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BACKGROUND Glioblastoma (GBM) has dismal outcome of 14-16 months. One of the challenges of drug development in GBM is lack of requisite circulating-free (cfDNA) in blood samples to develop biomarker driven targeted therapy trials. The Exablate focused ultrasound with circulating microbubble resonators uses the concept of real-time imaging to treat small target spots focusing energy in a non-invasive manner, thereby disrupting the Blood-Brain Barrier (BBBD) with potential to increase cfDNA in blood. METHODS LIBERATE is a prospective, multi-center, self-controlled pivotal ongoing clinical trial in subjects with suspected GBM evaluating the safety and effectiveness of Exablate Model 4000 to disrupt BBB to achieve a greater proportion of cfDNA in samples taken post-BBB disruption as compared to the sample taken before BBBD. Fifty eligible subjects with suspected GBM who are scheduled to undergo brain tumor resection or biopsy at 10 centers in the U.S. will participate in this study. The primary endpoint is defined for each subject as ratio between his/her cfDNA amount found in the blood sample 1-hour post-BBBD procedure compared to the cfDNA amount found in the blood sample collected pre-BBBD procedure. This study proposes to demonstrate that on average there is at least 2-fold increase in cfDNA (measured by central laboratory) at 1 hour post BBBD. Confirmatory secondary analysis will evaluate correlation between patterns obtained in panel of biomarkers evaluated in the resected tumor tissue and/or biopsy sample and blood sample collected 1-hour post-BBBD. Exploratory endpoints will include: (1) sensitivity of detection of known somatic mutations in the circulating blood samples (circulating tumor DNA) before and after BBBD, (2) time of greatest yield of cfDNA in the samples collected post BBBD blood samples (at 30 min, 1-hour, 2-hour and 3-hour) to determine time of greatest yield, (3) correlation of biomarkers between the imaging and the post-BBBD biomarker samples. (NCT05383872)

BACKGROUND NSCLC is the most common cause of brain metastases. The Exablate focused ultrasound with circulating microbubble resonators uses the concept of real-time imaging to treat small target spots focusing energy through the skull in noninvasive manner, thereby disrupting the BBB. There is preclinical evidence of synergy of FUS-mediated BBB with immunotherapy beyond improved drug delivery due to BBB disruption (BBBD). METHODS LIMITLESS is a prospective, multi-center, randomized, two-arm, controlled, pivotal clinical trial to evaluate the safety and efficacy of additional targeted BBB disruption using Exablate Model 4000 for the treatment of NSCLC brain metastases in subjects who are undergoing planned pembrolizumab monotherapy compared to Pembrolizumab alone in 2:1 randomization. The inclusion criteria include age ≥ 18 years, KPS ≥ 70, NSCLC (EGFR and ALK negative) with up to 3 brain metastases, one of which meets the RANO-BM criteria for measurable Disease (1 cm x 1 cm) with normal organ function. The primary endpoint is to test superiority of Exablate BBBD targeted to their brain metastases over the standard of care without Exablate BBBD as determined by Objective Response Rate (ORR) based on RANO- BM by 6 months. The secondary endpoints include best objective response rate and time to response for brain metastases by treatment arm. Other end points include progression-free survival (PFS), overall survival (OS), Intracranial and extracranial PFS, quality of life assessments. The Bayesian design statistical analysis will assume superior ORR of 60% in Exablate group compared to 30% in SOC group for a total sample size of 96 subjects (64 subjects in Exablate and 32 in SOC) for 80% power using a two-sided Pearson's Chi-Square test with alpha = 0.05. For the upper-bound estimate ORR of 45% in Exablate group and 30% in SOC group will need 369 subjects (246 subjects in Exablate and 123 in SOC).

Lipid-polymer hybrid nanoparticles (LPHNPs) are next-generation core-shell nanostructures, conceptually derived from both liposome and polymeric nanoparticles (NPs), where a polymer core remains enveloped by a lipid layer. Although they have garnered significant interest, they remain not yet widely exploited or ubiquitous. Recently, a fundamental transformation has occurred in the preparation of LPHNPs, characterized by a transition from a two-step to a one-step strategy, involving synchronous self-assembly of polymers and lipids. Owing to its two-in-one structure, this approach is of particular interest as a combinatorial drug delivery platform in oncology. In particular, the outer surface can be decorated in multifarious ways for active targeting of anticancer therapy, delivery of DNA or RNA materials, and use as a diagnostic imaging agent. This review will provide an update on recent key advancements in design, synthesis, and bioactivity evaluation as well as discussion of future clinical possibilities of LPHNPs.

BACKGROUND MDNA55 is an IL4R-targeted toxin in development for treatment of recurrent glioblastoma (rGBM). MDNA55 binds to IL4R expressed by tumor cells and non-malignant cells of the tumor microenvironment. METHOD MDNA55-05 was an open-label, single-arm study of MDNA55 delivered by CED as a single treatment in patients with 1st or 2nd recurrence following de novo GBM, IDH wild type status and not indicated for resection at relapse. Dose volumes (up to 60mL) and concentration of MDNA55 (1.5 to 9.0 μg/mL) were studied. RESULTS MDNA55 showed an acceptable safety profile at all doses tested. Median OS (mOS) amongst all subjects was 11.9 months, OS-24 was 20%, and PFS-12 was 27%. Among subjects expressing high levels of IL4R (irrespective of MDNA55 dose) and low levels of IL4R expression administered high dose (≥ 180μg) of MDNA55 (IL4Rhi + IL4Rlo/hd), mOS further improved to 14.0 months with OS-24 of 20%. Unmethylated MGMT promoter status did not affect MDNA55 treatment outcomes. In the IL4Rhi + IL4Rlo/hd population (N=17), mOS was 14.9 months with OS-24 of 22%. Following treatment with high concentrations of MDNA55 (6.0 or 9.0 μg/mL), transient (median of 3 cycles) low dose Avastin (5mg/kg q2w or 7.5mg/kg q3w) was used for symptom control and steroid sparring. Among these subjects, mOS amongst all comers (N=9) and the IL4Rhi + IL4Rlo/hd group (N=8) increased to 21.8 and 18.6 months with OS-24 of 44% and 38%, respectively. CONCLUSIONS MDNA55 shows potential to benefit all rGBM patients treated at high dose irrespective of IL4R expression. In the 1:1 randomized Phase 3 trial, the study will enrol two-thirds of subjects in the SOC arm from a matched external control arm. Unlike conventional RCTs, the hybrid design sets a new precedent for GBM trials, allowing robust OS analysis while significantly reducing the number of subjects randomized to SOC arm.

