interactions are critical for promoting lung metastasis. Adult epithelial carcinomas induce fibrotic pathways in normal lung fibroblasts, whereas osteosarcoma, a pediatric mesenchymal tumor, exhibits fibrotic reprogramming in response to the aberrant wound-healing behaviors of an otherwise normal lung epithelium, which are induced by tumor cell interactions. Statement of translational relevance: Therapies that block metastasis have the potential to save the majority of lives lost due to solid tumors. Disseminated tumor cells must educate the foreign, inhospitable microenvironments they encounter within secondary organs to facilitate metastatic colonization. Our study elucidated that disseminated osteosarcoma cells survive within the lung by co-opting and amplifying the lung's endogenous wound healing response program. More broadly, our results support a model wherein mesenchymal-epithelial cooperation is a key driver of lung metastasis. Osteosarcoma, a pediatric mesenchymal tumor, undergoes lung epithelial induced fibrotic activation while also transforming normal lung epithelial cells towards a fibrosis promoting phenotype. Conversely, adult epithelial carcinomas activate fibrotic signaling in normal lung mesenchymal fibroblasts. Our data implicates fibrosis and abnormal wound healing as key drivers of lung metastasis across multiple tumor types that can be targeted therapeutically to disrupt metastasis progression.

Host-derived growth factors drive ERK phosphorylation and MCL1 expression to promote osteosarcoma cell survival during metastatic lung colonization.

PURPOSE: For patients with osteosarcoma, disease-related mortality most often results from lung metastasis-a phenomenon shared with many solid tumors. While established metastatic lesions behave aggressively, very few of the tumor cells that reach the lung will survive. By identifying mechanisms that facilitate survival of disseminated tumor cells, we can develop therapeutic strategies that prevent and treat metastasis. METHODS: We analyzed single cell RNA-sequencing (scRNAseq) data from murine metastasis-bearing lungs to interrogate changes in both host and tumor cells during colonization. We used these data to elucidate pathways that become activated in cells that survive dissemination and identify candidate host-derived signals that drive activation. We validated these findings through live cell reporter systems, immunocytochemistry, and fluorescent immunohistochemistry. We then validated the functional relevance of key candidates using pharmacologic inhibition in models of metastatic osteosarcoma. RESULTS: Expression patterns suggest that the MAPK pathway is significantly elevated in early and established metastases. MAPK activity correlates with expression of anti-apoptotic genes, especially MCL1. Niche cells produce growth factors that increase ERK phosphorylation and MCL1 expression in tumor cells. Both early and established metastases are vulnerable to MCL1 inhibition, but not MEK inhibition in vivo. Combining MCL1 inhibition with chemotherapy both prevented colonization and eliminated established metastases in murine models of osteosarcoma. CONCLUSION: Niche-derived growth factors drive MAPK activity and MCL1 expression in osteosarcoma, promoting metastatic colonization. Although later metastases produce less MCL1, they remain dependent on it. MCL1 is a promising target for clinical trials in both human and canine patients.

Evaluating potential predictors of weight loss response to liraglutide in adolescents with obesity: A post hoc analysis of the randomized, placebo-controlled SCALE Teens trial.

