Clinical Cutoff Research Articles

Assessing Avoidant/Restrictive Food Intake Disorder (ARFID) Symptoms Using the Nine Item ARFID Screen in >9000 Swedish Adults With and Without Eating Disorders.

The Nine Item ARFID Scale (NIAS) is a widely used measure assessing symptoms of avoidant/restrictive food intake disorder (ARFID). Previous studies suggest that individuals with eating disorders driven by shape/weight concerns also have elevated scores on the NIAS. To further describe NIAS scores among individuals with diverse current and previous eating disorders, we characterized NIAS scores in a large sample of individuals with eating disorders and evaluated overlap in symptoms measured by the NIAS and the Eating Disorder Examination-Questionnaire (EDE-Q) version 6.0. Our sample comprised 9148 participants from the Eating Disorders Genetics Initiative Sweden (EDGI-SE), who completed surveys including NIAS and EDE-Q. NIAS scores were calculated and compared by eating disorder diagnostic group using descriptive statistics and linear models. Participants with current anorexia nervosa demonstrated the highest mean NIAS scores and had the greatest proportion (57.0%) of individuals scoring above a clinical cutoff on at least one of the NIAS subscales. Individuals with bulimia nervosa, binge-eating disorder, and other specified feeding or eating disorder also demonstrated elevated NIAS scores compared to individuals with no lifetime history of an eating disorder (ps < 0.05). All subscales of the NIAS showed small to moderate correlations with all subscales of the EDE-Q (rs = 0.26-0.40). Our results substantiate that individuals with eating disorders other than ARFID demonstrate elevated scores on the NIAS, suggesting that this tool is inadequate on its own for differentiating ARFID from shape/weight-motivated eating disorders. Further research is needed to inform clinical interventions addressing the co-occurrence of ARFID-related drivers and shape/weight-related motivation for dietary restriction.

Silent Struggles: Traumatic Brain Injuries and Mental Health in Law Enforcement.

To determine the prevalence of head injuries (HIs), posttraumatic stress disorder (PTSD), and depressive symptoms in law enforcement officers (LEOs) and (2) the association between HIs and psychological health conditions. County-level survey administered via Research Electronic Data Capture. A total of 381 LEOs completed the survey (age=43±11years; 40 [11%] females; time as LEO=1-50years, median=15years). Cross-sectional study. We examined the prevalence of HIs (the Ohio State University Traumatic Brain Injury Identification Method), PTSD (PTSD Checklist-Civilian [PCL-C]), and depressive symptoms (Patient Health Questionnaire-9 [PHQ-9]). We used Mann-Whitney U and chi-square analyses to compare PTSD and depressive symptoms between those with and without a HI history. There were 282 (74%) participants who reported a lifetime history of 1 or more HIs; 116 (30%) sustained 1 or more HIs on the job. PCL-C scores ranged 17 to 85 (median=27); 33 (10%) participants met or exceeded the clinical cutoff score of 50 to indicate a positive PTSD screening. Participants with a HI history (median=29) had higher PCL-C scores than those with no HI history (median=24; P <.001), but the proportion of participants who met the clinical cutoff for PTSD was not different between those with (n =28, 11%) and without (n =5, 5%) a HI history (X2=2.52, P =.112, odds ratio=2.18; 95% confidence interval, 0.82-5.83). PHQ-9 scores ranged 0 to 20 (median=3); 124 (36%) participants reported mild or greater depressive symptoms. Participants with a HI history (median=3) had higher depressive symptoms than those with no HI history (median=2; P =.012). The proportion of participants with mild or greater depressive symptoms was higher among those with a HI history (n =99, 39%) than without (n =25, 27%; X2=4.34, odds ratio=1.74; 95% confidence interval, 1.03-2.93). HIs are prevalent in LEOs, which may have consequences for their performance, well-being, and career longevity. PTSD and depressive symptoms are higher in those with a HI history, suggesting LEOs need better traumatic brain injuries and mental health resources.

Trait-based Anxiety Symptoms are Associated with Higher Incidence of Nightmare Frequency in the Wisconsin Sleep Cohort

ABSTRACT Objectives Nightmares affect up to 12% of the population and are often comorbid with psychiatric disorders like anxiety and depression. Limited research has examined their influence on nightmare frequency. This study investigates the relationship between depression and trait-anxiety symptoms on incident nightmare frequency at follow-up. Method Cross-sectional and longitudinal analyses were conducted on 758 Wisconsin Sleep Cohort participants. Trait anxiety and depression symptom severity were measured using the State Trait Anxiety Inventory and Zung Depression Scale. Ordinal regression determined nightmare frequency cutoffs based on anxiety and depression severity. Cross-sectional associations were assessed with Spearman and Kruskal–Wallis tests. Longitudinal associations were analyzed using adjusted binomial regression of binary nightmare frequency (low: <4/month, high: >5/month) against clinical cutoffs of trait anxiety and depression. Results Adjusted models indicated a small correlation between baseline nightmare frequency and trait anxiety (β = 0.01, p = .010) and depression symptoms (β = 0.01, p = .005). High baseline trait-anxiety symptoms were associated with frequent nightmares at follow-up (OR = 3.75, CI95% [1.306,10.793], p < .014), but depression symptoms were not (OR = 1.35, CI95%[0.399, 4.587], p = .627). Conclusions Our findings suggest that high trait-anxiety symptoms are associated with increased incident nightmare frequency, when adjusted for depression. However, high depression symptoms were not associated with an increase in nightmare frequency when adjusted for trait-anxiety.