Purpose: The current study compared the standard response assessment in neuro-oncology (RANO), immunotherapy RANO (iRANO), and modified RANO (mRANO) criteria as well as quantified the association between progression-free (PFS) and overall survival (OS) in an immunotherapy trial in recurrent glioblastoma (rGBM). Patients and Methods: A total of 47 patients with rGBM were enrolled in a prospective phase II convection-enhanced delivery of an IL4R-targeted immunotoxin (MDNA55-05, NCT02858895). Bidirectional tumor measurements were created by local sites and centrally by an independent radiologic faculty, then standard RANO, iRANO, and mRANO criteria were applied. Results: A total of 41 of 47 patients (mean age 56 ± 11.7) were evaluable for response. PFS was significantly shorter using standard RANO compared with iRANO (log-rank, P < 0.0001; HR = 0.3) and mRANO (P < 0.0001; HR = 0.3). In patients who died and had confirmed progression on standard RANO, no correlation was observed between PFS and OS (local, P = 0.47; central, P = 0.34). Using iRANO, a weak association was observed between confirmed PFS and OS via local site measurements (P = 0.017), but not central measurements (P = 0.18). A total of 24 of 41 patients (59%) were censored using iRANO and because they lacked confirmation of progression 3 months after initial progression. A strong correlation was observed between mRANO PFS and OS for both local (R2 = 0.66, P < 0.0001) and centrally determined reads (R2 = 0.57, P = 0.0007). Conclusions: No correlation between radiographic PFS and OS was observed for standard RANO or iRANO, but a correlation was observed between PFS and OS using the mRANO criteria. Also, the iRANO criteria was difficult to implement due to need to confirm progression 3 months after initial progression, censoring more than half the patients.

ObjectiveTo determine whether chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow–derived mesenchymal stromal/stem cells (SB623).MethodsThis 6-month interim analysis of the 1-year double-blind, randomized, surgical sham–controlled, phase 2 Stem Cell Therapy for Traumatic Brain Injury (STEMTRA) trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multicenter trial (n = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 106, 5.0 × 106, or 10 × 106 SB623 cells or control. Safety was assessed in patients who underwent surgery (n = 61), and efficacy was assessed in the modified intent-to-treat population of randomized patients who underwent surgery (n = 61; SB623 = 46, control = 15).ResultsThe primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (least square [LS] mean) 8.3 (standard error 1.4) vs 2.3 (standard error 2.5) for control at 6 months, the LS mean difference was 6.0 (95% confidence interval 0.3–11.8, p = 0.040). Secondary efficacy endpoints improved from baseline but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients (p = 0.25).ConclusionsSB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls.ClinicalTrials.gov Identifier:NCT02416492.Classification of EvidenceThis study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.

Objectives Pituitary adenoma (PA), among the most commonly encountered sellar pathologies, accounts for 10% of primary intracranial tumors. The reported incidence of postoperative diabetes insipidus (DI) is highly variable. In this study, we report our experience with DI following endoscopic transsphenoidal surgery (TSS) for PAs, elucidating the risk factors of postoperative DI, the likelihood of long-term DI, and the impact of DI on the length of stay (LOS). Methods The study included 178 patients who underwent endoscopic resection of PAs. Early DI was defined as that occurring within the first postoperative week. The mean follow-up was 36 months. Long-term DI was considered as DI apparent in the last follow-up visit. Results Of the 178 patients included in the study, 77% of the tumors were macroadenomas. Forty-seven patients (26%) developed early DI. Long-term DI was observed in 18 (10.1%) of the full cohort. Age younger than 50 years was significantly associated with a higher incidence of long-term DI (p = 0.02). Macroadenoma and gross total resection were significantly associated with higher incidence of early DI (p = 0.05 and p = 0.04, respectively). The mean LOS was 4 days for patients with early postoperative DI and 3 days for those without it. Conclusion The reported incidence of postoperative DI is significantly variable. We identified age younger than 50 years a risk factor for developing long-term postoperative DI. Gross total surgical resection and tumor size (> 1 cm) were associated with development of early DI. Early DI increased the LOS on average by 1 day.

Aim: Genomically matched trials in primary brain tumors (PBTs) require recent tumor sequencing. We evaluated whether circulating tumor DNA (ctDNA) could facilitate genomic interrogation in these patients. Methods: Data from 419 PBT patients tested clinically with a ctDNA NGS panel at a CLIA-certified laboratory were analyzed. Results: A total of 211 patients (50%) had ≥1 somatic alteration detected. Detection was highest in meningioma (59%) and gliobastoma (55%). Single nucleotide variants were detected in 61 genes, with amplifications detected in ERBB2, MET, EGFR and others. Conclusion: Contrary to previous studies with very low yields, we found half of PBT patients had detectable ctDNA with genomically targetable off-label or clinical trial options for almost 50%. For those PBT patients with detectable ctDNA, plasma cfDNA genomic analysis is a clinically viable option for identifying genomically driven therapy options.

BACKGROUND MDNA55 is an IL4R-targeted toxin in development for GBM, a universally fatal disease. IL4R is over-expressed in GBM, the tumor microenvironment, and high expression is associated with poor outcomes in GBM. METHOD MDNA55-05 is an open-label, single-arm study of MDNA55 delivered by CED as a single treatment in rGBM patients at 1st or 2nd recurrence with an aggressive form of GBM (de novo GBM, IDH wild-type, not-resectable at recurrence, ~ 50% expressing high levels of IL4R). Primary endpoint is mOS, secondary endpoint includes impact of IL4R status on mOS. A Synthetic Control Arm (SCA) served as an external comparator constructed from patient registries at neurosurgery centers under IRB-approved protocols. Propensity score weighting corrected for imbalances in baseline characteristics between the two groups. RESULTS MDNA55 showed an acceptable safety profile at doses up to 240μg. In all evaluable subjects (n=44) mOS was 11.6 and OS-12 was 46%. A sub-population (n=32) consisting of all IL4RHigh subjects + only IL4RLow subjects treated with high dose (median 180µg) showed most benefit: mOS is 15 months, OS-12 is 55%. Tumor control, assessed by mRANO criteria, was seen in 81% (26/32) of this sub-population, including those that had pseudo-progression (15/26). In these subjects, tumor control was associated with longer mPFS (4.7 months) and mOS (15.0 months) than those with progressive disease (mPFS 1.0 month, mOS 7.7 months). Comparison against the SCA demonstrated > 100% increase in mOS: 15.7 months vs 7.2 months (HR 0.52, 95% CI 0.30, 0.91). CONCLUSIONS MDNA55 demonstrates improved survival and tumor control in this study design and has potential to benefit all rGBM patients treated at high dose irrespective of IL4R expression. There are no approved therapies for rGBM that can extend survival by 50%; the potential for MDNA55 to extend survival by > 100% is promising for this devastating disease.

