Natural History Study Research Articles

Vascular Ehlers-Danlos Syndrome: A Comprehensive Natural History Study in a Dutch National Cohort of 142 Patients.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in COL3A1. The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch multicenter cohort to optimize patient care and increase awareness of the disease. Individuals with vEDS throughout the Netherlands were included. The phenotype was charted by retrospective analysis of molecular and clinical data, combined with a one-time physical examination. A total of 142 individuals (50% female) participated the study, including 46 index patients (32%). The overall median age at genetic diagnosis was 41.0 years. More than half of the index patients (54.3%) and relatives (53.1%) had a physical appearance highly suggestive of vEDS. In these individuals, major events were not more frequent (P=0.90), but occurred at a younger age (P=0.01). A major event occurred more often and at a younger age in men compared with women (P<0.001 and P=0.004, respectively). Aortic aneurysms (P=0.003) and pneumothoraces (P=0.029) were more frequent in men. Aortic dissection was more frequent in individuals with a COL3A1 variant in the first quarter of the collagen helical domain (P=0.03). Male sex, type and location of the COL3A1 variant, and physical appearance highly suggestive of vEDS are risk factors for the occurrence and/or early age of onset of major events. This national multicenter cohort study of Dutch individuals with vEDS provides a valuable basis for improving guidelines for the diagnosing, follow-up, and treatment of individuals with vEDS.

Effect of sirolimus on muscle in inclusion body myositis observed with magnetic resonance imaging and spectroscopy.

Finding sensitive clinical outcome measures has become crucial in natural history studies and therapeutic trials of neuromuscular disorders. Here, we focus on 1-year longitudinal data from quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy (31P MRS) in a placebo-controlled study of sirolimus for inclusion body myositis (IBM), also examining their links to functional, strength, and clinical parameters in lower limb muscles. Quantitative MRI and 31P MRS data were collected at 3T from a single site, involving 44 patients (22 on placebo, 22 on sirolimus) at baseline and year-1, and 21 healthy controls. Assessments included fat fraction (FF), contractile cross-sectional area (cCSA), and water T2 in global leg and thigh segments, muscle groups, individual muscles, as well as 31P MRS indices in quadriceps or triceps surae. Analyses covered patient-control comparisons, annual change assessments via standard t-tests and linear mixed models, calculation of standardized response means (SRM), and exploration of correlations between MRI, 31P MRS, functional, strength, and clinical parameters. The quadriceps and gastrocnemius medialis muscles had the highest FF values, displaying notable heterogeneity and asymmetry, particularly in the quadriceps. In the placebo group, the median 1-year FF increase in the quadriceps was 3.2% (P<0.001), whereas in the sirolimus group, it was 0.7% (P=0.033). Both groups experienced a significant decrease in cCSA in the quadriceps after 1year (P<0.001), with median changes of 12.6% for the placebo group and 5.5% for the sirolimus group. Differences in FF and cCSA changes between the two groups were significant (P<0.001). SRM values for FF and cCSA were 1.3 and 1.4 in the placebo group and 0.5 and 0.8 in the sirolimus group, respectively. Water T2 values were highest in the quadriceps muscles of both groups, significantly exceeding control values in both groups (P<0.001) and were higher in the placebo group than in the sirolimus group. After treatment, water T2 increased significantly only in the sirolimus group's quadriceps (P<0.01). Multiple 31P MRS indices were abnormal in patients compared to controls and remained unchanged after treatment. Significant correlations were identified between baseline water T2 and FF at baseline and the change in FF (P<0.001). Additionally, significant correlations were observed between FF, cCSA, water T2, and functional and strength outcome measures. This study has demonstrated that quantitative MRI/31P MRS can discern measurable differences between placebo and sirolimus-treated IBM patients, offering promise for future therapeutic trials in idiopathic inflammatory myopathies such as IBM.

The burden and natural history of cardiac pathology at TB diagnosis in a high-HIV prevalence district in Zambia: protocol for the TB-Heart study

BackgroundTuberculosis (TB) continues to be a major cause of death across sub-Saharan Africa (SSA). In parallel, non-communicable disease and especially cardiovascular disease (CVD) burden has increased substantially in the region. Cardiac manifestations of TB are well-recognised but the extent to which they co-exist with pulmonary TB (PTB) has not been systematically evaluated. The aim of this study is to improve understanding of the burden of cardiac pathology in PTB in those living with and without HIV in a high-burden setting.MethodsThis is a cross-sectional and natural history study to evaluate the burden and natural history of cardiac pathology in participants with PTB in Lusaka, Zambia, a high burden setting for TB and HIV. Participants with PTB, with and without HIV will be consecutively recruited alongside age- and sex-matched TB-uninfected comparators on a 2:1 basis. Participants will undergo baseline assessments to collect clinical, socio-demographic, functional, laboratory and TB disease impact data followed by point-of-care and standard echocardiography. Participants with PTB will undergo further repeat clinical and functional examination at two- and six months follow-up. Those with cardiac pathology at baseline will undergo repeat echocardiography at six months.DiscussionThe outcomes of the study are to a) determine the burden of cardiac pathology at TB diagnosis, b) describe its association with patient-defining risk factors and biochemical markers of cardiac injury and stretch and c) describe the natural history of cardiac pathology during the course of TB treatment.

