Citations

AbstractBackgroundFrontotemporal dementia (FTD) can present with significant phenotypic heterogeneity. Most cases of sporadic FTD do not present for diagnosis until functional impairment is evident, making it difficult to identify and characterize the earliest features of FTD. Focusing on participants from families with known FTD‐causing pathogenic mutations allows for the characterization of the earliest features of FTD in genetic carriers.MethodThe ARTFL and LEFFTDS consortia (AG063911, AG045390, NS092089, AG016976) are joint, multi‐center cohort studies of patients with FTLD, including symptomatic and asymptomatic family members. For this study, a subset of ARTFL/LEFFTDS participants from families with known genetic mutations were selected if they were determined by a study physician to have (a) a phenotype of Mild Behavioral / Cognitive Impairment (MBI/MCI) and CDR®+NACC‐FTLD = 0.5 (44 participants, 19 C9orf72, 12 GRN, 13 MAPT mutations), or (b) CDR®+NACC‐FTLD = 1 (33 participants, 16 C9orf72, 10 GRN, 7 MAPT mutations). We examined the NACC Uniform Data Set (UDS) B9F form, bvFTD criteria. Pearson chi‐squared tests compared the frequency of identified bvFTD features between MBI/MCI and bvFTD participants.ResultThe most common bvFTD diagnostic criteria features questionably or definitely present in the 44 MBI/MCI participants were Apathy and Disinhibition, both at 30% (Within the early FTLD group: Apathy at 70% and Disinhibition at 72%). Neuropsychological testing deficits consistent with bvFTD were present in 27% (72%), and loss of empathy in 25% (72%). Impaired daily functioning was next at 16% (81%), Ritualistic behaviors were observed in 7%, (36%) and Hyperorality in 5% (33%). Chi‐squared tests revealed significant differences between the two groups for all features, with the largest numerical and statistical difference in impaired daily functioning.ConclusionApathy and Disinhibition were the most common neuropsychiatric symptoms noted in FLTD MBI/MCI. Development of impairments in daily functioning best distinguished the MBI/MCI and FTLD groups. This may be related to the requirement of functional impairment for the diagnosis of dementia. The relative frequency of different features in early dementia of genetic FTLD is similar to that reported in sporadic bvFTD. As more longitudinal data is collected, within‐subject assessment of the development of features in genetic bvFTD over time will be instructive.

AbstractBackgroundRecently, hearing loss has been identified as a promising modifiable risk factor for dementia. Several hypotheses explaining a potential underlying pathway have been proposed, including the sensory deprivation hypothesis, describing a direct causal relationship in which hearing loss leads to neuroplastic changes in the brain. Indeed, hearing loss has been associated with smaller macrostructural brain volumes, which is believed to at least partly explain the association between hearing loss and neurodegenerative disease. However, microstructural changes precede macrostructural changes. Therefore, we aimed to assess the association between hearing loss and microstructural integrity of the brain.Methods1,086 dementia‐free older adults from the Atherosclerosis Risk in Communities (ARIC) study (mean age = 75.2 [SD: 4.9], 61.4% female) underwent hearing assessment (2016‐2017) and magnetic resonance imaging (MRI) of the brain (2011‐2013). Hearing was assessed with pure‐tone audiometry. Microstructural integrity (fractional anisotropy (FA) and mean diffusivity (MD)) of multiple brain regions was determined with diffusion tensor imaging (DTI). Multivariable linear regression models were used to investigate the association between hearing loss and microstructural integrity of the lobes, temporal lobe gyri, medial temporal lobe structures and white matter (WM) tracts, adjusting for relevant confounders.ResultHearing loss was associated with lower WM microstructural integrity in the temporal lobe (difference in SD FA for moderate/severe hearing loss as compared to normal hearing: ‐0.19 [95% CI: ‐0.35, ‐0.03]; and difference in SD MD for moderate/severe hearing loss as compared to normal hearing: 0.15 [95% CI: 0.01, 0.28]). Hearing loss was associated with lower gray matter (GM) microstructure of the hippocampus, but not the amygdala. Moreover, hearing loss was associated with lower WM microstructural integrity of the limbic tracts and the uncinate fasciculus (Figure 1).ConclusionOur results demonstrate that age‐related hearing loss is associated with lower WM microstructural integrity in the temporal lobe, the limbic tracts and the uncinate fasciculus and lower GM microstructure in the hippocampus. These associations suggest that poorer hearing may affect brain regions that are important for different cognitive processes. However, the results should be interpreted with caution as this study is of a cross‐sectional design.