2513 Background: MDNA55 is an engineered IL-4 fused to pseudomonas exotoxin A being developed for GBM, an aggressive, universally fatal disease. No curative therapy exists and 75% of patients are not eligible for resection at recurrence. MDNA55 targets IL4R overexpressed in GBM, the immunosuppressive tumor microenvironment, and high expression is associated with poor survival outcomes in GBM. A Ph 2b trial of MDNA55 was completed in rGBM using convection-enhanced delivery to bypass the BBB. Here we report results from the Ph 2b trial and comparison against a matched Synthetic Control Arm (SCA). Methods: MDNA55-05 is an open-label, single-arm study of intratumoral delivery of ≤ 240 μg MDNA55 as a single treatment via ≤ 4 catheters in de novo GBM without IDH1/2 mutation at 1st or 2nd recurrence not eligible for resection, tumors ≤ 4 cm, KPS ≥ 70. IL4R expression in GBM tissues was determined by H-Score using a validated IHC assay. 1o endpoint is median overall survival (mOS); 2o endpoint includes the impact of IL4R status on mOS. An eligibility-matched SCA was identified retrospectively from patient registries at major neurosurgery centers with access to GBM tumor tissue banks under IRB-approved protocols. Results: 44 subjects comprise the MDNA55 per protocol analysis population: median age 56 (35 - 77); median dose 177 mg (range 18 – 240 mg), 50% had KPS ≤ 80. No systemic toxicities observed, drug-related AEs were primarily neurological and characteristic of GBM, no deaths attributed to MDNA55. Median OS was 11.6 months (95% CI 7.9 – 15.2). When stratified by IL4R expression, mOS in IL4R High (n = 21) was 15 vs. 8.4 months in IL4R Low (n = 19); p = 0.2175. OS12 is 57% vs. 33%. When compared to the SCA (n = 81), MDNA55 subjects survived significantly longer: mOS 12.4 vs. 7.7 months; p = 0.0077. When comparing IL4R High groups, mOS in MDNA55 (n = 21) was 15.8 vs. 6.2 months in the SCA (n = 17); p = 0.0626. Subgroup analysis in unmethylated MGMT subjects also show better survival with MDNA55 (n = 23) than the SCA (n = 31); mOS 12.3 vs. 7.7 months (p = 0.0268), indicating that MDNA55 may be beneficial in patients resistant to temozolomide. Conclusions: MDNA55 subjects represent a difficult to treat population ( de novo GBM, IDH wild-type, not eligible for surgery at recurrence). Single treatment with MDNA55 prolongs survival by nearly 10 months in a subset of rGBM expressing high levels of IL4R when compared to a matched SCA, providing an unprecedented outcome for this highly lethal disease. Clinical trial information: NCT02858895 .

Management of high-grade gliomas (HGGs) remains a complex challenge with an overall poor prognosis despite aggressive multimodal treatment. New translational research has focused on maximizing tumor cell eradication through improved tumor cell targeting while minimizing collateral systemic side effects. In particular, biological intratumoral therapies have been the focus of novel translational research efforts due to their inherent potential to be both dynamically adaptive and target specific. This two part review will provide an overview of biological intratumoral therapies that have been evaluated in human clinical trials in HGGs, and summarize key advances and remaining challenges in the development of these therapies as a potential new paradigm in the management of HGGs. Part II discusses vector-based therapies, cell-based therapies and radioimmunotherapy.

Intratumoral glioblastoma therapy has been limited by suboptimal spatial distribution of therapeutic agents. MR-guided convection-enhanced delivery (CED) of MDNA-55 (interleukin-4 fused to Pseudomonasexotoxin) is underway in a Phase 2 open-label study in up to 43 patients with recurrent glioblastoma. Gadolinium-based contrast agent (Gd-DTPA) is co-infused with MDN55 to optimize intra-tumoral catheter placement, monitor drug distribution and identify non-functional catheters. MR images acquired prior to, during, and following infusion are used to determine drug distribution, tissue response, and disease status. Depending on the tumor size up to 60 mL of MDNA55 at a concentration of 1.5 μg/mL is administered as a single infusion through each catheter for a maximum dose of 90 μg. We report preliminary results of tumor distribution in 6 subjects that underwent MR-guided delivery of MDNA55 via implantable flexible catheters. Target enhancing tumor volume varied between 1.5 to 24 mL and tumor diameter varied between 1.8 to 4.7cm. Volume of infusion ranged between 14 to 66 mL and was delivered via 1 to 3 catheters at a flow rate of up to 15mL/min per catheter. MR was employed to monitor initial infusion, allowing adjustment of catheter depth as needed. The bulk of the delivery was performed outside the MR scanner in awake patients. MR confirmation of the distribution was performed within 4 hours post-infusion. In all patients, remarkable tumoral and peri-tumoral distribution has been observed. Tumor coverage ranged from 43% to 100%. Ratio of volume of distribution (Vd) to the volume infusion (Vi) ranged from 2.2 to 0.6. Lower Vd/Vi ratios were associated with drug leakage into the CSF space and/or resection cavity. When catheter placement was inaccurate, real-time imaging of Gd-DTPA distribution enabled adjustments to catheter depth which dramatically improved tumor coverage. MR-guidance during CED is therefore critical for optimal drug distribution in brain tumors.

Glioblastoma (GBM), the most malignant primary brain cancer, is mainly diagnosed initially based on tumor appearance on magnetic resonance (MR) images. Segmentation of GBM tumors is an important early step in image analysis to characterize tumor phenotypic features. However, manual segmentation performed by radiologists is a laborious and time-consuming process. Also, automated lesion segmentation is a challenging task due to the heterogeneous appearance of GBM. Traditional image segmentation methods may not consistently show robust performance. Recently, deep convolutional neural networks (CNNs) demonstrate great potential in image classification and recognition tasks. Here we applied a CNN architecture called U-Net that had recently been developed to segment neuronal structures in electron microscopic images and had shown good performance in segmenting lung lesions on CT images, which had not been applied to brain lesion segmentation on MR images. We trained the CNN framework to segment whole tumors on 2-dimentional MR contrast-enhanced T1 axial images. We acquired hand-drawn regions of interest (ROI) circumscribing whole GBM tumors for a total of 8280 images from 490 cases in two independent cohorts (from the Stanford University Medical Center and the Cancer Genome Atlas), with multiple tumor image slices from each case. We trained our CNN segmentation framework on 80% of the combined dataset, evaluated on 10%, and tested on the remaining 10%. After training for 20 epochs, our framework achieved a mean dice coefficient of 79% on the test set, which is comparable in performance to the published state-of-the-art brain tumor segmentation deep learning algorithm evaluated on another dataset. Further analysis needs to be performed to compare the two frameworks using the same dataset. This deep learning framework in our analysis may be extended to segmenting lower grade gliomas or other solid tumors visualized on medical images.

