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Alessandra Spagnolo, Roberta P. Glick, Henry Lin, Edward P. Cohen, Douglas L. Feinstein, and Terry Lichtor


In this study the authors explored the benefits of treating C57Bl/6 mice with an established intracerebral glioma by combining immunotherapy with interleukin (IL)-2–secreting syngeneic/allogeneic fibroblasts administered into the tumor bed along with the chemotherapeutic agent pioglitazone, a thiazolidinedione (TZD). The TZDs are agonists of the peroxisome proliferator-activated receptor–γ. They have been found to exert antiproliferative effects on several transformed cell lines. Data from prior studies by these authors have revealed the immunotherapeutic properties of the IL-2–secreting fibroblasts in treating intracerebral gliomas in mice.


The sensitivity of GL261 glioma cells and primary astrocytes to pioglitazone was determined in vitro by incubating the cells with increasing amounts of the drug. Viability was assessed by measuring lactate dehydrogenase release, and effects on metabolism were determined by measuring superoxide production and levels of superoxide dismutase. The GL261 cells were injected intracerebrally into C57Bl/6 mice, followed by treatment with pioglitazone either orally or intracerebrally into the tumor bed. The effect of the combined therapy was determined by injecting C57Bl/6 mice with an established intracerebral GL261 glioma with IL-2–secreting allogeneic fibroblasts and pioglitazone directly into the tumor bed through a unique cannula system.

Pioglitazone was found to induce cell death in GL261 glioma cells grown in vitro while causing only modest damage to astrocytes. The application of pioglitazone also resulted in a significantly greater induction of cellular superoxide in glioma cells than in astrocytes, which can activate apoptotic pathways. Pioglitazone administered intracerebrally (p < 0.05) but not orally was found to prolong survival in mice harboring an intracerebral glioma. Synergistic effects of combination therapy on prolonging survival were found in mice receiving both pioglitazone and IL-2–secreting fibroblasts (p < 0.005, compared with untreated animals). Pioglitazone induces metabolic and oxidative stresses that are tolerated by astrocytes but not glioma cells, which could account for selective vulnerability and increased sensitivity to IL-2, suggesting potential for the use of this Food and Drug Administration–approved drug in the treatment of brain tumors.


The data indicate the beneficial effects of combination therapy using pioglitazone and immunotherapy in mice harboring intracerebral glioma.

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Alan R. Tang, Philip J. Davis, Kristen L. Williams, Alan Z. Grusky, Katherine S. Hajdu, Brian Q. Hou, Aaron M. Yengo-Kahn, Scott L. Zuckerman, and Douglas P. Terry


Adolescents sustaining sport-related concussion often experience difficulties with the return-to-learn (RTL) process. Whereas the initial symptom burden has predicted prolonged RTL, no studies have established a relationship between acute cognitive symptoms and RTL duration. The authors sought to evaluate the relationship between initial cognitive symptoms and RTL duration.


A retrospective single-institution cohort study of adolescent athletes aged 12–23 years who were evaluated within 5 days of a diagnosed sport-related concussion between November 2017 and October 2020 was conducted. Athletes missing cognitive symptom ratings and RTL data were excluded. The primary exposure variable was the Cognitive Symptom Ratio (CSR), defined as total cognitive symptom cluster score divided by total Post-Concussion Symptom Scale (PCSS) score from the initial clinic visit. Primary and secondary outcomes were time to RTL and total length of care, respectively. Multivariable Cox proportional hazards modeling was used to assess the effect of CSR on RTL duration.


Of 653 athletes evaluated within 5 days of injury, 346 patients were included in the final cohort. Athletes reported a median initial PCSS score of 21 (interquartile range [IQR] 6–37) and a median cognitive symptom score of 4 (IQR 0–9). Most patients endorsed some degree of difficulty concentrating (n = 212, 61.3%). The median CSR was 0.18 (IQR 0.00–0.27). On multivariable regression analysis, a higher CSR was associated with prolonged RTL duration (HR 0.30, 95% CI 0.13–0.69, p = 0.004). When initial PCSS score was added to the model, the previously significant association between CSR and RTL was no longer significant (HR 0.67, 95% CI 0.29–1.59, p = 0.367). When dichotomized based on frequency distribution, a higher proportion of patients with low CSR achieved RTL by 7 days postinjury (82.2% vs 69.9%, p = 0.007), a difference not seen at 14 days (92.2% vs 87.3%, p = 0.133).


An acute ratio of cognitive symptoms may predict patients at increased risk for prolonged RTL and those with normal PCSS scores who may experience difficulties once resuming school activities.

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Oral Presentations

2010 AANS Annual Meeting Philadelphia, Pennsylvania May 1–5, 2010