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Background The current standard of care for glioblastoma (GBM) constitutes maximal safe surgical resection, followed by fractionated radiation and temozolomide. This treatment regimen is logistically burdensome, and in a health care system in which access to care is variable, there may be patients with worsened outcomes due to inadequate access to optimal treatment. Methods The National Cancer Database was queried for patients with diagnoses of GBM in 2006-2014. Patients were grouped according to insurance status: private insurance, Medicare, Medicaid, or uninsured. Treatments provided (surgery, radiation, and chemotherapy) were compared between groups in univariate and multivariable logistic regression analysis. Results A total of 61614 patients were analyzed. Compared with private insurance, the odds of surgery for Medicaid and uninsured patients were 0.72 (95% CI: 0.66-0.79) and 0.77 (95% CI: 0.69-0.87), respectively (P < 0.001). The multivariable odds of receiving radiotherapy were 0.91 (95% CI: 0.86-0.96), 0.62 (95% CI: 0.57-0.68), and 0.47 (95% CI: 0.43-0.52) for Medicare, Medicaid, and uninsured patients, respectively (all P < 0.001). In addition, the odds of receiving chemotherapy were 0.94 (95% CI: 0.89-0.99), 0.53 (95% CI: 0.49-0.57), and 0.41 (95% CI: 0.38-0.46) for Medicare, Medicaid, and uninsured patients, respectively (all P < 0.001). Conclusion Insurance status and type of insurance coverage appear to impact treatments rendered for GBM, independently of other variables. Furthermore, we find that such differential access to care significantly impacts survival. Ensuring adequate access to care for all patients with diagnoses of glioblastoma is critical to optimize survival, especially as therapies continue to advance.

OBJECTIVE The K16ApoE peptide enhances delivery of multiple agents across the blood-brain barrier (BBB). Transgenic mouse models are central to elucidating the underlying pathophysiology of Alzheimer’s Disease (AD) and provide a system for evaluating novel therapeutic strategies. PET imaging plays a central clinical role in diagnosing human cases of AD but has had variable performance in mouse models. We investigated the role of K16ApoE to enhance delivery of a radiolabeled PET imaging tracer, 11C-PiB and assess whether this corresponds to improved PET sensitivity in APP/PS1 transgenic mice. METHODS Brain-delivery of 11C-PiB was accomplished by successive injections of K16ApoE and 11C-PiB. Distribution of 11C-PiB to the brain and heart was quantified via dynamic PET/CT imaging and digital autoradiography. RESULTS K16ApoE increased the brain uptake of 11C-PiB in both wild-type (WT) and APP/PS1 mice. Administration of K16ApoE increased the PET standard uptake value of 11C-PiB at 5 minutes in WT mice from 1.132 to 2.963 (p=0.006) and in APP/PS1 mice from 0.842 to 3.268 (p=0.016). Enhancement peaked at 5 minutes. Binding was reversible with similarly increased kinetics in both WT and APP/PS1 mice. The absolute values were higher in APP/PS1 mice suggesting increased retention. The increased retention in APP/PS1 mice was consistent with specific binding to A-beta plaques as unlabeled PiB reduced 11C-PiB signal retention. CONCLUSION K16ApoE mediates enhancement of 11C-PiB signal in APP/PS1 mice brains with increased PET sensitivity. There is increased uptake kinetics in both WT and APP/PS1 mice with specific A-beta plaque binding in the latter. This enhanced delivery of the PET tracer has implications for development and testing of new hypotheses and the efficacy of novel therapeutic paradigms. K16ApoE has potential for improving delivery of several agents across the BBB. This has implication for delivery of diagnostic and therapeutic agents for neurodegenerative and neuro-oncologic diseases.