While intratumoral delivery of immunotherapies allows for targeted distribution and minimal systemic toxicity, optimal spatial distribution of therapeutic agents remains a challenge. MR-guided convection-enhanced delivery of MDNA55, interleukin-4 cytokine fused to Pseudomonas exotoxin, is currently being explored in a Phase 2 open label study in up to 52 patients with recurrent glioblastoma. MDNA55 is coinfused with a Gadolinium-based contrast agent (GdDTPA) and delivered as a single infusion using implantable flexible catheters. MRI was employed to monitor initial infusion, allowing adjustment of catheter depth as needed. The bulk of the delivery was performed outside the MRI scanner while patients were awake. MRI confirmation of distribution was performed within 4 hours post-infusion. Here we report preliminary results of tumor distribution in 23 subjects. Total volume of MDNA55 (ranging from 12 mL to 66 mL) was initially administered to subjects (n=12) based on tumor size. This achieved a mean coverage of 75% (range 46 – 94%) with 17% showing volume of distribution > 100 mL. Review by the Safety Committee determined that improvements to drug distribution could be further enhanced by moving to a fixed volume of 60 mL administered via 4 catheters and allowing placement outside the peritumoral area if necessary. Treatment in the next 11 subjects showed that infusion volumes exceeding 40 mL and placement of catheters outside the enhancing tumor led to increased volumes of drug distribution (45% showed volume of distribution > 100 mL) but did not improve the target percentage coverage of the tumor (mean 60%, range 22 – 97%) and its immediate penumbra. Therefore, under the current protocol version, all subjects are receiving individualized volume of MDNA55 (according to tumor size), but not exceeding 40 mL. Further optimization is underway to ensure adequate coverage and improve drug distribution.

Background Patient stratification to identify subtypes with different disease manifestations, severity, and expected survival time is a critical task in cancer diagnosis and treatment. While stratification approaches using various biomarkers (including high-throughput gene expression measurements) for patient-to-patient comparisons have been successful in elucidating previously unseen subtypes, there remains an untapped potential of incorporating various genotypic and phenotypic data to discover novel or improved groupings. Methods Here, we present HOCUS, a unified analytical framework for patient stratification that uses a community detection technique to extract subtypes out of sparse patient measurements. HOCUS constructs a patient-to-patient network from similarities in the data and iteratively groups and reconstructs the network into higher order clusters. We investigate the merits of using higher-order correlations to cluster samples of cancer patients in terms of their associations with survival outcomes. Results In an initial test of the method, the approach identifies cancer subtypes in mutation data of glioblastoma, ovarian, breast, prostate, and bladder cancers. In several cases, HOCUS provides an improvement over using the molecular features directly to compare samples. Application of HOCUS to glioblastoma images reveals a size and location classification of tumors that improves over human expert-based stratification. Conclusions Subtypes based on higher order features can reveal comparable or distinct groupings. The distinct solutions can provide biologically- and treatment-relevant solutions that are just as significant as solutions based on the original data. Electronic supplementary material The online version of this article (doi:10.1186/s12920-017-0256-3) contains supplementary material, which is available to authorized users.

Recently identified molecular subgroups of medulloblastoma have shown potential for improved risk stratification. We hypothesized that distinct MR imaging features can predict these subgroups.All patients with a diagnosis of medulloblastoma at one institution, with both pretherapy MR imaging and surgical tissue, served as the discovery cohort (n = 47). MR imaging features were assessed by 3 blinded neuroradiologists. NanoString-based assay of tumor tissues was conducted to classify the tumors into the 4 established molecular subgroups (wingless, sonic hedgehog, group 3, and group 4). A second pediatric medulloblastoma cohort (n = 52) from an independent institution was used for validation of the MR imaging features predictive of the molecular subtypes.Logistic regression analysis within the discovery cohort revealed tumor location (P.001) and enhancement pattern (P = .001) to be significant predictors of medulloblastoma subgroups. Stereospecific computational analyses confirmed that group 3 and 4 tumors predominated within the midline fourth ventricle (100%, P = .007), wingless tumors were localized to the cerebellar peduncle/cerebellopontine angle cistern with a positive predictive value of 100% (95% CI, 30%-100%), and sonic hedgehog tumors arose in the cerebellar hemispheres with a positive predictive value of 100% (95% CI, 59%-100%). Midline group 4 tumors presented with minimal/no enhancement with a positive predictive value of 91% (95% CI, 59%-98%). When we used the MR imaging feature-based regression model, 66% of medulloblastomas were correctly predicted in the discovery cohort, and 65%, in the validation cohort.Tumor location and enhancement pattern were predictive of molecular subgroups of pediatric medulloblastoma and may potentially serve as a surrogate for genomic testing.

Author(s): Liu, Tiffany T; Achrol, Achal S; Mitchell, Lex A; Rodriguez, Scott A; Feroze, Abdullah; Iv, Michael; Kim, Christine; Chaudhary, Navjot; Gevaert, Olivier; Stuart, Josh M; Harsh, Griffith R; Chang, Steven D; Rubin, Daniel L | Abstract: BackgroundIn previous clinical trials, antiangiogenic therapies such as bevacizumab did not show efficacy in patients with newly diagnosed glioblastoma (GBM). This may be a result of the heterogeneity of GBM, which has a variety of imaging-based phenotypes and gene expression patterns. In this study, we sought to identify a phenotypic subtype of GBM patients who have distinct tumor-image features and molecular activities and who may benefit from antiangiogenic therapies.MethodsQuantitative image features characterizing subregions of tumors and the whole tumor were extracted from preoperative and pretherapy perfusion magnetic resonance (MR) images of 117 GBM patients in 2 independent cohorts. Unsupervised consensus clustering was performed to identify robust clusters of GBM in each cohort. Cox survival and gene set enrichment analyses were conducted to characterize the clinical significance and molecular pathway activities of the clusters. The differential treatment efficacy of antiangiogenic therapy between the clusters was evaluated.ResultsA subgroup of patients with elevated perfusion features was identified and was significantly associated with poor patient survival after accounting for other clinical covariates (P values l.01; hazard ratios g 3) consistently found in both cohorts. Angiogenesis and hypoxia pathways were enriched in this subgroup of patients, suggesting the potential efficacy of antiangiogenic therapy. Patients of the angiogenic subgroups pooled from both cohorts, who had chemotherapy information available, had significantly longer survival when treated with antiangiogenic therapy (log-rank P=.022).ConclusionsOur findings suggest that an angiogenic subtype of GBM patients may benefit from antiangiogenic therapy with improved overall survival.