Defining the Functional Sensitivity for the Siemens Atellica Calcitonin Assay: Insight From a Single-Center Study

BackgroundDetectable, and especially rising postthyroidectomy serum calcitonin and carcinoembryonic antigen levels, as per American Thyroid Association guidelines, indicate potential disease presence, requiring frequent calcitonin measurement or imaging for early detection of persistent or recurrent medullary thyroid carcinoma. Thus, defining the clinical cutoff value of detection of calcitonin assays relative to imaging and clinical status is crucial for patient care. This study aimed to evaluate postoperative calcitonin levels using the new Siemens Atellica assay system to determine the most appropriate levels for clinical decision-making. MethodsA retrospective analysis was conducted using Siemens Atellica for calcitonin testing on 56 samples from 40 patients between September 27, 2022 and August 11, 2023. Only calcitonin results performed at least 3 months post-total thyroidectomy were included. Imaging studies, within 6 months of the calcitonin report, were assessed. Carcinoembryonic antigen results were also reviewed. ResultsPrecision analysis at 2.94 and 5.24 pg/mL revealed coefficients of variation at 16.49% and 8.87%, respectively. For the evidence of post-total thyroidectomy persistent or recurrent medullary thyroid carcinoma confirmed by imaging, using a 1.89 pg/mL cutoff for calcitonin yielded 43% sensitivity and 67% specificity. Using a 5.00 pg/mL cutoff resulted in 0% sensitivity and 100% specificity. ConclusionsOur findings indicate the potential suitability of a 5 pg/mL calcitonin cutoff on the Siemens Atellica platform for evaluating tumor persistence or recurrence in post-thyroidectomy patients in our institution. However, individual laboratories should establish their own clinical cutoff value when evaluating calcitonin levels for monitoring tumor recurrence post-thyroidectomy.

Sustained metabolic dysregulation and the emergence of diabetes: associations between HbA1c and metabolic syndrome components in Tunisian diabetic and nondiabetic groups

IntroductionMetabolic Syndrome (MetS), diabetes, and other noncommunicable diseases (NCDs) have been a major focus of research in recent decades as the prevalence of these conditions continues to rapidly increase globally. However, the timing and patterns of development from metabolic risk factors to disease states are less well understood and are especially critical to understand in low- and middle-income countries (LMICs) and populations undergoing epidemiological transitions.MethodsNationally representative sociodemographic, anthropometric, and point-of-care biomarker data from the 2016 Tunisian Health Examination Survey (n = 8170) were used to determine the prevalence of diabetes and MetS components in Tunisia and to investigate associations between glycated hemoglobin (HbA1c) and MetS components (blood pressure [BP], HDL cholesterol [HDL], triglycerides [TG], and waist circumference [WC]) in participants aged 15-97 years old. To better understand how sustained metabolic dysregulation and disease states impact these associations, diabetic and nondiabetic groups were analyzed separately.ResultsThe overall prevalence of diabetes based on measured HbA1c was 18.2%. The diabetic groups had a higher prevalence of each individual MetS component, and significantly higher (BP, TG, WC, and HbA1c) and lower (HDL) values than the nondiabetic groups. Yet, there were a higher number of significant associations between HbA1c and MetS components found in nondiabetic women and men when compared to diabetic women and men. HbA1c was positively associated with the cumulative number of MetS components, irrespective of diabetes status in men and women.ConclusionsThe prevalence of both diabetes and MetS components (particularly low HDL cholesterol and elevated TG) is high among the Tunisian population. More MetS components were associated with HbA1c in nondiabetic individuals, showing a strong connection between the development of MetS components and diabetes. However, once the diabetes disease state manifests, there is more variability in the relationships. These results show the potential for HbA1c to be an indicator of metabolic health below clinical disease cutoffs, which may allow insights into the physiological changes that precipitate the emergence of diabetes.

Internalized Phobia, Community Connectedness, Outness, and Mental Health Risk and Protection in LGBTQ Persons.