BACKGROUND: As childhood obesity prevalence increases, determining which patients respond to anti-obesity medications would strengthen personalized approaches to obesity treatment. In the SCALE Teens trial among pubertal adolescents with obesity (NCT02918279), liraglutide 3.0 mg (or maximum tolerated dose) significantly reduced body mass index (BMI) standard deviation score on average versus placebo. That said, liraglutide effects on BMI reduction varied greatly among adolescents, similar to adults. OBJECTIVES: To identify post hoc characteristics predictive of achieving ≥5% and ≥10% BMI reductions at 56 weeks with liraglutide versus placebo in adolescents from the SCALE Teens trial. METHODS: Logistic regression analysis was performed in 251 adolescents treated with liraglutide (n = 125) or placebo (n = 126) for 56 weeks. Baseline characteristics (selected a priori) included sex, race, ethnicity, age, Tanner (pubertal) stage, glycemic status (hyperglycemia [type 2 diabetes/prediabetes] vs. normoglycemia), obesity category (Class II/III vs. I), severity of depression symptoms (Patient Health Questionnaire-9), and weight variability (weight fluctuations over time). The effects of early responder status (≥4% BMI reduction at week 16) on week 56 response were assessed using descriptive statistics. RESULTS: Baseline characteristics did not affect achievement of ≥5% and ≥10% BMI reductions at week 56 in adolescents treated with liraglutide. Further, there was no association between weight variability and BMI reduction. Early liraglutide responders appeared to have greater BMI and body weight reductions at week 56 compared with early non-responders. CONCLUSIONS: This secondary analysis suggests that adolescents with obesity may experience significant BMI reductions after 56 weeks of liraglutide treatment, regardless of their sex, race, ethnicity, age, pubertal stage, glycemic status, obesity category, severity of depression symptoms, or weight variability. Early response may predict greater week 56 response.

Osteosarcoma tumors maintain intra-tumoral transcriptional heterogeneity during bone and lung colonization.

BACKGROUND: Tumors are complex tissues containing collections of phenotypically diverse malignant and nonmalignant cells. We know little of the mechanisms that govern heterogeneity of tumor cells nor of the role heterogeneity plays in overcoming stresses, such as adaptation to different microenvironments. Osteosarcoma is an ideal model for studying these mechanisms-it exhibits widespread inter- and intra-tumoral heterogeneity, predictable patterns of metastasis, and a lack of clear targetable driver mutations. Understanding the processes that facilitate adaptation to primary and metastatic microenvironments could inform the development of therapeutic targeting strategies. RESULTS: We investigated single-cell RNA-sequencing profiles of 47,977 cells obtained from cell line and patient-derived xenograft models as cells adapted to growth within primary bone and metastatic lung environments. Tumor cells maintained phenotypic heterogeneity as they responded to the selective pressures imposed during bone and lung colonization. Heterogenous subsets of cells defined by distinct transcriptional profiles were maintained within bone- and lung-colonizing tumors, despite high-level selection. One prominent heterogenous feature involving glucose metabolism was clearly validated using immunofluorescence staining. Finally, using concurrent lineage tracing and single-cell transcriptomics, we found that lung colonization enriches for multiple clones with distinct transcriptional profiles that are preserved across cellular generations. CONCLUSIONS: Response to environmental stressors occurs through complex and dynamic phenotypic adaptations. Heterogeneity is maintained, even in conditions that enforce clonal selection. These findings likely reflect the influences of developmental processes promoting diversification of tumor cell subpopulations, which are retained, even in the face of selective pressures.

Structurally Complex Osteosarcoma Genomes Exhibit Limited Heterogeneity within Individual Tumors and across Evolutionary Time.

Osteosarcoma is an aggressive malignancy characterized by high genomic complexity. Identification of few recurrent mutations in protein coding genes suggests that somatic copy-number aberrations (SCNA) are the genetic drivers of disease. Models around genomic instability conflict-it is unclear whether osteosarcomas result from pervasive ongoing clonal evolution with continuous optimization of the fitness landscape or an early catastrophic event followed by stable maintenance of an abnormal genome. We address this question by investigating SCNAs in >12,000 tumor cells obtained from human osteosarcomas using single-cell DNA sequencing, with a degree of precision and accuracy not possible when inferring single-cell states using bulk sequencing. Using the CHISEL algorithm, we inferred allele- and haplotype-specific SCNAs from this whole-genome single-cell DNA sequencing data. Surprisingly, despite extensive structural complexity, these tumors exhibit a high degree of cell-cell homogeneity with little subclonal diversification. Longitudinal analysis of patient samples obtained at distant therapeutic timepoints (diagnosis, relapse) demonstrated remarkable conservation of SCNA profiles over tumor evolution. Phylogenetic analysis suggests that the majority of SCNAs were acquired early in the oncogenic process, with relatively few structure-altering events arising in response to therapy or during adaptation to growth in metastatic tissues. These data further support the emerging hypothesis that early catastrophic events, rather than sustained genomic instability, give rise to structural complexity, which is then preserved over long periods of tumor developmental time. Significance: Chromosomally complex tumors are often described as genomically unstable. However, determining whether complexity arises from remote time-limited events that give rise to structural alterations or a progressive accumulation of structural events in persistently unstable tumors has implications for diagnosis, biomarker assessment, mechanisms of treatment resistance, and represents a conceptual advance in our understanding of intratumoral heterogeneity and tumor evolution.