2039 Background: IL4 receptor (IL4R) is frequently and intensely expressed on a variety of human cancers and is associated with poor survival outcomes. Determining the role of the IL4R biomarker in glioblastoma (GBM) will be important for treatment with targeted therapies such as the IL4 fusion toxin MDNA55. Methods: A classification for IL4Rα expression in GBM tissues by H-Score was developed using a validated immunohistochemistry-based approach. MDNA55-05 is an open-label study of MDNA55 administered intratumorally via convection enhanced delivery in recurrent GBM. Levels of IL4Rα expression were assessed retrospectively in 24 subjects in the clinical trial and were correlated with GBM history, imaging responses and survival outcomes following treatment with MDNA55 to explore clinical validation. Results: Range, linearity, specificity and sensitivity testing using a rabbit polyclonal antibody to IL4Rα were performed using normal cortex (negative control) and a panel of normal human tissues and GBM cases from tissue banks. A total of 41 GBM samples were screened and grouped by reactivity thresholds: H-Scores ≥50 were observed in 95% of cases (39/41), H-Scores ≥200 were observed in 51% of cases (21/41), and H-Scores ≥250 were observed in 24% of cases (10/41). GBM tissues obtained at initial diagnosis from subjects enrolled in the trial show that moderate/high IL4R expression (H-Score > 75) was associated with shorter time to first relapse when compared to subjects with low IL4R expression (H-Score ≤ 75) (10.3 mos vs. 16.7 mos, respectively) after upfront standard-of-care treatment, consistent with published findings that IL4R expression is associated with more aggressive disease. Remarkable decreases in tumor size seen in some subjects following MDNA55 treatment were associated only with moderate/high IL4R expression and survival rate at 12 months in this group was also improved (OS12 = 55%) compared to subjects with low IL4R expression (OS12 = 30%). Conclusions: Treatment options for patients with recurrent GBM are very limited and positive outcomes remain rare. Targeting therapies such as MDNA55 by IL4R status may improve patient outcomes and help guide patient selection strategies for future clinical studies. Clinical trial information: NCT02858895.

Cerebral aneurysms are common vascular lesions. Little is known about the pathogenesis of these lesions and the process by which they destabilize and progress to rupture. Treatment decisions are motivated by a desire to prevent rupture and the devastating morbidity and mortality associated with resulting subarachnoid hemorrhage (SAH). For patients presenting with SAH, urgent intervention is required to stabilize the lesion and prevent re-rupture. Those patients fortunate enough to survive a presenting SAH and subsequent securing of their aneurysm must still face a spectrum of secondary sequelae, which can include cerebral vasospasm, delayed ischemia, seizures, cerebral edema, hydrocephalus, and endocrinologic and catecholamine-induced systemic dysfunction in cardiac, pulmonary, and renal systems. Increased focus on understanding the pathophysiology and molecular characteristics of these secondary processes will enable the development of targeted therapeutics and novel diagnostics for improved patient selection in personalized medicine trials for SAH. In unruptured cerebral aneurysms, treatment decisions are less clear and currently based solely on treating larger lesions, using rigid aneurysm size cutoffs generalized from recent studies that are the subject of ongoing controversy. Further compounding this controversy is the fact that the vast majority of aneurysms that come to clinical attention at the time of a hemorrhagic presentation are of smaller size, suggesting that small aneurysms are indeed not benign lesions. As such, patient-specific biomarkers that better predict which aneurysms represent high-risk lesions that warrant clinical intervention are of vital importance. Recent advancements in genomic and proteomic technologies have enabled the identification of molecular characteristics that may prove useful in tracking aneurysm growth and progression and identifying targets for prophylactic therapeutic interventions. Novel quantitative neuroimaging technologies have also recently emerged, capable of non-invasive characterization of hemodynamic factors, inflammation, and structural changes in aneurysmal walls. The combined use of these quantitative neuroimaging and molecular-based approaches, called Radiogenomics, is a technique that holds great promise in better characterizing individual aneurysms. In the near future, these radiogenomic techniques may help improve quality of life and patient outcomes via patient-specific approaches to the treatment of unruptured cerebral aneurysms and personalized medical management of secondary processes following aneurysmal SAH.

Brain tumor-initiating cells (BTICs) are self-renewing multipotent cells critical for tumor maintenance and growth. Using single-cell microfluidic profiling, we identified multiple subpopulations of BTICs coexisting in human glioblastoma, characterized by distinct surface marker expression and single-cell molecular profiles relating to divergent bulk tissue molecular subtypes. These data suggest BTIC subpopulation heterogeneity as an underlying source of intra-tumoral bulk tissue molecular heterogeneity, and will support future studies into BTIC subpopulation-specific therapies.

Background Parasellar invasion of pituitary adenomas (PAs) into the cavernous sinus (CS) is common. The management of the CS component of PA remains controversial. Objective The objective of this study was to analyze CS involvement in PA treated with endoscopic endonasal approaches, including incidence, surgical risks, surgical strategies, long-term outcomes, and our treatment algorithm. Methods We reviewed a series of 176 surgically treated PA with particular attention to CS involvement and whether the CS tumor was approached medial or lateral to the internal carotid artery. Results The median duration of follow-up was 36 months. Macroadenomas and nonfunctional adenomas represented 77 and 60% of cases, respectively. CS invasion was documented in 23% of cases. CS involvement was associated with a significantly diminished odds of gross total resection (47 vs. 86%, odds ratio [OR]: 5.2) and increased the need for subsequent intervention (4 vs. 40%, OR: 14.4). Hormonal remission was achieved in 15% of hormonally active tumors. Rates of surgical complication were similar regardless of CS involvement. Conclusion Our tailored strategy beginning with a medial approach and adding lateral exposure as needed resulted in good outcomes with low morbidity in nonfunctional adenomas. Functional adenomas involving the CS were associated with low rates of hormonal remission necessitating higher rates of additional treatment.

Background and purposeTumor location has been shown to be a significant prognostic factor in patients with glioblastoma. The purpose of this study was to characterize glioblastoma lesions by identifying MR imaging voxel-based tumor location features that are associated with tumor molecular profiles, patient characteristics, and clinical outcomes.Materials and methodsPreoperative T1 anatomic MR images of 384 patients with glioblastomas were obtained from 2 independent cohorts (n = 253 from the Stanford University Medical Center for training and n = 131 from The Cancer Genome Atlas for validation). An automated computational image-analysis pipeline was developed to determine the anatomic locations of tumor in each patient. Voxel-based differences in tumor location between good (overall survival of >17 months) and poor (overall survival of

Stem cell therapies can promote neural repair and regeneration, yet controversy regarding optimal cell source and mechanism of action has slowed clinical translation, potentially due to undefined cellular heterogeneity. Single-cell resolution is needed to identify clinically relevant subpopulations with the highest therapeutic relevance. We combine single-cell microfluidic analysis with advanced computational modeling to study for the first time two common sources for cell-based therapies, human NSCs and MSCs. This methodology has the potential to logically inform cell source decisions for any clinical application.