Community connectedness, outness, and internalized phobia are potential protective and risk factors for mental health in lesbian, gay, bisexual, transgender, and queer (LGBTQ) individuals. However, these interrelated factors have generally been examined in isolation and for the LGBTQ community in aggregate. As such, there may be undetected effects of factors on mental health for each LGBTQ group. We examined the associations between mental health (i.e., depression and anxiety) and risk/protective factors (i.e., internalized phobia, community connectedness, outness) in each LGBTQ subgroup separately. A large national U.S. sample (N = 1,030) of individuals who identified as LGBTQ completed an anonymous internet survey during fall 2019. Participants answered questionnaires about community connectedness, outness, internalized homophobia or transphobia, anxiety, and depression. On average, most subgroups reported symptoms of depression and anxiety above clinical cutoffs. Less outness and greater internalized phobia were associated with more severe depression and anxiety, but this pattern was not consistent across LGBTQ subgroups. Greater community connectedness was generally associated with more severe anxiety and depression. LGBTQ subgroups vary in how risk and protective factors relate to mental health outcomes. Our findings highlight the importance of examining LGBTQ subgroups separately and examining risk/protective factors simultaneously to identify the unique contribution of each factor. More research is needed to understand potential LGBTQ mental health risks and protective factors, and future researchers should examine the unique roles of risk and protective factors in separate LGBTQ subgroups.

Improved Scoring of the Center for Epidemiologic Studies Depression Scale – Revised: An Item Response Theory Analysis

The Center for Epidemiologic Studies Depression Scale – Revised (CESD-R) is a popular self-report screening measure for depression. A 20-item questionnaire with scores ranging from 0 to 4 for each item, the CESD-R can produce total scores ranging from 0 to 80. However, the typical scoring protocol for the CESD-R restricts the range of possible scores to between 0 and 60 to retain the same range and clinical cutoff scores as the original CES-D. Despite the widespread adoption of this scoring approach, the psychometric impact has never been systematically examined. In an undergraduate and community adult sample (n = 869), item response theory analyses indicated that scoring the CESD-R with all 5 response options (CESD-R5opt) provided nearly twice as much information about a person’s latent depression for individuals with high levels of depression than did scoring the CESD-R with 4 response options per item (CESD-R4opt). The CESD-R5opt retained the strong reliability and factor structure of the CESD-R4opt and was more sensitive to individual differences for participants at high levels of depression compared to the CESD-R4opt. Results provide preliminary evidence that researchers and clinicians should score the CESD-R using the full 0-to-80 scale and a clinical cutoff score of 29.

Teacher-Rated Mental Health of Siblings of Children with Chronic Disorders

AbstractSiblings of children with chronic disorders are at a heightened risk for internalizing and externalizing problems. Studies on sibling mental health typically use parent report, and sometimes sibling self-report, but do not include the perspectives of teachers. We investigated how teachers and parents in Norway rated sibling mental health to gain a more coherent picture of siblings’ well-being and functioning across the home and school contexts. We compared how siblings aged 8–16 years (45% boys, 54% girls) were scored on the strengths and difficulties questionnaire by teachers (n = 125), mothers (n = 115), and fathers (n = 81) with population norms and clinical cutoffs. For boys, the mean teacher scores did not indicate problems for total difficulties or any subscale except hyperactivity–inattention, but mean parent scores were higher for total difficulties and most subscales (d = .44 to .96). For girls, teachers indicated higher than norm scores for total difficulties, emotional problems, hyperactivity–inattention and peer problems (d = .26 to .46), while parents indicated higher total difficulties and problems across most subscales (d = .31 to .54). Prosocial behavior was as a relative strength of siblings across all raters. Siblings may not display the same level of mental health problems in school as at home, and teachers can offer an important perspective on siblings’ mental health and functioning.

Biomarkers for Prediction of Alcohol-Related Liver Cirrhosis: A General Population–Based Swedish Study of 537,250 Individuals

The study sought to examine which biomarkers have the best predictive capabilities for future alcohol-related liver cirrhosis (ARLC) in a general population setting. This population-based cohort study includes approximately 35% of the inhabitants of Stockholm County who had left a blood sample at an outpatient visit in primary care or occupational health screening from 1985 to 1996. All subjects with a blood sample measurement of alanine aminotransferase and aspartate aminotransferase (AST) were included, exclusions were made for persons with known liver disease. We ascertained incident ARLC by linkage to Swedish national health registers between to the end of 2011. Associations between biomarkers and incident ARLC were analyzed with Cox regression models and discrimination was assessed using C-statistics. In all, 537,230 adult subjects were included. The mean age was 45 years and 53% were men. During a mean follow-up of 19.0 years, 2725 (0.51%) subjects developed ARLC. The biomarkers with the highest discrimination (C-index) for incident ARLC at 5 years were: AST (0.89), mean corpuscular volume (0.88), and γ-glutamyltransferase (0.81). Scoring systems including Fibrosis-4 (0.86) and the AST/alanine aminotransferase ratio (0.81) performed similarly well. The negative predictive value for ARLC was generally high (∼99.6%) across biomarkers, using routine clinical cutoffs to identify pathological values. However, positive predictive values were generally low (0.6%-15.9%). Biomarkers commonly used in primary care settings are highly associated with incident ARLC in the general population. Elevation of these commonly available biomarkers should prompt consideration of further investigation of a possible high level of alcohol consumption.

Qualification of a 21-valent pneumococcal urine antigen detection assay and development of clinical positivity cutoffs.