Abstract PURPOSE Previous secondary analysis of NRG/RTOG 0933 provided hypothesis-generating data supporting a relationship between larger volumes of MR-determined pre-treatment WMI and developing neurocognitive decline following HA-WBRT. The current study examines the relationship between pre-treatment WMI and neurocognitive function (NCF) following WBRT+memantine +/-HA in a substantially larger cohort. METHODS NCF testing was performed at baseline,2,4,6,and 12 months post-WBRT, and included Hopkins Verbal Learning Test–Revised (HVLT-R), Trail Making Test (TMT) Parts A and B, and Controlled Oral Word Association (COWA). Pre-treatment WMI was measured by FLAIR volume corrected for whole brain volume and corrected for the FLAIR volume associated with metastases (FLAIR/(whole brain volume – metastasis FLAIR volume). Pearson correlation coefficients were used to assess association between pre-treatment WMI and change from baseline for each standardized NCF score. RESULTS Of 518 randomized patients, 442 (217,WBRT+Memantine; 225,HA-WBRT+Memantine) had WMI data and were included. In the entire cohort, mean FLAIR volume was 9.3cc (0.1-68.2cc), mean metastases FLAIR volume was 61.5cc (0-423.5cc), mean Whole Brain volume was 1336.4cc (949.4-2397.8cc). At 2 months, there were no significant correlations between neurocognitive test change scores and pre-treatment WMI volume. However, at 4 months, both HVLT-R Total Recall and TMT Part B change score and pre-treatment WMI volume were significantly negatively correlated on the HA-WBRT+Memantine arm (ρ=-0.22 p=0.042 and ρ=-0.27, p=0.013). At 12 months, both TMT Part A and TMT Part B change scores and pre-treatment WMI volume were significantly negatively correlated on the HA-WBRT+Memantine arm (ρ=-0.30, p=0.046 and ρ=-0.53, p< 0.001). CONCLUSIONS Pre-treatment WMI volume was a significant imaging-biomarker predictor of post-treatment neurocognitive decline at 4-and 12-months following HA-WBRT+Memantine. This suggests patients with greater pre-treatment WMI were more susceptible to neurocognitive decline, specifically when undergoing HA-WBRT, but not following standard WBRT. Dose heterogeneity inherent to HA-WBRT delivery may contribute to these findings and are hypothesis generating.

Abstract Background: Tumor infiltrating lymphocytes (TILs) play an important, but incompletely understood role in chemotherapy response and prognosis. In breast cancer, there appear to be distinct immune responses by subtype, but most studies have used limited numbers of protein markers or bulk sequencing of RNA to characterize immune response, in which spatial organization cannot be assessed. Methods: To identify immune phenotypes of Basal-like vs. Luminal breast cancer we used the GeoMx® (NanoString) platform to perform digital spatial profiling (DSP) of immune-related proteins in tumor whole sections and tissue microarrays (TMA). Visualization of CD45, CD68, or pan-Cytokeratin by immunofluorescence was used to select regions of interest (ROIs) in formalin-fixed paraffin embedded tissue sections. 44 antibodies representing stromal markers and multiple immune cell types were applied to quantify the tumor microenvironment. Results: In whole tumor slides, immune hot spots (CD45+) had increased expression of many immune markers, suggesting a diverse and robust immune response. In epithelium-enriched areas, immune signals were also detectable and varied by subtype, with Regulatory T cell (Treg) markers (CD4, CD25, FOXP3) being higher in Basal-like vs. Luminal breast cancer. Extending these findings to TMAs with more patients (n=75), we confirmed subtype-specific immune profiles, including enrichment of Treg markers in Basal-likes. Conclusion: This work demonstrated that immune responses can be detected in epithelium-rich tissue, and that TMAs are a viable approach for obtaining important immunoprofiling data. In addition, we found that immune marker expression is associated with BC subtype, suggesting possible prognostic or targetable differences. Citation Format: Andrea Walens, Linnea T. Olsson, Xiaohua Gao, Alina M. Hamilton, Erin L. Kirk, Stephanie M. Cohen, Bentley R. Midkiff, Yongjuan Xia, Mark E. Sherman, Nana Nikolaishvili-Feinberg, Katherine A. Hoadley, Melissa A. Troester, Benjamin C. Calhoun. Protein-based immune profiles of basal-like vs luminal breast cancers [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-090.

AbstractObjectiveMAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach.MethodsWe studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers’ clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson’s disease (1), and mild cognitive impairment (1). We performed voxel‐based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype.ResultsSymptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers.InterpretationA subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

Abstract Background Glioblastomas (GBMs) are the main primary brain tumors in adults with almost 100% recurrence rate. Patients with lateral ventricle proximal GBMs (LV-GBMs) exhibit worse survival compared to distal locations for unknown reasons. One hypothesis is the proximity of these tumors to the cerebrospinal fluid (CSF) and its chemical cues that can regulate cellular phenotype. We therefore investigated the role of CSF on GBM gene expression and the role of a CSF-induced gene, SERPINA3, in GBM malignancy in vitro and in vivo. Methods We utilized human CSF and GBM brain tumor-initiating cells (BTICs). We determined the impact of SERPINA3 expression in glioma patients using The Cancer Genome Atlas (TCGA) database. SERPINA3 expression changes were evaluated at mRNA and protein levels. The effects of knockdown (KD) and overexpression (OE) of SERPINA3 on cell migration, viability and cell proliferation were evaluated. Stem cell characteristics on KD cells were evaluated by differentiation and colony formation experiments. Tumor growth was studied by intracranial and flank injections. Results GBM-CSF increased BTIC migration accompanied by upregulation of the SERPINA3 gene. In patient samples and TCGA data, we observed SERPINA3 to correlate directly with brain tumor grade and indirectly with GBM patient survival. SERPINA3 KD induced a decrease in cell proliferation, migration, invasion, and stem cell characteristics, while SERPINA3 OE increased cell migration. In vivo, SERPINA3 KD BTICs showed increased survival in a murine model. Conclusions SERPINA3 plays a key role in GBM malignancy and its inhibition results in a better outcome using GBM preclinical models.

Background Metastasectomy is standard of care for pediatric patients with metastatic sarcoma with limited disease. For patients with unresectable disease, stereotactic body radiotherapy (SBRT) may serve as an alternative. Herein, the authors report the results of a prospective, multi‐institutional phase 2 trial of SBRT in children and young adults with metastatic sarcoma. Methods Patients aged >3 years and ≤40 years with unresected, osseous metastatic nonrhabdomyosarcoma sarcomas of soft tissue and bone were eligible. Patients received SBRT to a dose of 40 Gray (Gy) in 5 fractions. Local control (LC), progression‐free survival (PFS), and overall survival (OS) were calculated using the Kaplan‐Meier method. Results Fourteen patients with a median age of 17 years (range, 4‐25 years) were treated to 37 distinct metastatic lesions. With a median follow‐up of 6.8 months (30.5 months in surviving patients), the Kaplan‐Meier patient‐specific and lesion‐specific LC rates at 6 months were 89% and 95%, respectively. The median PFS was 6 months and the median OS was 24 months. In a post hoc analysis, PFS (median, 9.3 months vs 3.7 months; log‐rank P = .03) and OS (median not reached vs 12.7 months; log‐rank P = .02) were improved when all known sites of metastatic disease were consolidated with SBRT compared with partial consolidation. SBRT was well tolerated, with 2 patients experiencing grade 3 toxicities. Conclusions SBRT achieved high rates of LC in pediatric patients with inoperable metastatic nonrhabdomyosarcoma sarcomas of soft tissue and bone. These results suggest that the ability to achieve total consolidation of metastatic disease with SBRT is associated with improved PFS and OS.

Abstract Attendance at professional conferences is an important component of career development, because conferences are a major forum for presenting new research, interacting with colleagues and networking. An extensive literature documents differences in the professional experiences of women and men, including experiences at professional conferences. We hypothesized that women are less likely than men to ask questions at conferences, thus forgoing opportunities for professional development. To address this issue, we analyzed the question-asking behavior of women and men at the 2019 Annual Meeting and Exposition of the American Society of Hematology. In all, 112 sessions (55% of those eligible) were randomly chosen for coding, yielding data on 577 presentations. Although approximately 50% of moderators and speakers were women, the proportion of questions asked by women was significantly lower compared with the estimated proportion of women attending the conference (23% vs 39%; P < .0001). Women were more likely to ask questions if another woman asked the first question or if the session topic was red cells. These results suggest that although women are represented equally as moderators and speakers, they are less likely to engage in the postpresentation discourse by asking questions. Encouraging women to speak up in professional situations and providing training on question-asking skills can help address this gender gap that potentially contributes to disparities in professional visibility and career advancement for women in hematology.