Long-term clinical and radiological trajectories of craniocervical vasculopathy in children with PHACE syndrome.

To describe the rates of stroke and craniocervical vasculopathy progression in children with posterior fossa malformations, hemangioma, arterial anomalies, coarctation of the aorta/cardiac defects, and eye abnormalities (PHACE) syndrome. A single-center, retrospective natural history study of children with PHACE syndrome. Clinical and sequential neuroimaging data were reviewed to study the characteristics and progression of vasculopathy and calculate the rates of arterial ischemic stroke (AIS) and transient ischemic stroke (TIA). Vasculopathy progression was defined as worsening or new vascular findings on follow-up magnetic resonance angiography. Thirty-four children with cerebrovascular abnormalities at the PHACE syndrome diagnosis were studied (age range = 2 to 18 years, 85% females). Median age at the initial diagnosis was 5.5 months (interquartile range = 1-52 months); median age at the last follow-up was 8 years 6 months (range = 2-18 years). Overall, 10 (29%) patients had radiological progression of their vasculopathy, with a cumulative progression-free rate of 73% (95% confidence interval [CI] = 0.57-0.89), and a cumulative TIA-free and AIS-free rate of 87% (95% CI = 0.745-0.99). Vasculopathy was continuously progressive in six patients (18%) at the last follow-up. Three patients (9%) had TIA and all had progressive vasculopathy. One patient had presumed perinatal AIS at the initial PHACE diagnosis, while no other patient experienced an AIS during the follow-up. In children with PHACE syndrome, craniocervical vasculopathy is non-progressive and asymptomatic in the majority of cases. The risk of ischemic stroke in these children is very low. Larger and prospective studies are necessary to confirm these findings.

Findings from the ILLUMINATE Prospective Natural History Study (NHS) in Individuals with Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (P3-9.001)

Findings from the ILLUMINATE Prospective Natural History Study (NHS) in Individuals with Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (P3-9.001)

Genotype-phenotype Correlations and Sex Differences in ZC4H2-associated Rare Disorder (ZARD): Results from the ZARD Natural History Study (S37.004)

Genotype-phenotype Correlations and Sex Differences in ZC4H2-associated Rare Disorder (ZARD): Results from the ZARD Natural History Study (S37.004)

Results from a 12-month Natural History Study of Patients with Cerebral Cavernous Malformations (S41.006)

Results from a 12-month Natural History Study of Patients with Cerebral Cavernous Malformations (S41.006)

A study concept of expeditious clinical enrollment for genetic modifier studies in Charcot-Marie-Tooth neuropathy 1A.

Caused by duplications of the gene encoding peripheral myelin protein 22 (PMP22), Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common hereditary neuropathy. Despite this shared genetic origin, there is considerable variability in clinical severity. It is hypothesized that genetic modifiers contribute to this heterogeneity, the identification of which may reveal novel therapeutic targets. In this study, we present a comprehensive analysis of clinical examination results from 1564 CMT1A patients sourced from a prospective natural history study conducted by the RDCRN-INC (Inherited Neuropathy Consortium). Our primary objective is to delineate extreme phenotype profiles (mild and severe) within this patient cohort, thereby enhancing our ability to detect genetic modifiers with large effects. We have conducted large-scale statistical analyses of the RDCRN-INC database to characterize CMT1A severity across multiple metrics. We defined patients below the 10th (mild) and above the 90th (severe) percentiles of age-normalized disease severity based on the CMT Examination Score V2 and foot dorsiflexion strength (MRC scale). Based on extreme phenotype categories, we defined a statistically justified recruitment strategy, which we propose to use in future modifier studies. Leveraging whole genome sequencing with base pair resolution, a future genetic modifier evaluation will include single nucleotide association, gene burden tests, and structural variant analysis. The present work not only provides insight into the severity and course of CMT1A, but also elucidates the statistical foundation and practical considerations for a cost-efficient and straightforward patient enrollment strategy that we intend to conduct on additional patients recruited globally.