Aim: Serotype-specific assays detecting pneumococcal polysaccharides in bodily fluids are needed to understand the pneumococcal serotype distribution in non-bacteremic pneumonia.Methods: We developed a urine antigen detection assay and using urine samples from adult outpatients without pneumonia developed positivity cutoffs for both a previously published 15-valent and the new 21-valent assay. Clinical sensitivity was confirmed with samples from patients with invasive pneumococcal disease.Results: Total assay precision ranged from 7.6 to 17.8% coefficient of variation while accuracy ranged between 80 and 150% recovery, except for three serotypes where recoveries ranged from 32 to 60%. Clinical sensitivity was 86.4% and specificity was 96.5% across all 30 serotypes.Conclusion: The assay could potentially assess serotype-distribution in non-infected and infected participants with pneumococcal disease.

Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial

CASSIOPEIA part 1 demonstrated superior depth of response and prolonged progression-free survival with daratumumab in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) alone as an induction and consolidation regimen in transplant-eligible patients newly diagnosed with myeloma. In CASSIOPEIA part 2, daratumumab maintenance significantly improved progression-free survival and increased minimal residual disease (MRD)-negativity rates versus observation. Here, we report long-term study outcomes of CASSIOPEIA. CASSIOPEIA was a two-part, open-label, phase 3 trial of patients done at 111 European academic and community-based centres. Eligible patients were aged 18-65 years with transplant-eligible newly diagnosed myeloma and an Eastern Cooperative Oncology Group performance status of 0-2. In part 1, patients were randomly assigned (1:1) to pre-transplant induction and post-transplant consolidation with D-VTd or VTd. Patients who completed consolidation and had a partial response or better were re-randomised (1:1) to intravenous daratumumab maintenance (16 mg/kg every 8 weeks) or observation for 2 years or less. An interactive web-based system was used for both randomisations, and randomisation was balanced using permuted blocks of four. Stratification factors for the first randomisation (induction and consolidation phase) were site affiliation, International Staging System disease stage, and cytogenetic risk status. Stratification factors for the second randomisation (maintenance phase) were induction treatment and depth of response in the induction and consolidation phase. The primary endpoint for the induction and consolidation phase was the proportion of patients who achieved a stringent complete response after consolidation; results for this endpoint remain unchanged from those reported previously. The primary endpoint for the maintenance phase was progression-free survival from second randomisation. Efficacy evaluations in the induction and consolidation phase were done on the intention-to-treat population, which included all patients who underwent first randomisation, and efficacy analyses in the maintenance phase were done in the maintenance-specific intention-to-treat population, which included all patients who were randomly assigned at the second randomisation. This analysis represents the final data cutoff at the end of the study. The trial is registered with ClinicalTrials.gov, NCT02541383. Between Sept 22, 2015 and Aug 1, 2017, 1085 patients were randomly assigned to D-VTd (n=543) or VTd (n=542); between May 30, 2016 and June 18, 2018, 886 were re-randomised to daratumumab maintenance (n=442) or observation (n=444). At the clinical cutoff date, Sept 1, 2023, median follow-up was 80·1 months (IQR 75·7-85·6) from first randomisation and 70·6 months (66·4-76·1) from second randomisation. Progression-free survival from second randomisation was significantly longer in the daratumumab maintenance group than the observation-alone group (median not reached [95% CI 79·9-not estimable (NE)] vs 45·8 months [41·8-49·6]; HR 0·49 [95% CI 0·40-0·59]; p<0·0001); benefit was observed with D-VTd with daratumumab maintenance versus D-VTd with observation (median not reached [74·6-NE] vs 72·1 months [52·8-NE]; 0·76 [0·58-1·00]; p=0·048) and VTd with daratumumab maintenance versus VTd with observation (median not reached [66·9-NE] vs 32·7 months [27·2-38·7]; 0·34 [0·26-0·44]; p<0·0001). The long-term follow-up results of CASSIOPEIA show that including daratumumab in both the induction and consolidation phase and the maintenance phase led to superior progression-free survival outcomes. Our results confirm D-VTd induction and consolidation as a standard of care, and support the option of subsequent daratumumab monotherapy maintenance, for transplant-eligible patients with newly diagnosed multiple myeloma. Intergroupe Francophone du Myélome, Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research & Development.

IMpower010: Final disease-free survival (DFS) and second overall survival (OS) interim results after ≥5 years of follow up of a phase III study of adjuvant atezolizumab vs best supportive care in resected stage IB-IIIA non-small cell lung cancer (NSCLC).

