precision medicine algorithm for n=30 patients with reports being dissemi- nated to treating neuro-oncology teams. WES data is ultimately presented at.
Abstracts
precision medicine algorithm for n=30 patients with reports being disseminated to treating neuro-oncology teams. WES data is ultimately presented at the multi-disciplinary precision medicine tumor board on a bi-weekly basis. The reporting mechanism time interval from initial receipt of all materials necessary for WES is roughly 6-8 weeks. Roughly 20% of somatic alterations detected from WES sequencing have yielded molecular targets that may have specificity for FDA approved compounds. CONCLUSION: We strongly encourage patients to enroll in our precision medicine pathway. The WES platform capture reads for over 20,000 genes and offers a unique data set that may shed light on both known cancer relevant somatic alterations but also functional relevance for less known mutations on a case-specific basis. PDTB-28. TARGETING MEDULLOBLASTOMA WITH BENZODIAZAPINES DELIVERED USING TUNABLE BIODEGRADABLE HYDROGELS Laura Kallay1, Daniel Pomeranz Krummel1, Kashi Reddy Methuku2, Zhaobin Zhang1, James Cook2, Jeffrey Olson1, Daniel Brat1, Tobey MacDonald1, Stefanie Sydlik3 and Soma Sengupta1; 1Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA, 2University of Wisconsin, Milwaukee, WI, USA, 3Carnegie Mellon University, Pittsburgh, PA, USA Medulloblastoma (MB) is a common pediatric malignant primary brain tumor originating in the posterior fossa. MB is generally classified into one of four molecular subgroups: Wnt, Shh, Group 3, and Group 4. Subgroup 3 is the most clinically aggressive of the four and exhibits a molecular signature that includes over expression of the GABRA5 receptor. Previously, we reported on use of a novel microdevice to screen a broad range of benzodiazepine compounds that functioned as GABRA5 agonists (Jonas et al., 2016). This study identified a new benzodiazepine compound (KRM-II-08) that was particularly efficacious and thus an attractive candidate as a therapeutic against Group 3 medulloblastoma. The Cook laboratory have now synthesized a new series of benzodiazepine derived allosteric modulators. These compounds will initially be tested in tissue culture, those that are efficacious will be tested in the nude mouse tumor xenograft model. While the microdevice used previously provided a superb platform to screen a number of compounds in the same tumor, it is not a satisfactory system to bring forward into the clinic for brain tumor treatment. We are therefore exploring use of biodegradable hydrogels where the compounds are chemically “clicked” onto a modified chondroitan sulfate or hyaluronic acid (HA). Importantly, the hydrogels being employed have mechanical properties and covalent modifications to allow for the tunable release of the benzodiazepines in targeting medulloblastoma tumors. We will report on the progress in characterizing the new benzodiazepine compounds under study and the design of and observations regarding use of hydrogel formulations employed. Reference: Jonas O., Calligaris D., Muthuku K.R. et al. (2016) J. Biomed. Nanotech. 12: 1-6.
QUALITY OF LIFE QLIF-01. PERCEIVED EFFECTIVENESS OF MANAGEMENT STRATEGIES USED BY NEURO-ONCOLOGY FAMILY CAREGIVERS Mary C. Roberge1, Susan H. Hughes1, Jason Weimer1, Susan Misko1, Terri Armstrong2, Paula Sherwood1,3 and Heidi Donovan1; 1University of Pittsburgh School of Nursing, Pittsburgh, PA, USA, 2University of Texas Health Science Center, Houston, TX, USA, 3University of Pittsburgh Medical Center, Pittsburgh, PA, USA BACKGROUND: Family caregivers (CG’s) of patients with primary malignant brain tumors (PMBT) face psychological and physical health challenges as a consequence of providing this level of care. These CG’s are high-risk for poor outcomes as they manage both cancer-related and neurodegenerative-related issues. SmartCare© (R01 NR013170) is a 3-arm randomized-controlled trial testing an Internet- and telephone-based caregiver support intervention. PURPOSE: This analysis presents the most common care issues worked on by CG’s in the intervention arm, types of strategies used to manage issues, and types of strategies perceived as most effective. METHODS: Of the 66 CG’s randomized to SmartCare© intervention, 33 CG’s selected issues, wrote goals, developed strategies and evaluated the effectiveness of these strategies. Individual CG strategies were classified according to seven dimensions of the Health Education Impact Questionnaire, an evaluation measure for psycho-educational interventions. RESULTS: Caregivers selected 22 of 32 possible issues during intervention. The four most-commonly chosen issues were: maintaining CG emotional health, maintaining CG physical health, managing patient muscle weakness (each n=6; 10.5%), and changes in patient thinking and behavior (n=5; 8.8%). Caregivers worked on an average 1.6+/-0.79 issues
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during the intervention and used 4+/-1.56 types of strategies. Most common strategy-types used were Health-Directed Behaviors (e.g. exercise), Skill Acquisition, and Healthcare Navigation. The type of strategy with the highest effectiveness rating was Positive and Active Engagement in Life (e.g. taking a break from caregiving) (8.13+/-1.66); the strategy rated least effective was Skill Acquisition (6.82+/-2.93). CONCLUSIONS: Understanding how family caregivers select and use management strategies to effectively work to manage care is critical to advancing the science of caregiver interventions. QLIF-03. MUTANT IDH1 PROMOTES TUMOR-ASSOCIATED EPILEPSY IN GLIOMA PATIENTS Hao Chen1, Jonathon Judkins2, Farhad Ghamsari2, Pamela Lein1 and Craig Horbinski3; 1University of California, Davis, Davis, CA, USA, 2Northwestern University Feinberg School of Medicine, Chicago, IL, USA, 3Departments of Pathology and Neurosurgery at Northwestern University, Chicago, IL, USA Seizures are a major quality-of-life issue for patients with infiltrative gliomas. Over 50% will experience at least one seizure during the course of their disease, and over 30% will develop tumor-associated epilepsy (TAE), defined as multiple seizures. Lower-grade gliomas are more likely to cause TAE than glioblastomas (GBMs), though the reasons for this are unclear. Grade II-III gliomas are far more likely to contain mutations in isocitrate dehydrogenase 1 (IDH1mut) than grade IV GBMs. The product of IDH1mut, D-2-hydroxyglutarate (D2HG), is released by tumor cells into the microenvironment. D2HG is structurally similar to a powerful excitatory neurotransmitter, glutamate, which triggers neuronal depolarization by opening NMDA channels. Therefore, we hypothesized that IDH1mut increases seizure risk through the activity of D2HG on neurons within and around the tumor. In 3 cohorts from separate institutions (total N=712), seizures were a part of the presenting symptoms in 18-34% of IDH1 wild-type (IDH1wt) patients and in 59-74% of IDH1mut patients (P