187 Achondroplasia Natural History Study (CLARITY): 60-Year Experience With Hydrocephalus in Achondroplasia From Four Skeletal Dysplasia Centers

INTRODUCTION: This study is the largest to date to look at the treatment of hydrocephalus in achondroplasia. METHODS: CLARITY (The Achondroplasia Natural History Study) is a registry for clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2017. Data included surgeries with indications and complications, medical diagnoses, and radiographic information. RESULTS: 1374 patients with achondroplasia were included in this study. 124 (9%) of these patients underwent treatment of hydrocephalus at a median age of 14.6 months. There was wide variation by center and decade of birth, with treatment ranging from 0% to 28% of patients, although in the most recent decade, it fell to 3.4% of patients. Requiring cervicomedullary decompression (CMD) predicted treatment of hydrocephalus with an odds ratio of 5.8 (95% CI 3.9-8.4), although that association has disappeared in those born since 2010 with an odd’s ratio of 1.1 (95% CI 0.2-5.7). In patients born since 1990, treatment of hydrocephalus with an ETV has become more common. Kaplan Meier analysis suggests a single ETV will treat hydrocephalus in roughly half of these patients. CONCLUSIONS: While children with achondroplasia have enlarged intracranial CSF spaces and macrocephaly, treatment of hydrocephalus has become relatively unusual in the last twenty years. Historically there was a significant association between symptomatic foramen magnum (FM) stenosis and treatment of hydrocephalus, although concurrent treatment of both has fallen out of favor since CMD alone will treat hydrocephalus in some patients. While understood as communicating hydrocephalus, endoscopic third ventriculostomy (ETV) appears to be reasonably successful in certain patients and should be considered an option in selected patients.

Low level viremia is associated with Serious Non-AIDS Events in People Living with HIV

Abstract Background The consequences of low-level viremia in people living with HIV are unclear. We used data from the U.S. Military HIV Natural History Study (NHS) to examine the association of low-level viremia (LLV) and serious non-AIDS events (SNAEs). Methods Included participants initiated antiretroviral therapy (ART) after 1996, had ≥3 viral loads (VLs) measured, using an assay with a lower limit of detection of &amp;lt;50 copies/mL, ≥6 months after ART initiation. VLs were categorized as lower levels of LLV (51-199 copies/mL), higher level of low-level viremia (HLLV-200-999 copies/mL), and virologic failure (VF- ≥200 copies/mL on 2 or more successive determinations or a single VL ≥1000 copies/mL), and virologic suppression (VS- i.e., VL &amp;lt;50 copies/mL). Viral blips [i.e., VLs between 50 and 999 copies/mL that are preceded and succeeded by VL &amp;lt;50 copies/mL] were analyzed in the VS category. Cox Proportional Hazards models were used to examine the association of LLV and SNAEs, adjusted hazard ratios and 95% CI are presented. Results A total of 439 (17.4%) SNAEs were recorded among the 2528 participants (93% male, 40% Caucasian, 43% African American) followed for a median of 11 years. In 8.5% and 4.6% of the participants, respectively, LLV and HLLV were the highest recorded viremia strata. Compared with VS, SNAEs were associated with LLV (1.3, [1.2 to 1.4]), HLLV (1.6, [1.5 to 1.7]), and VF (1.7, [1.7 to 1.8]). Conclusion The results of this study suggest that LLV is associated with the occurrence of SNAEs and needs further study.

Evaluation of partial volume correction and analysis of longitudinal [18F]GTP1 tau PET imaging in Alzheimer's disease using linear mixed-effects models.

We evaluated the impact of partial volume correction (PVC) methods on the quantification of longitudinal [18F]GTP1 tau positron-emission tomography (PET) in Alzheimer's disease and the suitability of describing the tau pathology burden temporal trajectories using linear mixed-effects models (LMEM). We applied van Cittert iterative deconvolution (VC), 2-compartment, and 3-compartment, and the geometric transfer matrix plus region-based voxelwise methods to data acquired in an Alzheimer's disease natural history study over 18 months at a single imaging site. We determined the optimal PVC method by comparing the standardized uptake value ratio change (%ΔSUVR) between diagnostic and tau burden-level groups and the longitudinal repeatability derived from the LMEM. The performance of LMEM analysis for calculating %ΔSUVR was evaluated in a natural history study and in a multisite clinical trial of semorinemab in prodromal to mild Alzheimer's disease by comparing results to traditional per-visit estimates. The VC, 2-compartment, and 3-compartment PVC methods had similar performance, whereas region-based voxelwise overcorrected regions with a higher tau burden. The lowest within-subject variability and acceptable group separation scores were observed without PVC. The LMEM-derived %ΔSUVR values were similar to the per-visit estimates with lower variability. The results indicate that the tested PVC methods do not offer a clear advantage or improvement over non-PVC images for the quantification of longitudinal [18F]GTP1 PET data. LMEM offers a robust framework for the longitudinal tau PET quantification with low longitudinal test-retest variability. NCT02640092 and NCT03289143.

Advancing clinical development for neuronopathic Hunter syndrome through a quantitatively-driven reverse translation framework.

