Erick M. Westbroek

Magnetic resonance image features identify glioblastoma phenotypic subtypes with distinct molecular pathway activities

Quantitative imaging stratifies glioblastoma into three different phenotypes with distinct molecular activities independent of established molecular markers and clinical status. Brain images create cancer clusters When directing therapies toward tumors, a sample of the cancerous tissue is needed to identify molecular targets. For patients with glioblastoma, however, it is invasive to biopsy the brain. Itakura et al. sought to identify noninvasive determinants of tumor phenotype that would potentially correlate with molecular pathways, thus allowing for targeted therapy without such brain invasion. The authors used magnetic resonance imaging to look at solitary, unilateral tumors from 121 glioblastoma patients and then generated nearly 400 unique image features that could be used to describe each tumor. The tumors could be grouped into three different phenotypes or “clusters”: pre-multifocal cluster, with highly irregular tumor shapes; spherical cluster, with defined edges; and rim-enhancing cluster, with a hypointense center ringed by hyperintensity. The distinct clusters were further validated in a separate cohort of 144 patients. These clusters could be used to stratify patients not only according to molecular pathways for targeted therapy but also by survival, indicating the potential for such noninvasive image-based quantitative biomarkers to be used for patient prognosis. Glioblastoma (GBM) is the most common and highly lethal primary malignant brain tumor in adults. There is a dire need for easily accessible, noninvasive biomarkers that can delineate underlying molecular activities and predict response to therapy. To this end, we sought to identify subtypes of GBM, differentiated solely by quantitative magnetic resonance (MR) imaging features, that could be used for better management of GBM patients. Quantitative image features capturing the shape, texture, and edge sharpness of each lesion were extracted from MR images of 121 single-institution patients with de novo, solitary, unilateral GBM. Three distinct phenotypic “clusters” emerged in the development cohort using consensus clustering with 10,000 iterations on these image features. These three clusters—pre-multifocal, spherical, and rim-enhancing, names reflecting their image features—were validated in an independent cohort consisting of 144 multi-institution patients with similar tumor characteristics from The Cancer Genome Atlas (TCGA). Each cluster mapped to a unique set of molecular signaling pathways using pathway activity estimates derived from the analysis of TCGA tumor copy number and gene expression data with the PARADIGM (Pathway Recognition Algorithm Using Data Integration on Genomic Models) algorithm. Distinct pathways, such as c-Kit and FOXA, were enriched in each cluster, indicating differential molecular activities as determined by the image features. Each cluster also demonstrated differential probabilities of survival, indicating prognostic importance. Our imaging method offers a noninvasive approach to stratify GBM patients and also provides unique sets of molecular signatures to inform targeted therapy and personalized treatment of GBM.

Cavernous malformation of brainstem, thalamus, and basal ganglia: a series of 176 patients.

BACKGROUND Cavernous malformations (CMs) in deep locations account for 9% to 35% of brain malformations and are surgically challenging. OBJECTIVE To study the clinical features and outcomes following surgery for deep CMs and the complication of hypertrophic olivary degeneration (HOD). METHODS Clinical records, radiological findings, operative details, and complications of 176 patients with deep CMs were reviewed retrospectively. RESULTS Of 176 patients with 179 CMs, 136 CMs were in the brainstem, 27 in the basal ganglia, and 16 in the thalamus. Cranial nerve deficits (51.1%), hemiparesis (40.9%), numbness (34.7%), and cerebellar symptoms (38.6%) presented most commonly. Hemorrhage presented in 172 patients (70 single, 102 multiple). The annual retrospective hemorrhage rate was 5.1% (assuming CMs are congenital with uniform hemorrhage risk throughout life); the rebleed rate was 31.5%/patient per year. Surgical approach depended on the proximity of the CM to the pial or ependymal surface. Postoperatively, 121 patients (68.8%) had no new neurological deficits. Follow-up occurred in 170 patients. Delayed postoperative HOD developed in 9/134 (6.7%) patients with brainstem CMs. HOD occurred predominantly following surgery for pontine CMs (9/10 patients). Three patients with HOD had palatal myoclonus, nystagmus, and oscillopsia, whereas 1 patient each had limb tremor and hemiballismus. At follow-up, 105 patients (61.8%) improved, 44 (25.9%) were unchanged, and 19 (11.2%) worsened neurologically. Good preoperative modified Rankin Score (98.2% vs 54.5%, P = .001) and single hemorrhage (89% vs 77.3%, P < .05) were predictive of good long-term outcome. CONCLUSION Symptomatic deep CMs can be resected with acceptable morbidity and outcomes. Good preoperative modified Rankin Score and single hemorrhage are predictors of good long-term outcome.

Multimodality management of Spetzler-Martin Grade III arteriovenous malformations.