Opinions from the experts: Experiences of adolescents with severe obesity participating in meal replacement therapy.

BACKGROUND: Meal replacement therapy (MRT) is a structured treatment that is effective for short-term weight reduction in adolescents with severe obesity. However, like other interventions, MRT response is variable. OBJECTIVE: The goal of the current study was to characterize the experience of adolescents with severe obesity participating in MRT. METHODS: Seventeen adolescents with severe obesity participated in semi-structured, individual interviews about their experience participating in MRT. The authors used a biopsychosocial model as the theoretical framework and data was analysed using Interpretive Phenomenological Analysis. A biopsychosocial model views an individual's health as a blend of biological characteristics, behavioural factors, and social conditions. RESULTS: Results showed that adolescents with severe obesity described three biopsychosocial factors that were central to their experience with MRT: (1) scheduling and planning, (2) social support and pressure, and (3) intrapersonal factors. Specifically, adolescents with severe obesity identified that planning ahead, social support, and intrapersonal changes (e.g. self-confidence) can promote engagement in MRT. On the other hand, unplanned schedule changes, social pressures, and different intrapersonal factors (e.g., taste preference) can make engagement challenging. CONCLUSIONS: Adolescents provided information on factors that supported or hindered their engagement in MRT, and themes were consistent with prior literature on health behaviour change. Overall, adolescents would recommend MRT to other teenagers who carry extra weight. Future research can use the rich information provided by adolescents with severe obesity to enhance and individualize treatment options.

Lurbinectedin Inhibits the EWS-WT1 Transcription Factor in Desmoplastic Small Round Cell Tumor.

Desmoplastic small round cell tumor (DSRCT) is a rare pediatric sarcoma with poor overall survival. This tumor is absolutely dependent on the continued expression and activity of its defining molecular lesion, the EWS-WT1 transcription factor. Unfortunately, the therapeutic targeting of transcription factors is challenging, and there is a critical need to identify compounds that inhibit EWS-WT1. Here we show that the compound lurbinectedin inhibits EWS-WT1 by redistributing the protein within the nucleus to the nucleolus. This nucleolar redistribution interferes with the activity of EWS-WT1 to reverse the expression of over 70% of the transcriptome. In addition, the compound blocks the expression of the EWS-WT1 fusion protein to inhibit cell proliferation at the lowest GI50 ever reported for this compound in any cell type. The effects occur at concentrations that are easily achievable in the clinic and translate to the in vivo setting to cause tumor regressions in multiple mice in a xenograft and PDX model of DSRCT. Importantly, this mechanism of nucleolar redistribution is also seen with wild-type EWSR1 and the related fusion protein EWS-FLI1. This provides evidence for a "class effect" for the more than 18 tumors driven by EWSR1 fusion proteins. More importantly, the data establish lurbinectedin as a promising clinical candidate for DSRCT.

Exenatide for weight-loss maintenance in adolescents with severe obesity: A randomized, placebo-controlled trial.