A quantitatively-driven evaluation of existing clinical data and associated knowledge to accelerate drug discovery and development is a highly valuable approach across therapeutic areas, but remains underutilized. This is especially the case for rare diseases for which development is particularly challenging. The current work outlines an organizational framework to support a quantitatively-based reverse translation approach to clinical development. This approach was applied to characterize predictors of the trajectory of cognition in Hunter syndrome (Mucopolysaccharidosis Type II; MPS-II), a rare X-linked lysosomal storage disorder, highly heterogeneous in its course. Specifically, we considered ways to refine target populations based on age, cognitive status, and biomarkers, that is, cerebrospinal fluid glycosaminoglycans (GAG), at trial entry. Data from a total of 138 subjects (age range 2.5 to 10.1 years) from Takeda-sponsored internal studies and external natural history studies in MPS-II were included. Quantitative analyses using mixed-effects models were performed to characterize the relationships between neurocognitive outcomes and potential indicators of disease progression. Results revealed a specific trajectory in cognitive development across age with an initial progressive phase, followed by a plateau between 4 and 8 years and then a variable declining phase. Additionally, results suggest a faster decline in cognition among subjects with lower cognitive scores or with higher cerebrospinal fluid GAG at enrollment. These results support differences in the neurocognitive course of MPS-II between distinct groups of patients based on age, cognitive function, and biomarker status at enrollment. These differences should be considered when designing future clinical trials.

Abstract 2155: The impact of urban residence on symptom duration, treatment initiation, and survival among primary brain tumor patients: A large cohort analysis

Abstract Primary brain tumors (PBT) are rare, accounting for less than 2% of all cancers, present acutely, and often require specialized care to determine treatment approaches. Neuro-Oncology clinics are located in densely populated urban areas resulting in additional access barriers, such as longer travel time, for those in non-urban areas. To better understand how proximity to our facility affects patient outcomes among PBT patients enrolled in the National Institutes of Health (NIH) Natural History Study (NCT02851706, PI: Armstrong), we assessed the association of population density with symptom duration before diagnosis, time to first treatment, and overall survival among a cohort of 666 adult PBT patients. More urbanized areas were defined as areas with a core population density of more than 1,000 persons per square mile. T-tests and chi-squared tests were performed to assess differences in patient and tumor characteristics based on population density (more urbanized vs. less urbanized). We used ordinal logistic regression (odds ratio [OR], 95% confidence intervals [CI]) to assess the association between duration of presenting symptoms (&amp;lt;6 months, 6 months-1 year, ≥1 year) and linear regression (beta coefficient, 95% CI) for time to treatment and population density. We adjusted for age at cancer diagnosis and sex (male, female), and results were stratified according to residential distance to the NIH (short distance=&amp;lt;200 miles, long distance=200+ miles), to control for local referral patterns. Kaplan-Meier estimates were used to assess overall survival by population density levels, overall, and by residential distance. All models were then further stratified by tumor grade (low, high). Among 666 patients diagnosed with PBTs, 401 (60%) lived in more urbanized areas, 40% were long distance, and 24% had low-grade tumors. Patients living in more urbanized areas were more racially diverse (p&amp;lt;0.001), had higher educational attainment (p&amp;lt;0.001), and were more likely to be single (p=0.008). In the overall cohort and when stratified by distance to NIH or tumor grade, there were no associations between population density level and symptom duration prior to diagnosis. Time to treatment for radiation and chemotherapy was longer for PBT patients living in less urbanized areas and longer distances from the NIH (β=0.63; 95%CI=0.08,1.17) compared to those living in more urbanized areas. There were no differences in the 5-year survival rates between more or less urbanized groups. In conclusion, access to care for those in less urbanized areas was demonstrated, although survival was not impacted. Future consideration should be given to novel approaches to increase access to specialized care, particularly for PBT patients living further from urban areas. Citation Format: Macy L. Stockdill, Jacqueline B. Vo, Orieta Celiku, Zuena Karim, Yeonju Kim, Hope Miller, Elizabeth Vera, Terri S. Armstrong. The impact of urban residence on symptom duration, treatment initiation, and survival among primary brain tumor patients: A large cohort analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2155.

Abstract 6299: Psychometric evaluation of the FACIT-SP 12 in a primary brain tumor patient population