Brain arteriovenous malformations (BAVMs) are an important cause of intracranial hemorrhage (ICH) in young adults. Gene expression profiling of blood has led to the identification of stroke biomarkers, and may help identify BAVM biomarkers and illuminate BAVM pathogenesis. It is unknown whether blood gene expression profiles differ between 1) BAVM patients and healthy controls, or 2) unruptured and ruptured BAVM patients at presentation. We characterized blood transcriptional profiles in 60 subjects (20 unruptured BAVM, 20 ruptured BAVM, and 20 healthy controls) using Affymetrix whole genome expression arrays. Expression differences between groups were tested by ANOVA, adjusting for potential confounders. Genes with absolute fold change ≥ 1.2 (false discovery rate corrected p ≤ 0.1) were selected as differentially expressed and evaluated for over-representation in KEGG biological pathways (p ≤ 0.05). Twenty-nine genes were differentially expressed between unruptured BAVM patients and controls, including 13 which may be predictive of BAVM. Patients with ruptured BAVM compared to unruptured BAVM differed in expression of 1490 genes, with over-representation of genes in 8 pathways including MAPK, VEGF, Wnt signaling and several inflammatory pathways. These results suggest clues to the pathogenesis of BAVM and/or BAVM rupture and point to potential biomarkers or new treatment targets.

e18546Background: Access to cancer treatment clinical trials is a key measure for the delivery of quality cancer care. When available, cancer clinical trials should be offered up front and practice...

Background and Purpose— To evaluate whether increased neuroimaging use is associated with increased brain arteriovenous malformation (BAVM) detection, we examined detection rates in the Kaiser Permanente Medical Care Program of northern California between 1995 and 2004. Methods— We reviewed medical records, radiology reports, and administrative databases to identify BAVMs, intracranial aneurysms (IAs: subarachnoid hemorrhage [SAH] and unruptured aneurysms), and other vascular malformations (OVMs: dural fistulas, cavernous malformations, Vein of Galen malformations, and venous malformations). Poisson regression (with robust standard errors) was used to test for trend. Random-effects meta-analysis generated a pooled measure of BAVM detection rate from 6 studies. Results— We identified 401 BAVMs (197 ruptured, 204 unruptured), 570 OVMs, and 2892 IAs (2079 SAHs and 813 unruptured IAs). Detection rates per 100 000 person-years were 1.4 (95% CI, 1.3 to 1.6) for BAVMs, 2.0 (95% CI, 1.8 to 2.3) for OVMs, and 10.3 (95% CI, 9.9 to 10.7) for IAs. Neuroimaging utilization increased 12% per year during the time period ( P P P =0.858), and decreased for BAVMs ( P =0.001). Detection rates increased 15% per year for unruptured IAs ( P P =0.903). However, rates decreased 7% per year for unruptured BAVMs ( P =0.016) and 3% per year for ruptured BAVMs ( P =0.005). Meta-analysis yielded a pooled BAVM detection rate of 1.3 (95% CI, 1.2 to 1.4) per 100 000 person-years, without heterogeneity between studies ( P =0.25). Conclusions— Rates for BAVMs, OVMs, and IAs in this large, multiethnic population were similar to those in other series. During 1995 to 2004, a period of increasing neuroimaging utilization, we did not observe an increased rate of detection of unruptured BAVMs, despite increased detection of unruptured IAs.

Background: Polymorphisms in the proinflammatory cytokine interleukin (IL)-1β gene have been associated with systemic atherogenesis, thrombosis and rupture. The aim of this study was to investigate associations between single nucleotide polymorphisms (SNPs) in IL-1β and intracranial hemorrhage (ICH) in the natural course of brain arteriovenous malformation (BAVM) patients. Method: Two IL-1β promoter SNPs (–511C→T, –31T→C) and 1 synonymous coding SNP in exon 5 at +3953C→T (Phe) were genotyped in 410 BAVM patients. We performed a survival analysis of time to subsequent ICH, censoring cases at first treatment, death or last follow-up. A Cox regression analysis was performed to obtain hazard ratios (HRs) for genotypes adjusted for age, sex, Caucasian race/ethnicity and hemorrhagic presentation. Results: Subjects with the –31 CC genotype (HR = 2.7; 95% CI 1.1–6.6; p = 0.029) or the –511 TT genotype (HR = 2.6; 95% CI 1.1–6.5; p = 0.039) had a greater risk of subsequent ICH compared with reference genotypes, adjusting for covariates. The +3953C→T SNP was not significantly associated with an increased ICH risk (p = 0.22). The IL-1β promoter polymorphisms were also associated with BAVM susceptibility among a subset of 235 BAVM cases and 255 healthy controls of Caucasian race/ethnicity (p < 0.001). Conclusion: IL-1β promoter polymorphisms were associated with an increased risk of ICH in BAVM clinical course and with BAVM susceptibility. These results suggest that inflammatory pathways, including the IL-1β cytokine, may play an important role in ICH.

Purpose: Intracranial aneurysm (IA) growth is associated with increased morbidity. We sought to establish a quantitative computational method based on contrast-enhanced MR angiography (CE-MRA) for estimating aneurysmal volume changes over time. Materials and Methods: Computational volume calculations were tested against a distensible phantom. Untreated patients with IA were followed longitudinally with annual MRI. Maximal linear dimensions along the longitudinal axis and two transverse axes were determined by visual review of maximum intensity projection (MIP) data, and aneurysm volume was approximated as (length x width x height)/2. Averages of the visual approximations were compared to the lumenal volume as determined with a computational algorithm using the MRI data. Results: MRI-based measurements accurately represented volume changes in the phantom (R-2 = 0.97, Y = 1.06x + 271 CM3). In the clinical study there were a total of 11 intervals of one-year follow-up in six patients (mean +/- SD age = 53 +/- 20 years). The raw one-year growth using the computational volume was 9% +/- 17%. The corresponding value for the averaged measurement of the reviewers was 8% +/- 14%. Neither the mean values nor the SDs were different (P = .51). Conclusion: MRI-based measurement of aneurysm volume appears feasible for longitudinal studies of aneurysm natural history.