OBJECTIVE: This study sought to evaluate the effect of 52 weeks of exenatide extended release (XR) on the maintenance of meal replacement therapy (MRT)-induced BMI reduction in adolescents with severe obesity. METHODS: In this randomized, double-blind, placebo-controlled trial, 100 participants aged 12 to 18 years with BMI ≥ 1.2 × 95th percentile were enrolled in a short-term MRT run-in phase. Those who achieved ≥5% BMI reduction during the run-in were then randomized to 52 weeks of exenatide XR 2.0 mg or placebo weekly. Both groups also received lifestyle therapy. The prespecified primary end point was mean percent change in BMI from randomization (post run-in) to 52 weeks in the intention-to-treat population. RESULTS: A total of 100 participants were enrolled, and 66 (mean age 16 = [SD 1.5] years; 47% female) achieved ≥5% BMI reduction with MRT and were randomized (33 to exenatide XR and 33 to placebo). From randomization (post run-in) to 52 weeks, mean BMI increased 4.6% and 10.1% in the exenatide XR and placebo groups, respectively. The placebo-subtracted exenatide XR treatment effect was -4.1% (95% CI: -8.6% to 0.5%, p = 0.078). CONCLUSIONS: Although not achieving statistical significance, exenatide XR, compared with placebo, may partly mitigate the propensity toward BMI rebound in adolescents who achieved initial weight loss with dietary intervention.

BMI metrics and their association with adiposity, cardiometabolic risk factors, and biomarkers in children and adolescents.

BACKGROUND: There are limited data comparing the relative associations of various BMI metrics with adiposity and cardiometabolic risk factors in youth. OBJECTIVE: Examine correlations of 7 different BMI metrics with adiposity, cardiometabolic risk factors, and biomarkers (i.e. blood pressure, waist circumference, cholesterol, leptin, insulin, high molecular weight adiponectin, high-sensitivity c-reactive protein (hsCRP)). METHODS: This was a cross-sectional analysis of youth in all BMI categories. BMI metrics: BMI z-score (BMIz), extended BMIz (ext.BMIz), BMI percentile (BMIp), percent of the BMI 95th percentile (%BMIp95), percent of the BMI median (%BMIp50), triponderal mass index (TMI), and BMI (BMI). Correlations between these BMI metrics and adiposity, visceral adiposity, cardiometabolic risk factors and biomarkers were summarized using Pearson's correlations. RESULTS: Data from 371 children and adolescents ages 8-21 years old were included in our analysis: 52% were female; 20.2% with Class I obesity, 20.5% with Class II, and 14.3% with Class III obesity. BMIp consistently demonstrated lower correlations with adiposity, risk factors, and biomarkers (r = 0.190-0.768) than other BMI metrics. The %BMIp95 and %BMIp50 were marginally more strongly correlated with measures of adiposity as compared to other BMI metrics. The ext.BMIz did not meaningfully outperform BMIz. CONCLUSION: Out of all the BMI metrics evaluated, %BMIp95 and %BMIp50 were the most strongly correlated with measures of adiposity. %BMIp95 has the benefit of being used currently to define obesity and severe obesity in both clinical and research settings. BMIp consistently had the lowest correlations. Future research should evaluate the longitudinal stability of various BMI metrics and their relative associations with medium to long-term changes in adiposity and cardiometabolic outcomes in the context of intervention trials.

Predictive Value of Developmental Assessment in a Neonatal Intensive Care Unit (NICU) Follow-Up Clinic.