Abstract Spirituality is a social determinant of health associated with psychosocial adjustment to serious illnesses including cancer but is not often assessed in clinical care. Here we perform psychometric evaluation of a tool developed to report spiritual well-being in chronic illness in a cohort of 248 patients with primary brain tumors (PBT) enrolled in a natural history study (NCT02851706, PI: T. Armstrong). Participants completed the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being 12 (FACIT-SP 12) as part of yearly clinical outcome assessments. Total score, Meaning/Peace and Faith scores were calculated. Internal consistency (Cronbach’s alpha) and construct validity (principal components analysis with varimax rotation) evaluated psychometric properties of the FACIT-SP 12; one-way ANOVAs, one-sample t-test and Wilcoxon signed rank tests evaluated group differences (sig. p&amp;lt;0.05) on patient report of spirituality/beliefs including belief in god(s)/higher power, being religious, and prayer and in comparison to scores of previously reported studies. Participants were majority male (57%), white (79%) with high grade tumor (59%) and a median age of 48 (range: 20-82). Seven different religions were reported (majority Christianity [55%]) but also spiritual non-religious (9%), no beliefs (13%), and 6% preferring not to answer. The principal components analysis confirmed the original 2 factor solution (Meaning/Peace and Faith) and explained 66.8% of the variance (KMO =0.87, 43% of residuals &amp;lt; 0.05), with one item not loading cleanly on either factor (“I know that whatever happens with my illness, things will be okay”). Cronbach’s alphas were 0.90, 0.90, and 0.89, for the total, Meaning/Peace, and Faith scales, respectively. For all three spiritual/belief questions, patients who responded “yes” had higher total and faith scores than those who responded “no"; but not in the Meaning/Peace score when reporting religion (p=0.108). This cohort reported lower total scores (mean=32.5), Meaning/Peace scores (mean=23.4, median=24.0) and Faith scores (mean=9.2, median=10.0) compared to the initial validation in other solid tumors and HIV/AIDs (means=38.5, 25.2, 13.6, respectively) and to a smaller, less diverse PBT sample (medians: Meaning/Peace=25.8, Faith=14.0). The FACIT-SP 12 demonstrated internal consistency and construct validity, with lower scores in comparison to populations in prior studies. More diverse belief systems than previously reported may contribute to differences among studies. Future analysis should explore the increased percentage of “prefer not to answer” respondents compared to earlier reports, associations with clinical and self-reported outcomes including symptoms and quality of life, evaluation of illness-related factors that contribute to poor spiritual well-being, and a longitudinal look at spiritual well-being. Citation Format: Elizabeth Vera, Byram Ozer, Alvina Acquaye-Mallory, Valentina Pillai, Anna Choi, Ewa Grajkowska, Tricia Kunst, Hope Miller, Kimberly Reinhart, Terri S. Armstrong, Macy Stockdill. Psychometric evaluation of the FACIT-SP 12 in a primary brain tumor patient population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6299.

Abstract 6305: Evaluating clinical and sociodemographic risk for symptom-related functional interference in the primary brain tumor population

Abstract Purpose: Primary brain tumors have a high propensity for causing physical and activity-related disabilities due to the location within the brain and use of targeted treatments resulting in significant symptom burden. In other cancers, physical function impacts mood, quality of life, and even mortality. This exploratory study aims to identify factors associated with activity-related functional interference in a cross-sectional cohort of 584 primary brain tumor patients enrolled in a natural history study (NCT03251989, PI: T.S. Armstrong). Methods: Sociodemographic (age, race, ethnicity, income, education, employment, body mass index [BMI]) and disease-related clinical data were collected at study entry. Activity-related interference (work, walking, and general activity) and health status were reported via the MD Anderson Symptom Inventory-Brain Tumor. Activity-related interference means ≥ 2 were categorized as moderate/severe. Logistic regression assessed univariate associations with moderate/severe interference, with sig. &amp;lt;0.05. Results: This sample had a median age of 49 years (range 18-85), and was mostly male (57%), with a high-grade tumor (grade 3/4) (74%), glioblastoma (39%), on active treatment (21%) and prior tumor recurrence (49%). Risk factors for moderate/severe activity-related interference included: ≥ 2 surgeries (OR = 1.55, 95% CI [1.11, 2.18], P = 0.011), ≥ 2 radiation treatments (OR = 2.87, 95% CI [1.59, 5.17], P &amp;lt; 0.001), currently on active treatment (OR = 1.47, 95% CI [0.97, 2.22], P = 0.066), disease progression (OR = 1.87, 95% CI [1.24, 2.84], P = 0.003), prior recurrence (OR = 1.57, 95% CI [1.13, 2.19], P = 0.007), and poor KPS (OR = 3.61, 95% CI [2.55, 5.12], P &amp;lt; 0.001), but not tumor grade (OR = 1.05, 95% CI [0.72, 1.54], P = 0.790). Sociodemographic risk factors for moderate/severe activity-related interference included: less than a high school education (OR = 2.03, 95% CI [1.18, 3.51], P = 0.011), on disability (OR = 3.20, 95% CI [1.79, 5.71], P &amp;lt; 0.001), or unemployed (OR = 3.81, 95% CI [2.34, 6.19], P &amp;lt; 0.001), an annual income less than $49,999 (OR = 2.62, 95% CI [1.28, 5.35], P = 0.008), or childhood in a rural area (OR = 1.87, 95% CI [1.24, 2.84], P = 0.003), but not BMI, smoking status, or past physical activity in the 10 years prior to report. Conclusion: As expected, activity-related interference is associated with disease and treatment associated clinical characteristics, with significant risk derived from sociodemographic factors such as education, childhood environment, employment, and household income. Future studies should further explore these associations longitudinally to identify individuals at the highest risk of activity-related interference due to their brain tumor as well as interventions designed for those who may be socioeconomically disadvantaged. Citation Format: Bennett Ann McIver, Tara S. Davis, Kimberly Reinhart, Elizabeth Vera, Anna Choi, Tricia Kunst, Morgan Johnson, Ewa Grajkowska, Hope Miller, Terri S. Armstrong, Michelle L. Wright. Evaluating clinical and sociodemographic risk for symptom-related functional interference in the primary brain tumor population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6305.