LBA8035 Background: IMpower010 (NCT02486718) met its primary endpoint of significant DFS improvement with atezo vs BSC after adj chemotherapy in resected NSCLC in the PD-L1 TC ≥1% and all-randomized stage II-IIIA populations, leading to worldwide approval of adj atezo for PD-L1 TC ≥1% or PD-L1 TC ≥50% stage II-IIIA NSCLC. At OS IA1, a trend favoring atezo was seen in the PD-L1 TC ≥1% stage II-IIIA population. Here we report findings from the DFS FA and OS IA2. Methods: The IMpower010 study design has been previously described (Felip et al, Lancet 2021). The primary DFS and secondary OS endpoints were tested hierarchically: DFS in the PD-L1 TC ≥1% (SP263) stage II-IIIA, then in the all-randomized stage II-IIIA, and then in the intent-to-treat (ITT; stage IB-IIIA) populations, followed by OS in the ITT population. Secondary endpoints included 3- and 5-y DFS and DFS in the PD-L1 TC ≥50% (SP263) stage II-IIIA population. OS in the ITT population could only be formally tested if the significance boundary for DFS in that population was crossed. Results: At the DFS FA and OS IA2 (clinical cutoff date: Jan 26, 2024), with a minimum follow-up of 60 mo, DFS and OS for the PD-L1 TC ≥1% and TC ≥50% stage II-IIIA populations were consistent with previously observed benefit; the difference in median (m) DFS between arms in the PD-L1 TC ≥1% population was 31.2 mo (Table). In the ITT population, the significance boundary for DFS was not crossed and OS was similar between arms, although data were immature. The safety profile of atezo was consistent with prior analyses. Conclusions: These results provide the first cancer immunotherapy data with ≥5 y of follow-up from a Phase III study in resectable NSCLC. Although the statistical boundary for the ITT population was not crossed, DFS benefit with adj atezo continues to translate into a positive OS trend vs BSC in the PD-L1 TC ≥1% and TC ≥50% stage II-IIIA populations. These results further support the use of adj atezo in PD-L1–selected populations. Clinical trial information: NCT02486718 . [Table: see text]

First Psychometric Evaluation of the English Version of the Semi-Structured Interview for Personality Functioning (STiP-5.1)

The Alternative Model for Personality Disorders provides a dimensional framework for the conceptualization of personality disorders where Criterion A concerns the assessment of one’s level of personality functioning (LPF). This study examines the psychometric properties of the English translation of the Semi-Structured Interview for Personality Functioning (STiP-5.1) to validate this translation for the assessment of LPF in English-speaking populations; and examine whether this measure increments self-report measures of LPF and personality pathology in predicting general functioning. The sample consisted of 129 emerging adults between 18 and 25 years of age (M = 20.54, SD = 2.08) from a mixed college and clinical sample. Results support a unidimensional factor structure of the STiP-5.1, good internal consistency, and high inter-rater reliability. Construct validity was supported through associations of the STiP-5.1 with self-report measures of LPF and personality pathology. The STiP-5.1 incremented self-report measures of personality pathology in predicting functional impairment, though additional variance explained was modest. Finally, STiP-5.1 scores differentiated individuals who obtained a score at or above the clinical cutoff from those below on self-report measures of personality pathology and LPF with large effect sizes. Findings support the validity of the English translation of the STiP-5.1 for the assessment of LPF.

The Effects of Breastfeeding on Childhood Behavioral and Emotional Development: A Prospective Cohort Study in China.

Breastfeeding could improve a child's health early on, but its long-term effects on childhood behavioral and emotional development remain inconclusive. We aimed to estimate the associations of feeding practice with childhood behavioral and emotional development. In this population-based birth cohort study, data on feeding patterns for the first 6 mo of life, the duration of breastfeeding, and children's emotional and behavioral outcomes were prospectively collected from 2489 mother-child dyads. Feeding patterns for the first 6 mo included exclusive breastfeeding (EBF) and non-exclusive breastfeeding (non-EBF, including mixed feeding or formula feeding), and the duration of breastfeeding (EBF or mixed feeding) was categorized into ≤6 mo, 7-12 mo, 13-18 mo, and >18 mo. Externalizing problems and internalizing problems were assessed with the Child Behavior Checklist (CBCL) and operationalized according to recommended clinical cutoffs, corresponding to T scores ≥64. Multivariable linear regression and logistic regression were used to evaluate the association of feeding practice with CBCL outcomes. The median (interquartile range) age of children at the outcome measurement was 32.0 (17.0) mo. Compared with non-EBF for the first 6 mo, EBF was associated with a lower T score of internalizing problems [adjusted mean difference (aMD): -1.31; 95% confidence interval (95% CI): -2.53, -0.10], and it was marginally associated with T scores of externalizing problems (aMD: -0.88; 95% CI: -1.92, 0.15). When dichotomized, EBF versus non-EBF was associated with a lower risk of externalizing problems (aOR: 0.54, 95% CI: 0.34, 0.87), and it was marginally associated with internalizing problems (aOR: 0.75, 95% CI: 0.54, 1.06). Regarding the duration of breastfeeding, breastfeeding for 13-18 mo versus ≤6 mo was associated with lower T scores of internalizing problems (aMD: -2.50; 95% CI: -4.43, -0.56) and externalizing problems (aMD: -2.75; 95% CI: -4.40, -1.10), and breastfeeding for >18 mo versus ≤6 mo was associated with lower T scores of externalizing problems (aMD: -1.88; 95% CI: -3.68, -0.08). When dichotomized, breastfeeding for periods of 7-12 mo, 13-18 mo, and >18 mo was associated with lower risks of externalizing problems [aOR (95% CI): 0.96 (0.92, 0.99), 0.94 (0.91, 0.98), 0.96 (0.92, 0.99), respectively]. Exclusive breastfeeding for the first 6 mo and a longer duration of breastfeeding, exclusively or partially, are beneficial for childhood behavioral and emotional development.