OBJECTIVE: Neonatal Intensive Care Unit (NICU) Follow-Up programs vary in the duration for which they monitor child development and neurocognitive outcomes. This study explores the early predictive value of a widely used developmental measure for intellectual functioning during early childhood to better inform whether there is value added in continued monitoring. METHODS: Participants were 209 children who had at least two assessments between the ages of 1 and 6 years old as part of NICU Follow-Up clinic. The Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) was administered when children were 1 and 2 years old and the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) was administered when children were 3 years and older. RESULTS: The Bayley-III at 1 year of age was a significant predictor of Bayley-III performance at age 2. Similarly, Bayley-III at ages 1 year and 2 years were significant predictors of WPPSI-IV performance. Strength of prediction was moderate with the majority of variance unexplained. Exploratory analyses examining whether early developmental abilities as assessed on the Bayley-III could identify patients at risk for poorer WPPSI-IV performance indicated appropriate specificity but inadequate sensitivity. CONCLUSIONS: This study supports ongoing assessment of children who were born with perinatal complications into at least early childhood. Assessing development only during the infant and toddler years did not sufficiently identify children who went on to have lower cognitive functioning in preschool and the early school years.

Contribution of Hedonic Hunger and Binge Eating to Childhood Obesity.

Background: Studies examining the association between hedonic hunger, that is, having frequent thoughts about food in the absence of an energy deficit, and obesity in youth show mixed results. This may be due to the confounding effect of binge eating, which has been associated with both hedonic hunger and obesity. The purpose of this study was to determine the extent to which hedonic hunger is associated with obesity independent of binge eating in youth. Methods: Data for this cross-sectional study were collected from youth enrolled in a larger study of cardiovascular disease and obesity. Linear regression models were used to assess the association between hedonic hunger measured by Power of Food Scale (PFS) and binge eating measured by Eating Disorder Examination-Questionnaire, on percent of the 95th BMI percentile (BMIp95). Results: Among 269 participants (mean age 12.8 years), 16.4% endorsed binge eating. PFS was positively associated with BMIp95 with a difference in percent of BMIp95 of 5.9% [95% confidence interval (1.5-10.3), p = 0.009]. However, when binge eating was added to the model, the relationship between PFS and BMIp95 was no longer significant. Conclusion: Hedonic hunger, above and beyond binge eating, may not be associated with BMI. Future research should examine whether screening for and targeting binge eating rather than hedonic hunger in weight management care may have more impact on obesity outcomes. Clinical Trial Registration number: NCT01508598.

Validity of the Adult Eating Behavior Questionnaire for adolescents treated in a weight management clinic.

BACKGROUND: The Child and Adult Eating Behavior Questionnaires (CEBQ, AEBQ) are established measures of eating behaviors. However, no similar measure is available for adolescents. Prior research has validated the AEBQ in adult samples, and one study has explored using the measure with adolescents. However, no studies to date have examined the validity of the AEBQ in adolescent clinical populations. Furthermore, no studies have examined associations between the AEBQ and indicators of health status in adolescents. METHODS: A total of 280 adolescents (12-17 years old, 60% female) seen in a pediatric weight management clinic completed the AEBQ at intake. Confirmatory factor analysis (CFA) was conducted with AEBQ items to evaluate the model fit of one-, two-, seven-, and eight-factor structures. Intercorrelations between scale scores from AEBQ Food Approach and Food Avoidance domains were calculated. Associations of AEBQ scales with body mass index (BMI) and binge-eating behaviors were examined using Spearman Rho correlations and independent t-tests. RESULTS: CFAs revealed that the best fitting model was a seven-factor structure excluding the Hunger scale, although overall model fit was only marginally acceptable (X2 = 980.94, CFI = 0.925, TLI = 0.915, RMSEA = 0.074). Intercorrelation analyses indicated that all Food Approach scales were significantly associated with one another (r = 0.243-0.654); Food Avoidance scales were inconsistently correlated (r = 0.034-0.439). No AEBQ scales were correlated with BMI (r = -0.101-0.082). Stronger links were found with binge eating; higher frequency binge-related behaviors were associated with higher Food Approach scores. CONCLUSIONS: The seven-factor structure of AEBQ demonstrates a marginally acceptable fit for treatment-seeking adolescents with obesity. The Food Approach scales demonstrated more convergent validity than the Food Avoidance scales. The Food Approach scales also exhibited some clinical utility for identifying patients with increased risk for binge eating, which is a common target for behavioral intervention. Implications for maximizing the AEBQ's potential for assessing eating behaviors in adolescents with obesity are discussed.