Abstract 7445: Association between C-reactive protein and cognitive impairment in IDH-mutant gliomas

Abstract Cognitive impairment is common in primary brain tumor (PBT) patients, as a result of the disease and secondary damage from directed and systemic therapy. Recently, the risk in patients with IDH-mutant gliomas and role of interconnectivity of the tumor with neurons and the tumor microenvironment has heightened interest in exploration of biomarkers of impairment to inform care. Here, we investigate Montreal Cognitive Assessment (MoCA) scores and peripheral blood levels of C-reactive protein (CRP) in a cross-sectional cohort of 47 adult IDH-mutant PBT patients enrolled in a natural history study (NHS, NCT02851706: PI T. Armstrong). MoCA raw scores (range 0-30) were dichotomized (≤ 25 = cognitive dysfunction). Baseline CRP was quantified in banked serum samples in duplicate using (V-Plex/Vascular Injury Panel-2, Meso Scale Discovery [MSD], Rockville, MD) in a QuickPlex SQ 120 instrument (MSD). Lab personnel were blinded to diagnosis and clinical status. To reduce skewness in CRP raw values, we used log transformation. Descriptive statistics, Pearson’s correlation, and logistic regression were conducted using IBM SPSS and SAS Statistics software. The sample was predominately male (62%), white (70%), with high-grade gliomas (III/IV) (68%) and an average age at diagnosis of 36 years (SD: 9; median: 34; range: 20-53). The mean MoCA score was 25 (SD: 5; median: 26; range: 11-30). Dichotomizing MoCA scores showed that less than half (43%) of participants exhibited moderate-severe (≤ 25) cognitive impairment. MoCA binary group was negatively correlated with levels of CRP (r=-0.42, p&amp;lt;.003). The log mean concentration of CRP was higher in participants with cognitive impairment (7.99, SD=0.47 vs 7.57, SD=0.45, p&amp;lt;.003) than those without impairment. Finally, when controlling for age and sex, CRP remained predictive of cognitive impairment (OR 8.18, 95% CI 1.70,39.23). Higher levels of CRP were associated with lower MoCA scores in a cross-sectional sample of patients with IDH-mutant gliomas, suggesting an association between the severity of inflammation and cognitive impairment in IDH-mutant glioma patients. Further analysis in large, more diverse longitudinal cohorts will be needed to validate these findings in this population and compare to those with IDH-WT tumors and develop predictive models to inform biomarker development. Citation Format: McKenzie C. Kauss, Michelle L. Wright, Dhaivat Raval, Emory Hsieh, Kaitlynn Slattery, Terri S. Armstrong, Tito R. Mendoza, Vivian A. Guedes. Association between C-reactive protein and cognitive impairment in IDH-mutant gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7445.

Abstract 7448: Serum IL-10 is associated with neurologic symptoms and interference in primary brain tumor patients

Abstract Background: Primary brain tumors (PBT) are associated with neurocognitive symptoms as a direct result of the tumor or its treatment. IDH-mutant gliomas are associated with longer survival, but with higher incidence of seizures and neurocognitive symptoms.​ Correlations between cytokines and neuroinflammation have been reported in other structural brain lesions but have not been evaluated in PBT. Here, we investigate elevated peripheral blood levels of proteins (cytokine levels) in a cross-sectional cohort (n=47) of adult, IDH-mutant PBT patients enrolled in a natural history study (NCT02851706, PI: T. Armstrong) versus healthy subjects (n=32) and the correlations between cytokine levels and patient-reported outcomes (PROs). Methods: Patient-reported symptoms and activity-related interference were collected via the MD Anderson Symptom Inventory-Brain Tumor at study entry. Serum samples were stored at -80°C for batch processing and used for biomarker analysis. Ten cytokines (interleukin-1β [IL-1β], IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ [IFN-γ], and tumor necrosis factor-α [TNF-α]) were quantified in duplicate using an immunoassay (V-Plex/Proinflammatory, Meso Scale Discovery [MSD], Rockville, MD). Lab personnel were blinded to diagnosis and patient clinical status. Mean concentration (pg/mL) levels or ‘present or not detectable’ values were used. Descriptive statistics, Mann-Whitney tests, and Spearman correlations were conducted at p &amp;lt;0.05. Results: The patient sample was mostly male (62%), White (70%), employed (64%), had no prior recurrence (62%), high grade (3-4) tumors (70%), and an average age at diagnosis of 36 years (SD: 9; median: 34; range: 20-53). The healthy subject sample was mostly female (53%) and White (72%), with an average age of 46 years (SD: 19; median: 50; range: 19-78). Five cytokines (IFN-γ, IL-6, IL-8, IL-10, and TNF-α) were detectable in patients and healthy subjects with levels of IL-6, IL-10, and TNF-α higher in patients than healthy subjects. Serum levels of IL-10 (mean rank=50.7 vs 24.3, p&amp;lt;0.001) and TNF-α (mean rank=50.6 vs 24.2, p&amp;lt;0.001) were higher in PBT patients when compared to healthy subjects. Only IL-10, but not other cytokines, positively correlated with severity of patient-reported symptoms [pain (r=0.290, p=0.048), numbness/tingling (r=0.302, p=0.039)], and activity-related interference, including work (r=0.323, p=0.027), and walking (r=0.402, p=0.005). Conclusions: Higher IL-10 levels and detection differences in other cytokines, may indicate a reduction in immune-mediating processes and heightening inflammation in patients. Future analysis will include replication of this work in a larger cohort across PBT types to evaluate risk, explore mechanisms, and associations with treatment types. Citation Format: Kaitlynn A. Slattery, Michelle L. Wright, Dhaivat Raval, Emory Hsieh, McKenzie C. Kauss, Terri S. Armstrong, Tito R. Mendoza, Vivian A. Guedes. Serum IL-10 is associated with neurologic symptoms and interference in primary brain tumor patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7448.