Multicenter study evaluating the utility of AI-aided HER2 scoring in the clinically relevant categories.

e15150 Background: The availability of multiple therapeutic options for breast cancer patients with varying levels of protein expression necessitates precise and standardized HER2 scoring. This study explored the clinical utility of AI-aided HER2 scoring of whole-slide digital images by pathologists in breast core needle biopsies and excisions. Methods: The study included patients (n=764) with multiple subtypes of invasive breast cancer from 3 US reference laboratories and 1 academic medical center. The non-interventional two-arm multi-reader study retrospectively compared manual digital vs. AI-aided HER2 scoring of 8 pathologists. The fully automated HER2 AI solution detects the invasive tumor area and then classifies the tumor cells based on staining pattern based and the 2023 ASCO/CAP guidelines to output slide-level HER2 score. Both study arms were compared to reference ground truth (GT) established by the consensus of two breast subspecialists, ground truthers (GTer), who reviewed the slides digitally. One site recorded the time taken for HER2 scoring of both arms to determine the efficacy of the HER2 AI solution. Results: The initial interobserver agreement among expert GT pathologists for each HER2 score, 0, 1+, 2+, 3+, were 83%, 63.8%, 46%, and 92.6, respectively. At the clinically meaningful cut-offs, the reader pathologists’ performance improved with the AI support. At the 0 vs. 1+/2+/3+ and 0/1+ vs 2+/3+ clinical cutoffs, the readers' accuracy was 86.3% vs 88.6% and 93.7%, 93.8% with and without AI support, respectively. The AI use contributed to approximately 12%-time savings for the readers at the medical center. The AI solution demonstrated high accuracy for HER2 scoring, with 89.2% agreement with GT for 0 vs 1+/2+/3+ scores and 93.1% for 0/1+ vs 2+/3+ cutoff. The results will be updated in the final submission with the additional site data. The reader feedback survey regarding the solution’s usability will also be presented. Conclusions: The pathologists demonstrated improvements in consistency, evidenced by inter-reader agreement and accuracy with the aid of the AI. The AI solution can improve efficiency toward accurate HER2 scoring. [Table: see text]

Clinic-Based Characterization of Adolescents and Young Adults With Migraine: Psychological Functioning, Headache Days, and Disability.

This cross-sectional observational study retrospectively examined clinical data collected from adolescents and young adults (AYAs) seeking care in a specialty headache clinic. We characterized participants' headache characteristics and psychological functioning and examined the association between self-reported anxiety and depressive symptoms and headache frequency, severity, and disability. During their clinic visit, AYAs (M age = 18.36; range = 14-32, 79.5% female) completed an intake questionnaire and reported about their headache characteristics (i.e., frequency, severity, and duration of symptoms in months), mental health history (i.e., previous diagnosis of an anxiety or depressive disorder), and utilization of emergency department (ED) services for migraine. AYAs also completed psychometrically validated screening tools for anxiety and depressive symptoms (i.e., the GAD-7 and PHQ-9). We computed descriptive statistics and examined associations among scores on psychological measures and headache characteristics, including migraine-related disability. We also tested whether individuals with clinically elevated GAD-7 and PHQ-9 scores had higher levels of disability relative to those with fewer/subclinical levels of anxiety and depressive symptoms. Participants (N = 283) reported more than 19 headache days per month on average, with more than 90% describing their average headache intensity as moderate or severe. Nearly half of AYAs reported severe headache-related disability. Approximately one-quarter of AYAs reported a previous diagnosis anxiety or depressive disorder diagnosis, and more than one-third scored above clinical cutoffs on the PHQ-9 and GAD-7. Higher scores on both psychological screening instruments were associated with greater headache frequency. More than 10% of patients endorsed current suicidal ideation; this was not related to headache-related disability. Participants reported a high degree of ED utilization for headache; these rates were unrelated to endorsement of psychological comorbidities. In this sample of AYAs, headache characteristics were generally unrelated to scores on measures on psychological functioning. However, the observed rates of clinically elevated anxiety/depressive symptoms and suicidality in this sample of AYAs underscore the importance of screening for psychological comorbidities in neurology clinics that serve this age group, irrespective of self-reported disability. Results also emphasize the need to expand access to behavioral health services for AYAs with headache disorders and the importance of incorporating a biopsychosocial perspective to the transition of health care from pediatrics to adult neurology practice.

Evaluation of VAL-083 in GBM AGILE, a phase 3 registration platform trial for newly diagnosed and recurrent glioblastoma.