BACKGROUND Oligodendrogliomas are classified as either WHO grade II or III depending on histologic features. Grade often influences treatment decisions. However, there is variability in patient outcome within tumors of similar grade. We hypothesized that copy number burden (CNB) and specific copy number variants (CNV) might be associated with oligodendroglioma grade and prognosis. METHODS Copy number array analyses were performed on 285 molecular oligodendrogliomas (IDH-mutant, 1p/19q-whole arm-codeleted) from the Mayo Clinic internal and consult neuropathology practice and 167 TCGA molecular oligodendrogliomas. CNB was defined as the total number of copy number alterations. The association of CNB and CNV with grade and overall survival (when available) was assessed. All Mayo and TCGA data were evaluated using the ChAS software suite (Thermo- Fisher) and blindly reviewed by a clinical cytogeneticist (RBJ). RESULTS The mean CNB was 5.0 and 10.4 in the Mayo WHO grade II and III oligodendrogliomas, respectively (p = 5.4 x 10–17). Among the TCGA WHO grade II and III oligodendrogliomas the mean CNB was 4.4 and 5.3, respectively (p = 0.034). Common CNVs (occurring in at least 5% of cases) were -4/4q-, +8/8q+, -9/9p-/cnLOH 9p, +11/11q+, -14/14q-, -15 and -18/18q-. Of these, -9/9p-/cnLOH 9p was significantly associated with higher grade in both the Mayo and TCGA cohorts (p = 8.3 x 10-10 and 0.018, respectively). In the TCGA cohort the presence of >10 CNVs or +11/11q+ was associated with a poorer survival (p = 0.016 and 0.006, respectively). CONCLUSIONS CNB is significantly associated with WHO grade in IDH-mutant, 1p/19q co-deleted oligodendrogliomas. The presence of a significantly elevated CNB in some WHO grade II tumors may be suspicious for the presence of unappreciated grade III histologic features. Longer follow-up will be necessary to determine if CNB or single CNVs are associated with survival.

BACKGROUND The prognostic importance of maximal resection of contrast enhancing and non-contrast enhancing disease has been established. Nonetheless, glioblastomas exist within the framework of complex neural circuitry serving cognition, movement, and behavior consequential leading to neurological impairments. The prognostic importance of neurological impairments on survival remains poorly understood. METHODS This is a retrospective, single cohort study from UCSF including 316 eligible patients diagnosed over 20 years with 9.6 years of follow-up. All patients underwent surgical resection for newly diagnosed glioblastoma for whom survival, molecular, preoperative and postoperative MRI images, and clinical data were available. All patients had chemoradiation treated IDH-wild-type glioblastoma with available preoperative and 1-month post-surgical resection neurological outcomes. We employed survival models and recursive partitioning (RPA) to investigate multivariate relationships of overall survival (OS). RESULTS Preoperative neurological impairments were present in 75.6% (n= 239) and new post resection impairments were identified in 37.3% (n=117). Univariate analysis confirmed that new postoperative cognitive impairment [HR 7.91, 95% CI 2.47-25.33] and hemiplegia [HR 3.38, 95% CI 0.83-13.67] (not hemiparesis) impact OS. Risk stratified grouping by RPA demonstrated that gross total resection of contrast enhancing tumor in patients with no new postoperative neurological impairments confers the longest OS (median OS 27.1 months 95%CI 21.5-33.7). Patients with any residual tumor volume after surgery but no new neurological deficits experience a similar survival to younger patients (under 65) with 1 or more new postoperative neurological deficits (median OS 16.6 months 95%CI 15.2-19.2). Shortest OS is identified in patients with any volume of residual tumor plus 1 or more new postoperative neurological deficits and age over 65 (median OS 11.4 months, 95%CI 9.3-13.5). CONCLUSIONS This study confirms that new postoperative neurological impairments impact overall survival in patients with chemoradiation treated IDH-wild-type glioblastoma.