Abstract 6304: Seizure self-report and monitoring: Agreement between patient and clinician report and implications for care in patients with IDH-mutant and IDH-wild type gliomas

Abstract Primary brain tumor (PBT) patients commonly experience seizures, which can be measured and monitored by a variety of tools. Here, we explore the concordance between 2 tools and their use in reporting seizures over time among PBT patients enrolled in a natural history study (NCT02851706, PI: T. Armstrong). Patients complete the M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT), which measures symptom severity (including seizure) within the last 24 hours from 0-10; and, as part of the same visit, pairs of clinicians and patients complete the Seizure Control Composite Index (RANO-SCCI), which includes the questions ‘Have you ever had a seizure’ (RANO-SCCIQ1) and ‘Have you had a seizure since your last clinic visit’ (RANO-SCCIQ2). Responses to each measure are reported in aggregate and by IDH status. Participants included 89 patients with gliomas who were primarily white (84%) males (62%) with a median age of 48 years (range: 27-78) and KPS ≥ 90 (85%). Based on patient reports, 65% endorsed ever having a seizure (RANO-SCCIQ1), 17% had a recent seizure (RANO-SCCIQ2), and 12% had a seizure within the last 24 hours (MDASI-BT). For the RANO-SCCIQ1 data, patients and clinicians generally agreed except for 6 pairs (7%) where clinicians indicated a seizure but patients did not. Of the 59 who reported recent seizures (RANO-SCCIQ2), two pairs (3%) disagreed, with patients indicating a recent seizure but clinicians not endorsing a seizure had occurred. Good overall agreement (86%) was observed between the RANO-SCCIQ2 and MDASI-BT for both clinician and patient responses, with 3 and 2 paired disagreements respectively, in which seizures were indicated in the last 24 hours but not recorded as a recent seizure on the (RANO-SCCIQ2). Comparing clinician report of seizures in those with IDH-mutated (n=39) to IDH-wildtype (n=15) tumors, 85% (33/39) versus 47% (7/15) reported ever having a seizure and 7 of 33 (21%) with IDH-mutant and 1 of 7 (14%) with IDH-wild type (IDH-WT) tumors respectively reported a seizure since the last visit. Disparities in recognition of seizures between patient and clinician highlights a need for patient education to increase awareness of events and recognition of ongoing risk. Although those with IDH-mutated tumors are at higher risk of having seizures, nearly half of those with IDH-WT reported ever having seizures, underscoring the need for all patients to be educated on recognizing and assessing seizure symptoms. Citation Format: Hope Miller, Ewa Grajkowska, Alvina Acquaye-Mallory, Anna Choi, Jennifer Reyes, Mark R. Gilbert, Edward K. Avila, Terri S. Armstrong, Elizabeth Vera. Seizure self-report and monitoring: Agreement between patient and clinician report and implications for care in patients with IDH-mutant and IDH-wild type gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6304.

Abstract 7453: Psychometric analysis of Neuro-QoL Perceived Cognitive Function tool in primary brain tumor patients