OBJECT Grade III arteriovenous malformations (AVMs) are diverse because of their variations in size (S), location in eloquent cortex (E), and presence of central venous drainage (V). Because they may have implications for management and outcome, the authors evaluated these variations in the present study. METHODS Between 1984 and 2010, 100 patients with Grade III AVMs were treated. The AVMs were categorized by Spetzler-Martin characteristics as follows: Type 1 = S1E1V1, Type 2 = S2E1V0, Type 3 = S2E0V1, and Type 4 = S3E0V0. The occurrence of a new neurological deficit, functional status (based on modified Rankin Scale [mRS] score) at discharge and follow-up, and radiological obliteration were correlated with demographic and morphological characteristics. RESULTS One hundred patients (49 female and 51 male; age range 5-68 years, mean 35.8 years) were evaluated. The size of AVMs was less than 3 cm in 28 patients, 3-6 cm in 71, and greater than 6 cm in 1; 86 AVMs were located in eloquent cortex and 38 had central drainage. The AVMs were Type 1 in 28 cases, Type 2 in 60, Type 3 in 11, and Type 4 in 1. The authors performed embolization in 77 patients (175 procedures), surgery in 64 patients (74 surgeries), and radiosurgery in 49 patients (44 primary and 5 postoperative). The mortality rate following the management of these AVMs was 1%. Fourteen patients (14%) had new neurological deficits, with 5 (5%) being disabling (mRS score > 2) and 9 (9%) being nondisabling (mRS score ≤ 2) events. Patients with Type 1 AVMs (small size) had the best outcome, with 1 (3.6%) in 28 having a new neurological deficit, compared with 72 patients with larger AVMs, of whom 13 (18.1%) had a new neurological deficit (p < 0.002). Older age (> 40 years), malformation size > 3 cm, and nonhemorrhagic presentation predicted the occurrence of new deficits (p < 0.002). Sex, eloquent cortex, and venous drainage did not confer any benefit. In 89 cases follow-up was adequate for data to be included in the obliteration analysis. The AVM was obliterated in 78 patients (87.6%), 69 of them (88.5%) demonstrated on angiography and 9 on MRI /MR angiography. There was no difference between obliteration rates between different types of AVMs, size, eloquence, and drainage. Age, sex, and clinical presentation also did not predict obliteration. CONCLUSIONS Multimodality management of Grade III AVMs results in a high rate of obliteration, which was not influenced by size, venous drainage, or eloquent location. However, the development of new neurological deficits did correlate with size, whereas eloquence and venous drainage did not affect the neurological complication rate. The authors propose subclassifying the Grade III AVMs according to their size (< 3 and ≥ 3 cm) to account for treatment risk.

Multimodality management of Spetzler-Martin Grade III arteriovenous malformations

OBJECT Grade III arteriovenous malformations (AVMs) are diverse because of their variations in size (S), location in eloquent cortex (E), and presence of central venous drainage (V). Because they may have implications for management and outcome, the authors evaluated these variations in the present study. METHODS Between 1984 and 2010, 100 patients with Grade III AVMs were treated. The AVMs were categorized by Spetzler-Martin characteristics as follows: Type 1 = S1E1V1, Type 2 = S2E1V0, Type 3 = S2E0V1, and Type 4 = S3E0V0. The occurrence of a new neurological deficit, functional status (based on modified Rankin Scale [mRS] score) at discharge and follow-up, and radiological obliteration were correlated with demographic and morphological characteristics. RESULTS One hundred patients (49 female and 51 male; age range 5-68 years, mean 35.8 years) were evaluated. The size of AVMs was less than 3 cm in 28 patients, 3-6 cm in 71, and greater than 6 cm in 1; 86 AVMs were located in eloquent cortex and 38 had central drainage. The AVMs were Type 1 in 28 cases, Type 2 in 60, Type 3 in 11, and Type 4 in 1. The authors performed embolization in 77 patients (175 procedures), surgery in 64 patients (74 surgeries), and radiosurgery in 49 patients (44 primary and 5 postoperative). The mortality rate following the management of these AVMs was 1%. Fourteen patients (14%) had new neurological deficits, with 5 (5%) being disabling (mRS score > 2) and 9 (9%) being nondisabling (mRS score ≤ 2) events. Patients with Type 1 AVMs (small size) had the best outcome, with 1 (3.6%) in 28 having a new neurological deficit, compared with 72 patients with larger AVMs, of whom 13 (18.1%) had a new neurological deficit (p < 0.002). Older age (> 40 years), malformation size > 3 cm, and nonhemorrhagic presentation predicted the occurrence of new deficits (p < 0.002). Sex, eloquent cortex, and venous drainage did not confer any benefit. In 89 cases follow-up was adequate for data to be included in the obliteration analysis. The AVM was obliterated in 78 patients (87.6%), 69 of them (88.5%) demonstrated on angiography and 9 on MRI /MR angiography. There was no difference between obliteration rates between different types of AVMs, size, eloquence, and drainage. Age, sex, and clinical presentation also did not predict obliteration. CONCLUSIONS Multimodality management of Grade III AVMs results in a high rate of obliteration, which was not influenced by size, venous drainage, or eloquent location. However, the development of new neurological deficits did correlate with size, whereas eloquence and venous drainage did not affect the neurological complication rate. The authors propose subclassifying the Grade III AVMs according to their size (< 3 and ≥ 3 cm) to account for treatment risk.