Medulloblastomas are the most common malignant brain tumors in children, comprising distinct molecular subgroups that differ in neuroanatomical predilection, clinical characteristics and overall survival. Here we compare genetic brain lineage and stromal immune profiling in N = 558 pediatric medulloblastomas against N = 426 adult glioblastomas. The medulloblastoma cohort included N = 114 SHH (20%), N = 34 WNT (6%), N = 156 Group 3 (28%), and N = 254 Group 4 (46%). Genetic brain lineage analyses revealed WNT and SHH medulloblastoma to be distinctly astrocytic and astroglial; more similar to adult mesenchymal/classical glioblastoma than other pediatric medulloblastoma. In contrast, Group 4 was distinctly neuronal and oligodendrocytic; more similar to adult proneural/neural glioblastoma than other pediatric medulloblastoma. Interestingly, Group 3 demonstrated no brain lineage enrichment-unlike any other pediatric or adult brain tumor subtype-suggesting a non-CNS etiology for this subgroup known for distinctive large-cell anaplastic histology, aggressive behavior, and uniquely high incidence of metastatic disease. Analysis of stromal immune signatures revealed significant macrophage-specific enrichment in WNT and SHH, but not Group 3 and 4 tumors. These myeloid signatures were characteristic of M2-polarized macrophages, unlike adult glioblastomas, which enriched in both M1 and M2 signatures. While myeloid responses in adult glioblastoma were predictive of poor overall survival, the opposite was true in pediatric medulloblastoma-with improved survival in children with robust immune responses. These data demonstrate that medulloblastoma subtypes display distinct brain lineages and share greater similarities to adult glioblastomas than other pediatric medulloblastomas, further supporting distinct cellular origins for each subtype. Furthermore, innate immune responses were distinctive between subtypes and, in contrast to adult tumors, predictive of good outcomes, suggesting prognostic significance of immune responses differs in children versus adults. Taken together, these findings highlight the distinctiveness of medulloblastoma subtypes with important clinical implications for the design of future targeted molecular therapy and immunotherapy trials in pediatric and adult brain tumor patients.

Background and Purpose— Cardiac abnormalities occur commonly after subarachnoid hemorrhage (SAH) and may be caused by excessive release of catecholamines from the myocardial sympathetic nerves. We hypothesized that adrenoceptor polymorphisms resulting in greater catecholamine sensitivity would be associated with an increased risk of cardiac injury. Methods— This was a prospective cohort study. The primary outcome variables were the serum level of cardiac troponin I (cTi, abnormal if >1.0 μg/L) and the left ventricular ejection fraction (LVEF, abnormal if β1AR Arg389Gly, β1AR Ser49Gly, β2AR Gly16Arg, β2AR Gln27Glu, β2AR Thr164Ile, and α2AR del322-325. The effect of each polymorphism on the risk of developing cardiac abnormalities was quantified using multivariable logistic regression. Results— The study included 182 patients. The CC genotype (Arg/Arg) of β1AR Arg389Gly (odds ratio [OR] 3.4, P =0.030) and the CC genotype (Gln/Gln) of β2AR Gln27Glu (OR 3.1, P =0.032) were predictive of cTi release. The presence of the α2AR deletion was predictive of reduced LVEF (OR 4.2, P =0.023). The combination of the β1AR 389 CC and the β2AR 27 CC genotypes resulted in a marked increase in the odds of cTi release (OR 15.5, P =0.012). The combination of the β1AR 389 CC and the α2AR deletion genotypes resulted in a marked increase in the odds of developing a reduced LVEF (OR 10.3, P =0.033). Conclusions— Genetic polymorphisms of the adrenoceptors are associated with an increased risk of cardiac abnormalities after SAH. These data support the hypothesis that cardiac dysfunction after SAH is a form of neurocardiogenic injury.

Background and Purpose— Identification of single-nucleotide polymorphisms (SNPs) associated with increased risk of new intracranial hemorrhage (ICH) after brain arteriovenous malformation (BAVM) diagnosis would facilitate risk stratification and identify potential targets for therapeutic intervention. Methods— Patients with BAVM were longitudinally followed. Primary outcome was new ICH after diagnosis; censoring events were last follow-up or any BAVM treatment. We genotyped 4 promoter SNPs in 2 inflammatory cytokine genes: interleukin-6 (IL-6–174G>C; IL-6–572G>C) and tumor necrosis factor-α (TNF-α–238G>A; TNF-α–308G>A). Association of genotype with risk of new ICH was screened using χ 2 ; SNPs associated with new ICH were further characterized using Cox proportional hazards. Results— We genotyped 280 patients (50% female; 59% white, mean±SD age at diagnosis 37±17 years; 40% presenting with ICH). TNF-α–238G>A was associated with increased risk of new ICH after diagnosis (χ 2 ; P =0.003). After adjusting for age, race/ethnicity, and clinical presentation, the risk of new ICH was increased for patients with TNF-α–238 AG genotype (hazard ratio, 4.01; P =0.015). No other SNP was found to be associated with new ICH. Conclusion— A TNF-α SNP was associated with increased risk of new ICH in the natural course of BAVMs. The role of inflammatory cytokines in the pathogenesis of BAVM hemorrhage merits further study.

We hypothesized that patients with unruptured arteriovenous malformations (AVMs) at presentation have an increased risk of deterioration compared with patients with ruptured AVMs.A consecutive series of 224 patients treated microsurgically by a single neurosurgeon during a period of 6.4 years was analyzed. Initial hemorrhagic presentation was the primary predictor variable. Neurological outcomes were assessed by use of the Modified Rankin Scale (MRS) and Glasgow Outcome Scale (GOS), and logistic regression identified predictors of deterioration at follow-up (mean duration, 1.3 yr) relative to baseline before any intervention.Overall, 120 patients (54%) presented with hemorrhage, and all 224 patients underwent microsurgical resection. Complete resection was achieved in 220 patients (98%). According to GOS score, 13 patients (5.8%) deteriorated; according to MRS score, 45 patients (20.1%) deteriorated. Fifteen patients (6.7%) died. Hemorrhagic presentation was associated with improved outcomes, with a mean change in MRS score of +0.89 in patients with ruptured AVMs and -0.38 in patients with unruptured AVMs (P0.001). The final mean MRS scores in patients with unruptured AVMs were better than those in patients with ruptured AVMs (1.44 versus 1.90; P = 0.048). Presentation with an unruptured AVM was a predictor of worsening MRS score (odds ratio, 2.33; 95% confidence interval, 1.3-4.3; P = 0.006) but not of worsening GOS score.Presentation with AVM hemorrhage is an underappreciated predictor of outcome after therapy that includes microsurgical resection. Patients with ruptured AVMs tended to have deficits at presentation and generally improved after surgery, whereas patients with unruptured AVMs tended to have normal or nearly normal neurological function at presentation and were susceptible to worsening, albeit slight, as measured by MRS scores. Sensitive outcome measures such as MRS detect subtle symptoms and impairments missed by coarser measures such as GOS. Patients should be counseled that the risks associated with elective resection of unruptured AVMs may be higher than recognized previously. Hemorrhagic brain injury and its secondary effects may mask this surgical morbidity.