The Effects of Anti-obesity Pharmacotherapy Interventions on Psychosocial Factors Among Adolescents with Obesity: a Scoping Review.

PURPOSE OF REVIEW: The purpose of this review was to investigate and synthesize psychosocial outcomes from pharmacotherapy experimental trials for weight loss among adolescents with obesity. RECENT FINDINGS: There is a paucity of research regarding pharmacological interventions for adolescents with obesity. These studies have typically reported reductions in weight, and side effects have been inconsistently described. Overall, medication seems to be a safe and effective obesity treatment modality for adolescents with obesity. Six articles were included in this review. Studies varied in medication type, medication dosing, lifestyle components, psychosocial measures, measurement intervals, and psychosocial outcomes. All studies found a reduction in weight and/or BMI. Studies were often underpowered to detect differences in psychosocial variables, which were always considered secondary or exploratory outcomes. Future research should include psychosocial outcomes as a primary endpoint of pharmacological interventions for adolescent obesity. Ultimately, the treatment of the complex disease of obesity deserves to be assessed through multiple health domains extending beyond weight reduction.

Clinical Assessment and Treatment of Early-Onset Severe Obesity.

PURPOSE OF REVIEW: This review describes clinical management of early-onset severe obesity, defined here as severe obesity in children ≤ 5 years old. It summarizes current information regarding (1) assessment, specifically growth, genetics, cardiometabolic risk, health behaviors, developmental considerations, and psychosocial factors, and (2) treatment, focusing on lifestyle modification including parent training and a brief summary of pharmacotherapy. RECENT FINDINGS: Prevalence of severe obesity in young children has remained stable yet most of these children will become adults with obesity. Interventions that address multiple health domains, such as eating habits, physical activity, and parenting skills, are necessary for addressing early-onset severe obesity. Research into pharmacotherapy remains limited but may provide future strategies for management. Early-onset severe obesity significantly influences children's long-term health and management should focus on intervention to promote BMI reduction. Further research into effective strategies is necessary to address the needs of this high-risk population.

Associations between paediatric fatigue and eating behaviours.

BACKGROUND: In adults, poor sleep quality is associated with increased obesogenic eating behaviours; less is known about this relationship in youth. The objectives of this study were to assess the strength of association between fatigue-related quality of life (QoL) and eating behaviours among youth and to describe the associations in participants with percent body fat (%BF) above and below the 90th percentile for sex and age. METHODS: Caregiver-reported measures of fatigue (Pediatric QoL Multidimensional Fatigue Scale) and eating behaviours (Child Eating Behaviour Questionnaire) were obtained from participants aged 8-17 years. %BF was measured by iDXA and grouped by sex- and age-specific percentiles. Multiple linear regression adjusting for age, sex and race/ethnicity was used. RESULTS: Of the 352 participants (49% male), 44.6% had %BF >90th percentile. General, sleep/rest and cognitive fatigue QoL was inversely associated with food approach behaviours: food responsiveness, enjoyment of food, emotional overeating and desire to drink. For participants with %BF >90th percentile, higher general fatigue QoL was associated with higher satiety responsiveness (0.13; 95% confidence interval [CI 0.03, 0.24]). For participants with %BF ≤90th percentile, higher general fatigue QoL was associated with less satiety responsiveness (-0.16; 95% CI [-0.31, -0.01]). CONCLUSION: Less fatigue symptoms were associated with less behaviours associated with food approach among paediatric participants. For participants with %BF >90th percentile, less symptoms of general fatigues corresponded with more satiety. Though causation has yet to be established, youth with elevated %BF should be screened for fatigue symptoms and offered counselling on sleep hygiene or a sleep medicine referral to help mitigate weight gain.