2005 Background: GBM AGILE (NCT03970447) is a phase 2/3 Bayesian adaptive registration platform trial testing multiple therapies efficiently against a common control (C) with a primary endpoint of overall survival (OS). VAL-083 (VAL) is a DNA targeting agent that, independent of O6-methylguanine DNA methyltransferase promoter methylation status, targets the N7 position of guanine residues and facilitates inter-strand DNA crosslinks, leading to DNA double-strand breaks and cell death. It entered the trial in January 2021, and it is the 2nd arm (of 6) to complete its evaluation. Methods: Patient subtypes considered in GBM AGILE are newly diagnosed methylated (NDM), ND unmethylated (NDU), &amp; recurrent disease (RD). C is temozolomide (in ND) &amp; lomustine (in RD). Arms open to all 3 subtypes are evaluated in 5 prospectively defined signatures (sig): NDU, NDM, RD, all ND and All. Randomization to C is 20% in each subtype. Exp arms in GBM AGILE have 1 or 2 stages. Efficacy is based on OS hazard ratio (HR) of arm/C. Efficacy goal is a final Bayesian probability ≥ 98% for HR &lt;1.00 in combined Stages 1 &amp; 2. Arms stop accruing in Stage 1 if they reach max sample size (N) or drop for futility or safety. Exp arms in Stage 1 are adaptively randomized with allocation being proportional to an arm’s current probability of having ≥ 30% benefit in OS, P(HR &lt;0.70). In stage 1, exp arms are evaluated monthly, and arms showing Bayesian predictive power (PP) ≥ 0.8, graduate into Stage 2 with fixed randomization in one sig. For all exp arms, follow up continues for 12 mos after accrual stops (clinical cutoff). Arms are declared futile at any monthly analysis when PP is &lt;0.25 for all sigs. Open to all 3 subtypes, VAL entered as the 1st arm in NDM and was randomized 1:1 to C in this subtype until additional arms entered. The target max N for VAL in its Stages 1 &amp; 2 were 150 and 50, resp. Results: At the interim after VAL reached max sample size in Stage 1, the PP for all signatures was &lt;0.8 and &gt;0.25 for at least one sig. Thus, VAL did not graduate nor drop for futility, but accrual stopped for maximum N in Stage 1 (see table). Final results will be presented at the meeting. Columns 2-5 show results at the interim after which VAL stopped for max N. Columns 6-8 show near final results. Conclusions: GBM AGILE is an efficient &amp; effective model for phase 3 drug development. VAL did not increase OS compared to C in any glioblastoma subtype. GBM AGILE evaluated this agent in less time, at lower cost, &amp; with fewer patients than typical registration trials &amp; is currently evaluating several other arms. Clinical trial information: NCT03970447 . [Table: see text]

Efficacy and safety of entrectinib in children with extracranial solid or primary central nervous system (CNS) tumors harboring NTRK or ROS1 fusions.

10000 Background: Entrectinib previously yielded durable responses in children with NTRKor ROS1fusion-positive extracranial solid or primary CNS tumors in STARTRK-NG (NCT02650401). We present updated data from STARTRK-NG, TAPISTRY (NCT04589845) and STARTRK-2 (NCT02568267): pediatric patients from these trials were combined to enable an integrated efficacy and safety analysis on a larger cohort than previously. Methods: Eligible patients were TRK or ROS1 inhibitor naïve and aged &lt; 18 years, had locally advanced or metastatic extracranial solid or primary CNS tumors harboring an NTRK or ROS1 fusion, and had measurable or evaluable-only disease. Once enrolled, patients received ≥1 daily dose of oral entrectinib until disease progression, unacceptable toxicity, or consent withdrawal. Tumor responses were confirmed by blinded independent central review (BICR) per RECIST v1.1 or RANO criteria. Patients were included if they had been followed for ≥6 months. The primary endpoint was confirmed objective response rate (ORR) per BICR. Key secondary endpoints included ORR in patients with baseline measurable disease per BICR, duration of confirmed response (DoR), time to confirmed response (TTR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Results: At clinical cutoff (16 July 2023), out of 91 safety-evaluable patients (regardless of fusion), 44 patients in the NTRKcohort and 20 patients in the ROS1cohort were efficacy evaluable. Median duration of survival follow-up was 24.2 months ( NTRK: range 1–66) and 27.6 months ( ROS1: range 1–73). The ORR was 68.2% (95% CI 52.4–81.4) in the NTRK cohort and 65.0% (95% CI 40.8–84.6) in the ROS1 cohort. In patients with baseline measurable disease, the ORR was 77.8% ( NTRK: n = 28/36; 95% CI 60.9–89.9) and 62.5% ( ROS1: n = 10/16; 95% CI 35.4–84.8). Efficacy outcomes are shown in the Table. The most common adverse events were pyrexia (50.5%), vomiting (40.7%) and anemia (40.7%). Conclusions: Entrectinib continued to yield rapid and durable responses in pediatric patients with extracranial solid or primary CNS tumors harboring an NTRK or ROS1 fusion. The safety profile of entrectinib was in line with previous reports. Clinical trial information: NCT02650401 / NCT04589845 / NCT02568267 . [Table: see text]

Effect of novel polygenetic variant of HUNT lung cancer model on lung cancer risk assessment over clinical model among light smokers (average &lt;9 pack-years).

