Faculty Bibliography

Glioblastoma (GBM) stem cells (GSCs) reside in both hypoxic and vascular microenvironments within tumors. The molecular mechanisms that allow GSCs to occupy such contrasting niches are not understood. We used patient-derived GBM cultures to identify GSC subtypes with differential activation of Notch signaling, which co-exist in tumors but occupy distinct niches and match their metabolism accordingly. Multipotent GSCs with Notch pathway activation reside in perivascular niches, and are unable to entrain anaerobic glycolysis during hypoxia. In contrast, most CD133-expressing GSCs do not depend on canonical Notch signaling, populate tumors regardless of local vascularity and selectively utilize anaerobic glycolysis to expand in hypoxia. Ectopic activation of Notch signaling in CD133-expressing GSCs is sufficient to suppress anaerobic glycolysis and resistance to hypoxia. These findings demonstrate a novel role for Notch signaling in regulating GSC metabolism and suggest intratumoral GSC heterogeneity ensures metabolic adaptations to support tumor growth in diverse tumor microenvironments.

Practice sharpens our perceptual judgments, a process known as perceptual learning. Although several brain regions and neural mechanisms have been proposed to support perceptual learning, formal tests of causality are lacking. Furthermore, the temporal relationship between neural and behavioral plasticity remains uncertain. To address these issues, we recorded the activity of auditory cortical neurons as gerbils trained on a sound detection task. Training led to improvements in cortical and behavioral sensitivity that were closely matched in terms of magnitude and time course. Surprisingly, the degree of neural improvement was behaviorally gated. During task performance, cortical improvements were large and predicted behavioral outcomes. In contrast, during nontask listening sessions, cortical improvements were weak and uncorrelated with perceptual performance. Targeted reduction of auditory cortical activity during training diminished perceptual learning while leaving psychometric performance largely unaffected. Collectively, our findings suggest that training facilitates perceptual learning by strengthening both bottom-up sensory encoding and top-down modulation of auditory cortex.

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

Importance: Research in facial aging has focused on soft-tissue changes rather than bony changes despite evidence of the importance of underlying bony structural changes. Research has also been limited by comparing different patients in separate age groups rather than the same patients over time. Objective: To longitudinally document patterns of change in the facial skeleton and determine a consistent methodology for measuring these changes. Design, Setting, and Participants: Case series study of university hospital system records using facial computed tomographic (CT) images timed at least 8 years apart in adults initially aged 40 to 55 years with no history of facial surgery who required repeated facial imaging that included the entire midface and cranium. Main Outcomes and Measures: Face CTs were analyzed for 3-dimensional constructions and 2-dimensional measurements to document changes in glabellar, piriform, and maxillary angles and piriform height and width. Results: Fourteen patients (5 men, 9 women; mean [SD] age, 51.1 [5.8] years) with mean (SD) follow-up of 9.7 (1.4) years were eligible for 2-dimensional analysis, which revealed statistically significant decreases in mean (SD) glabellar angles (from 68.8 degrees [7.6 degrees ] to 66.5 degrees [8.6 degrees ]) and maxillary angles on both the right (from 82.5 degrees [6.3 degrees ] to 81.0 degrees [7.1 degrees ]) and left (from 83.0 degrees [5.8 degrees ] to 81.0 degrees [7.0 degrees ]), as well as increases in mean (SD) piriform width (from 24.5 [1.6] mm to 25.5 [1.3] mm). Nine patients (3 men, 6 women; mean [SD] age, 51.4 [6.3] years) with mean (SD) follow-up imaging at 9.6 (1.5) years were eligible for 3-dimensional analysis, which revealed statistically significant decreases in mean (SD) maxillary angles (from 56.5 degrees [6.6 degrees ] to 51.6 degrees [7.6 degrees ]) and piriform angles (from 50.8 degrees [3.4 degrees ] to 49.1 degrees [3.4 degrees ]). Statistically significant differences between the sexes were also noted: Initial mean (SD) glabellar angle for men was 61.7 degrees (5.7 degrees ) vs 72.7 degrees (5.4 degrees ) for women, with final values of 57.9 degrees (4.9 degrees ) vs 71.2 degrees (6.0 degrees ). Mean (SD) maxillary angle initial values were 87.8 degrees (6.1 degrees ) (right) and 87.1 degrees (4.9 degrees ) (left) for men, with 79.6 degrees (4.3 degrees ) and 80.6 degrees (5.0 degrees ) for women, respectively. Final values were 87.0 degrees (4.4 degrees ) and 86.9 degrees (4.1 degrees ) for men and 77.7 degrees (6.1 degrees ) and 77.7 degrees (6.2 degrees ) for women, respectively. Mean (SD) piriform height for men was 35.0 (2.0) mm initially and 35.5 (2.1) mm finally, vs 31.3 (2.8) and 31.6 (3.0) mm for women, respectively. Conclusions and Relevance: Our pilot study of repeated CT images of patients over several years supports previous studies of bony facial aging and further characterizes these changes. This study is the first, to our knowledge, to document bony changes of the face in the same group of patients at different time points to better characterize facial aging. We also detail an improved methodology to study bony aging to contribute to additional research in the field. Level of Evidence: NA.

BACKGROUND: Concurrent chemoradiation (CCRT) and upfront surgery followed by adjuvant therapy both are recommended treatment options for patients with advanced stage squamous cell carcinoma (SCC) of the tonsil. To the authors' knowledge, the question of whether surgical-based treatments can achieve better survival compared with CCRT has never been compared in a clinical trial. The authors analyzed the National Cancer Data Base to measure the impact of different treatment modalities on overall survival (OS). METHODS: All patients aged