Abstract Cognitive dysfunction is commonly reported but variable in course and severity in the primary brain tumor (PBT) population. Brief, reliable, and sensitive measures of patient-reported outcomes (PRO) of cognitive symptoms on function are needed for clinical care and research. This study aims to assess the reliability and validity of the Neuro-QoL Perceived Cognitive Function tool (NQC) and explore associations with symptoms and objective testing of cognitive dysfunction in a cohort of PBT patients enrolled in a natural history study (NCT02851706: PI T. Armstrong). Patient sample characteristics and PROs, including NQC (&amp;lt;40 = moderate/severe (MS) dysfunction), a symptom burden measure (MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT), scores ≥5 = MS) and the Montreal Cognitive Assessment ((MoCA), scores ≤ 25 indicating cognitive impairment (range: 0-30)) were collected. Descriptive statistics and a psychometric analysis consisting of bivariate correlations, Cronbach’s alpha, and factor analyses using principal axis factoring with nonorthogonal rotation were performed. Cohen’s kappa and correlation were used to assess agreement between objective and subjective measures of cognitive function. The cohort included 327 patients who completed the NQC at study entry [median age: 47 years (range: 18-85), primarily white (78%) males (55%) with high-grade tumors (73%), 65% with a Karnofsky Performance Status (KPS) ≥ 90 (good), and 29% reporting MS cognitive dysfunction]. Factor analysis of the NQC identified two underlying factor groupings: concentration/focus and executive function with Cronbach’s alphas of 0.92 and 0.91 that are interpretable and provided adequate fit for the data. While the NQC was moderately correlated with several MDASI-BT symptom factors, it was highly associated with the cognitive factor (r = -.646). To assess agreement, a subset of patients also completed the MoCA (n=172). These were primarily male (58%), white (79%), had high-grade tumors (67%), and a good KPS score (67%). In this subset, 24% had MS cognitive dysfunction as measured by the NQC while 44% were cognitively impaired using the MoCA resulting in a kappa agreement of 0.07. The correlation between the MoCA score and NQC T-score was -0.292. Understanding the impact and prevalence of cognitive symptoms, objective cognitive testing, and perceived impact is essential for PBT patient care and identifying supportive care interventions. Select NQC psychometric properties demonstrate reliability and validity in this population, with strong agreement with self-report of cognitive symptoms but weaker correlation with objective testing, highlighting the variability in perceived impact. Future research in cognitive function will explore the use of objective testing and perceived impact, its predictors in select populations (i.e., IDH-mutant tumors), and examine its association with biomarkers. Citation Format: Morgan L. Johnson, Elizabeth Vera, Kimberly Reinhart, Hope Miller, Anna Choi, Tricia Kunst, Bennett McIver, Ewa Grajkowska, Michelle L. Wright, Terri S. Armstrong, Tito Mendoza. Psychometric analysis of Neuro-QoL Perceived Cognitive Function tool in primary brain tumor patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7453.

Abstract 1309: Assessment of geographic and socioeconomic factors in primary brain tumor patient accrual to a natural history study

Abstract Purpose: To better understand neuro-oncology trial access barriers in the United States (US), we assessed the role of geography, population density, and socioeconomic factors in the accrual of adult primary brain tumor patients in the Natural History Study (NHS, NCT02851706) at the National Institutes of Health (NIH). Methods: Participant addresses were linked to zip code geography and population data from the US Census and the Neighborhood Atlas Area Deprivation Index (ADI; 1 to 100 from least to most disadvantaged). Locations with population density greater than 1000 inhabitants per square mile were considered urban. Locations were categorized based on their distance from NIH as local (&amp;lt;50 mi), short-distance (50-200mi) and long-distance (&amp;gt;200 mi). T-tests, chi-square tests, and multivariate logistic regression compared socioeconomic and urbanity factors. Results: 667 NHS participants arrived from 43 states and territories, with the majority (61%) from Maryland and neighboring states, and other states contributing no more than 5% of the participants each. The home locations of the participants were disproportionately urban (60% versus 19% of all US locations, p &amp;lt;0.001) and socioeconomically advantaged (mean ADI 26.94 versus 57.30 across all US locations, p&amp;lt;0.001). Local participants (49%) had greater racial and ethnic diversity (73% White, 11% Black, 9% Asian, 2% other; 11% Hispanic/Latino) compared to short-distance participants (11% total; 96% White, 3% Black, 0% other; 0% Hispanic/Latino) and long-distance participants (39% total; 89% White, 3% Black, 3% Asian, 2% Other; 6% Hispanic/Latino). Local participants lived in the most socioeconomically advantaged locations (mean ADI 16.39) compared to short-distance (mean ADI 40.88, p&amp;lt;0.001) and long-distance (mean ADI 39.69, p&amp;lt;0.001) participants. Short-distance participants were from disproportionally non-urban areas (69%) compared to local (28%, p&amp;lt;0.001) and long-distance (46%, p&amp;lt;0.001) participants. Multivariate analysis also confirmed that local participants were more likely to live in more advantaged areas than short-distance (OR=0.90, p&amp;lt;0.001) and long-distance (OR=0.93, p&amp;lt;0.001) participants, and short-distance participants were less likely to live in urban areas compared to local (OR=0.19, p&amp;lt;0.001) and long-distance (OR=0.44, p=0.008) participants. Conclusion: The trial enrolled patients across the US, albeit with most participants arriving from neighboring states and socioeconomically advantaged, urban areas. Greater rural patient participation from nearby areas reflects the positive impact of NIH subsidies in reducing the financial challenges linked to participating in clinical trials. Current trends indicate that continued and targeted efforts to enable participation from local disadvantaged communities can ameliorate access to neuro-oncology clinical care and research. Citation Format: Yeonju Kim, Macy L. Stockdill, Elizabeth Vera, Hope Miller, Jacqueline B. Vo, Mark R. Gilbert, Terri S. Armstrong, Orieta Celiku. Assessment of geographic and socioeconomic factors in primary brain tumor patient accrual to a natural history study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1309.