e20066 Background: As lung cancer incidence and mortality increase, methods of early diagnosis are needed to increase survival. The validated HUNT Lung Cancer Model (HUNT LCM) predicts individual 6-year risk of lung cancer in ever smokers with an AUC of 0.87 based on eight clinical variables: sex, age, BMI, pack-years, smoking intensity number of cigarettes per day, quit time, daily cough, and daily indoors smoke exposure. We aimed to explore whether the performance of the HUNT model can be improved by adding genetic information, and in what group of ever smokers these differences in performance emerges. Methods: Based on the eight clinical variables of the HUNT LCM and 22 single nucleotide polymorphisms (SNPs) previously identified in the literature as highly associated with lung cancer risk, the novel lung cancer risk prediction model HUNT Lung-SNP was developed. Clinical and genetical data of ever-smokers from the HUNT2 population study (n = 30746, median follow-up 15.26 years) where 160 individuals were diagnosed with lung cancer within six years were used for the model fitting. External validation was performed in another population-based cohort, the Tromsø Study (n = 2663) where 39 were diagnosed with lung cancer within 6 years. Results: The integrated discrimination improvement index (IDI) between the HUNT Lung-SNP and the HUNT LCM shows that the HUNT Lung-SNP significantly improve the LC risk stratification within six years with an IDI of 0.019 (95% CI 0.015-0.025), p &lt; 0·001 and of 0.013 (95% CI 0.008-0.018), p &lt; 0·001 in the HUNT2 and Tromsø cohorts, respectively. Of the cases, 21/160 (13%) and 10/39 (25%) in the HUNT and Tromsø cohort respectively, were low risk by the HUNT LCM but high risk by the HUNT Lung-SNP model. The main difference in characteristics among cases predicted by the HUNT Lung-SNP model, but missed by the HUNT LCM, was the average number of pack-years: 8.22 vs. 29.8 (p &lt; 0.001) in HUNT2 and 7.7 vs. 33.7 (p &lt; 0.001) in Tromsø cohort. Conclusions: A genetic approach combined with clinical variables of the HUNT LCM can improve the lung cancer risk prediction significantly by increasing the sensitivity among light smokers. Thus, we identified a high-risk population in two independent cohorts that would not be eligible for screening by clinical cutoffs nor with a clinical risk prediction model. This novel HUNT Lung-SNP needs further validation in other populations to evaluate its clinical utility.

Association of RNA-sequencing signatures with clinical outcomes of pembrolizumab + chemotherapy in patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) enrolled in the phase 2 KEYNOTE-782 trial.

8578 Background: KEYNOTE-782 (NCT03664024) was a single-arm phase 2 study designed to assess possible biomarkers of response (objective response rate [ORR]) to first-line pembrolizumab + chemotherapy (pemetrexed + carboplatin or cisplatin) in patients with previously untreated metastatic nonsquamous NSCLC. Herein, we examined relationships between the T-cell–inflamed gene expression profile (TcellinfGEP) and other tumor microenvironment consensus signatures and efficacy of pembrolizumab + chemotherapy in an exploratory analysis of KEYNOTE-782. Methods: All patients were to receive pembrolizumab 200 mg Q3W, pemetrexed 500 mg/m2 Q3W, and 4 Q3W cycles of carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2. Using tumor samples, RNA sequencing was used to measure expression of the TcellinfGEP and 10 non-TcellinfGEP signatures (angiogenesis, gMDSC, glycolysis, hypoxia, mMDSC, MYC, proliferation, RAS, stromal/EMT/TGFβ, and WNT). The association between each signature and clinical outcomes was analyzed using logistic regression (ORR) and Cox proportional hazards regression (progression-free survival [PFS] and overall survival [OS]); the prespecified significance level was α = 0.05 for TcellinfGEP (hypothesized positive association) and α = 0.10 for non-TcellinfGEP signatures (hypothesized negative associations). The clinical utility of TcellinfGEP was descriptively assessed using a prespecified cutoff of the first tertile. The clinical database cutoff was November 5, 2021. Results: Of 117 patients enrolled, 69 (59.0%) had evaluable RNA-sequencing data. TcellinfGEP was not associated with ORR ( P = 0.183), PFS ( P = 0.071), or OS ( P = 0.142); the area under the receiver operating characteristic curve for discriminating response was 0.56 (95% CI, 0.42-0.71). None of the 10 non-TcellinfGEP consensus signatures showed a statistically significant association with clinical outcomes after adjusting for TcellinfGEP (multiplicity adjusted P &gt; 0.10). ORR and median PFS were comparable in the TcellinfGEP low and nonlow subgroups; there was a trend towards longer OS in the nonlow subgroup (Table). Conclusions: In this exploratory analysis of patients with metastatic nonsquamous NSCLC, none of the RNA-sequencing signatures evaluated were associated with clinical outcomes of pembrolizumab + chemotherapy. There was little evidence of clinical utility of TcellinfGEP when evaluated as a dichotomous variable. Data support the use of pembrolizumab + chemotherapy as first-line therapy for patients with nonsquamous NSCLC regardless of consensus signature status. Clinical trial information: NCT03664024 . [Table: see text]