INTRODUCTION: Gliomas are typified by genetic variability and instability. The full potential of molecular genetics to classify tumors has not been realized. We previously proposed a novel glioma classification system that increases the sensitivity and specificity of diagnosis and improve prognostication. We have completed copy number array mutational analyses and a targeted next-generation sequencing 50-gene glioma panel on 148 Mayo Clinic formalin-fixed paraffin-embedded gliomas with subsequent data validation performed on 419 gliomas from the TCGA. RESULTS: Median age at resection was 49 years (range: 17–80; 95% CI: 46.5–51.6 years). There were 36 (24.3%) IDH-mutant, 1p/19q codeleted oligodendrogliomas; 46 (31.1%) IDH-mutant, 1p/19q non-codeleted astrocytomas and 66 (44.6%) IDH-wildtype gliomas. Small terminal alterations (STAs) defined as copy number variations (CNVs) IDH-mutant, 1p/19q non-codeleted tumors. Acquisition of (3)2 STAs was observed in 47% IDH-mutant, 1p/19q non-codeleted versus 27% IDH-wildtype tumors (P=1.8x10(-5)). In the TCGA dataset, these were seen in 67% versus 26% respectively (P=2.8x10(-16)). STAs were glioma subclass-specific and did not correlate with overall genetic instability as determined manually or with a computational method. ATRX loss was observed in 27 of 41 (65.9%) tumors with an ATRX mutation versus 20 of 106 (18.9%) ATRX-wildtype tumors (P=1.3x10(-7)). ATRX loss also correlated with the alternative lengthening of telomeres (ALT) phenotype and was seen in 25 of 31 (80.6%) ALT-positive versus 7 of 55 (12.7%) ALT-negative tumors (P=1.5x10(-9)). STAs were present in 19 of 32 (59.4%) ALT-positive cases and 8 of 35 (22.9%) ALT-negative cases (P=0.0061). CONCLUSION: IDH-mutant, 1p/19q non-codeleted astrocytomas have a high prevalence of STAs. This is associated with ATRX loss and the ALT. These alterations do not appear to have de novo implications for survival but may provide novel diagnostic tools and therapeutic targets.

Meningiomas represent ~30% of primary neoplasms in adults but only 0.4–4.6% in children. Due to the paucity of cases, relatively few studies have addressed pediatric meningiomas and there are insufficient cell lines to conduct in vitro studies. We have established and characterized a new cell line (PED-24) from a 12-year-old male who presented with headaches and subsequently underwent gross total resection of a sporadic, large left frontal meningioma, WHO grade 2. The tumor was focally positive for EMA and GFAP. Whole-exome sequencing of the patient was negative for NF-2. Compared to three high grade glioma lines (two H3K27M DIPG tumors and one adult GBM), PED-24 showed significantly increased growth kinetics as assessed by real-time live-cell analysis. The cells were also successfully cultured as neurospheres in neurobasal medium. Ultrastructural analysis with SEM and TEM demonstrated unique cellular morphology. Average cellular diameter was 3.2 ± 0.3 µm and the cells had a microvilli-covered smooth surface. There was a high burden of transport vesicles and an extensive network of endoplasmic reticulum with evidence of autophagy events. This line provides a resource for further exploration of pathogenic mechanisms involved in sporadic pediatric meningiomas. One novel avenue of interest is the potential presence of a stem-like subpopulation within sporadic pediatric atypical meningiomas.

INTRODUCTION: Pediatric high-grade gliomas including Diffuse Intrinsic Pontine Gliomas (DIPGs) are among the most lethal cancers known with no effective cure. Recently, somatic mutations in the H3F3A or HIST1H3B genes have been detected in the majority of midline high-grade pediatric glioma cases which leads to an amino acid change at lysine 27 of H3 to methionine. In an effort to identify drugs for rapid clinical translation, we performed a rigorous high-throughput in vitro drug screen of FDA approved chemotherapeutics and epigenetic regulators. METHODS: Over 200 drugs were tested including FDA approved cancer drugs and a comprehensive library of epigenetic regulators in 6 H3K27M tumors lines and 3 wild type (WT) cell lines using a HTS platform. RESULTS: We identified several major classes of drugs that potently reduce cell viability of DIPG tumors with the H3K27M mutation. Based on these results we uncovered a major signaling pathway that has not been previously reported as a therapeutic target for DIPG. We found proteins in this pathway that were overexpressed in H3K27M tumors compared to WT tumors and normal brain. Furthermore, depletion or inhibition of this pathway selectively inhibit the proliferation of H3K27M mutant DIPG cells, decreases cell colony formation, increases apoptosis compared to WT expressing tumors and restores H3K27 trimethylation patterns. These findings were validated in orthotopic xenografts. CONCLUSION: Malignant gliomas including DIPG, are one of the most aggressive primary malignant brain tumors with no effective therapies at this time. Using a HTS we identified a class of drugs that utilize a specific signaling pathway that is critical for H3K27M tumors. These studies pave the way for developing molecularly targeted therapies as our understanding how these mutations lead to tumorigenesis unfold.