We recently reported that the GG genotype of the interleukin-6 (IL-6)-174G>C promoter polymorphism is associated with clinical presentation of intracranial hemorrhage in brain arteriovenous malformation (AVM) patients. In this study, we investigated whether tissue IL-6 expression was associated with IL-6-174G>C genotype, and whether IL-6 was linked to downstream targets involved in angiogenesis and vascular instability. Our results showed that the highest IL-6 protein levels in brain AVM tissue were associated with IL-6-174GG genotype (GG: 57.7 +/- 20.2; GC: 35.6 +/- 26.6; CC: 13.9 +/- 10.2pg/mg; p = 0.001). IL-6 protein levels were increased in AVM tissue from patients with hemorrhagic presentation compared with patients without hemorrhage (55 +/- 22 vs 40 +/- 27pg/mg; p = 0.038). IL-6 messenger RNA expression strongly correlated with messenger RNA levels of IL-1beta, tumor necrosis factor-alpha, IL-8, matrix metalloproteinase-3 (MMP-3), MMP-9, and MMP-12. We further investigated the plausibility of IL-6 being an upstream cytokine responsible for initiating the angiogenic cascade by cell culture and animal experiments. IL-6 induced MMP-3 and MMP-9 expression and activity in mouse brain and increased proliferation and migration of cerebral endothelial cells. Together, our results suggest that the IL-6 genotype associated with intracranial hemorrhage modulates IL-6 expression in brain AVM tissue, which is consistent with the hypothesis that inflammatory processes induce angiogenic activity possibly contributory to brain AVM intracranial hemorrhage.

We sought to discover subtypes of glioblastoma (GBM) defined by quantitative imaging features and to identify their canonical signaling pathways. Preoperative MR imaging from 121 Stanford patients with de novo, focal, unilateral GBM were analyzed. Two board-certified neuroradiologists and a neurosurgeon reached consensus in delineating Regions-of-Interest (ROIs) around areas of enhancement in each T1 post-contrast MR. We extracted 138 quantitative image features representing signal intensity and morphology of each lesion. We then used Consensus Clustering to define subtypes in the Stanford group. Next, Prediction Analysis for Microarrays (PAM) and the In-Group Proportion (IGP) statistic were used to validate the reproducibility and robustness of our subtype classification in a second cohort of subjects from The Cancer Genome Atlas (TCGA, n = 145). Finally, to map imaging subtypes to particular molecular signaling pathways, we performed Significance Analysis of Microarrays (SAM) on pathway activity estimates derived from analysis of TCGA tumor copy number and RNA sequencing data with the PARADIGM algorithm. Consensus Clustering analysis of the training set identified three clusters whose validity was confirmed in the TCGA cohort (p < 0.0001, p< 0.0001, p = 0.015). Cluster sizes for the TCGA validation cohort (i.e. 45%, 21% and 35%) were similar to those in the Stanford training set (57%, 17% and 26%). Cluster 1 was associated with 49 overexpressed pathways (FDR < 5%) including Wnt, hypoxia, apoptosis, cell proliferation, and angiogenesis signaling pathways while Cluster 2 was characterized by downregulation of these pathways (FDR < 5%). No pathway was significantly associated with Cluster 3. We identified three distinct, robust clusters of focal, unilateral GBM defined by quantitative image signatures. Subtypes identified in a homogeneous Stanford training set were validated in the heterogeneous multi-institutional TCGA data set. Two of our three clusters had significant associations with canonical signaling pathways.

We propose and discuss a method for doing gene expression meta-analysis (multiple datasets) across multiplex measurement modalities measuring the expression of many genes simultaneously (e.g. microarrays and RNAseq) using external control samples and a method of heterogeneity detection to identify and filter on comparable gene expression measurements. We demonstrate this approach on publicly available gene expression datasets from samples of medulloblastoma and normal cerebellar tissue and identify some potential new targets in the treatment of medulloblastoma.

We propose and discuss a method for doing gene expression meta-analysis (multiple datasets) across multiplex measurement modalities measuring the expression of many genes simultaneously (e.g. microarrays and RNAseq) using external control samples and a method of heterogeneity detection to identify and filter on comparable gene expression measurements. We demonstrate this approach on publicly available gene expression datasets from samples of medulloblastoma and normal cerebellar tissue and identify some potential new targets in the treatment of medulloblastoma. 1. Background

Spontaneous meningoencephalocele (SME) of the sphenoid wing is a rare cause of cerebrospinal fluid (CSF) leakage. Surgical closure of the fistula is usually required. The approach taken depends on the location of the defect and the extension of the meningoencephalocele. The endoscopic transpterygoid approach may be useful. We prospectively analyzed the three cases of SME of the sphenoid wing with lateral sphenoid sinus extension treated endoscopically at Stanford over the last 3 years with regard to imaging findings, operative technique, and operative morbidity. In our three cases, the extent of pterygopalatine fossa (PPF) exposure undertaken, complete in one and partial in two, depended on the defect site. Follow-up ranged from 17 to 25 months. The fistula was completely closed in all three cases. Extant literature reports a 97% rate of successful closure (N = 65 of 67, with a mean follow-up of 25 months) and no major complications. Endoscopic transpterygoid repair is a useful, safe alternative to traditional approaches for repair of SME of the sphenoid wing. Its feasibility depends on the site of the defect, which can be identified by preoperative imaging. Larger PPF exposure and postoperative lumbar drainage of CSF can be useful and have a low risk of morbidity.

Background Pituitary apoplexy is an acute clinical syndrome caused by pituitary gland hemorrhage or infarction. Rarely, this clinical syndrome is associated with cerebral infarction secondary to compression of an internal carotid artery. We report an unusual case of pituitary apoplexy associated with a cerebral infarct with a large ischemic penumbra. Case Description The patient presented with headaches and visual disturbance and was found to have pituitary apoplexy. Findings of his neurologic examination showed he had rapidly deteriorated, with obtundation, ophthalmoplegia, and left hemiplegia. Computed tomography perfusion images revealed a right hemispheric infarct with a large ischemic penumbra. Emergent decompressive transsphenoidal resection was performed. The patient had dramatic neurologic recovery, and postoperative imaging revealed salvage of most of the previously identified penumbra. Conclusions Cerebral perfusion imaging is a useful diagnostic tool for identifying the subset of pituitary apoplexy patients that may benefit from emergent surgical intervention.