BDNF Pretreatment of Human Embryonic-Derived Neural Stem Cells Improves Cell Survival and Functional Recovery After Transplantation in Hypoxic-Ischemic Stroke.

Intra-arterial neural stem cell (NSC) therapy has the potential to improve long-term outcomes after stroke. Here we evaluate if pretreatment of NSCs with brain-derived neurotrophic factor (BDNF) prior to transplantation improves cell engraftment and functional recovery following hypoxic–ischemic (HI) stroke. Human embryonic-derived NSCs with or without BDNF pretreatment (1 h, 100 ng/ml) were transplanted 3 days after HI stroke. Functional recovery was assessed using the horizontal ladder test. Cell engraftment was evaluated using bioluminescence imaging (BLI) and histological counts of SC121+ cells. Fluoro-Jade C (FJC) and NeuN stains were used to evaluate neuroprotection. The effect of BDNF on NSCs was analyzed using a migration assay, immunocytochemistry, Luminex proteomic assay, and RT-qPCR.BLI analysis demonstrated significantly higher photon flux in the BDNF-treated NSC group compared to untreated NSC (p = 0.049) and control groups (p = 0.0021) at 1 week after transplantation. Immunohistochemistry confirmed increased transplanted cell survival in the cortex (p = 0.0126) and hippocampus (p = 0.0098) of animals injected with BDNF-treated NSCs compared to untreated NSCs. Behavioral testing revealed that the BDNF-treated NSC group demonstrated increased sensorimotor recovery compared to the untreated NSC and control groups (p < 0.001) over the 1-month period (p < 0.001) following transplantation. A significant improvement in performance was found in the BDNF-treated NSC group compared to the control group at 14, 21, and 28 (p < 0.05) days after transplantation. The cortex and hippocampus of the BDNF-treated NSC group had significantly more SC121+ NSCs (p = 0.0125, p = 0.0098), fewer FJC+ neurons (p = 0.0370, p = 0.0285), and a higher percentage of NeuN+ expression (p= 0.0354) in the cortex compared to the untreated NSC group. BDNF treatment of NSCs resulted in significantly greater migration to SDF-1, secretion of M-CSF, VEGF, and expression of CXCR4, VCAM-1, Thrombospondins 1 and 2, and BDNF. BDNF pretreatment of NSCs results in higher initial NSC engraftment and survival, increased neuroprotection, and greater functional recovery when compared to untreated NSCs.

Intraoperative Angiography for Cranial Dural Arteriovenous Fistula

BACKGROUND AND PURPOSE: IA is a valuable adjunct during surgery for a variety of neurovascular diseases; however, there are no reported series describing IA for DAVFs. This study was undertaken to evaluate the safety and efficacy of IA for DAVFs. MATERIALS AND METHODS: A retrospective review of DAVF surgical cases during a 20-year period was conducted, and cases with IA were evaluated. Clinical details, surgical and angiographic findings, and postoperative outcomes were reviewed. The incidence of residual fistula on IAs, the utility of the surgical procedure, and the incidence of false-negative findings on IA were also determined. RESULTS: IA was performed in 29 patients (31 DAVFs) for DAVFs. The distribution of the fistulas was the following: transverse-sigmoid (n = 9), tentorial (n = 6), torcular (n = 3), cavernous sinus (n = 4), SSS (n = 4), foramen magnum (n = 3), and temporal-middle fossa (n = 2). Twelve patients had undergone prior embolization, while 6 patients had unsuccessful embolization procedures. Thirty-eight surgeries were performed for DAVF in 29 patients, and IA was performed in 34 surgeries. Forty-four angiographic procedures were performed in the 34 surgeries. Nine patients underwent multiple angiographies. In 11 patients (37.9%), IA revealed residual fistula after the surgeon determined that no lesion remained. This led to further exploration at the same sitting in 10 patients, while in 1 patient, further surgery was performed at a later date. False-negative findings on IA occurred in 3 patients (10.7%). CONCLUSIONS: IA is an important adjunct in surgery for DAVF. In this series, it resulted in further surgical treatment in 37.9% of patients. However, there was a 10% false-negative rate, which justified subsequent postoperative angiography.

Declining complication rates with flow diversion of anterior circulation aneurysms after introduction of the Pipeline Flex: analysis of a single-institution series of 568 cases

OBJECTIVEThe second-generation Pipeline embolization device (PED), Flex, has several design upgrades, including improved opening and the ability to be resheathed, in comparison with the original device (PED classic). The authors hypothesized that Flex is associated with a lower rate of major complications.METHODSA prospective, IRB-approved, single-institution database was analyzed for all patients with anterior circulation aneurysms treated by flow diversion. The PED classic was used from August 2011 to January 2015, and the Pipeline Flex has been used since February 2015.RESULTSA total of 568 PED procedures (252 classic and 316 Flex) were performed for anterior circulation aneurysms. The average aneurysm size was 6.8 mm. Patients undergoing treatment with the Flex device had smaller aneurysms (p = 0.006) and were more likely to have undergone previous treatments (p = 0.001). Most aneurysms originated along the internal carotid artery (89% classic and 75% Flex) but there were more anterior cerebral artery (18%) and middle cerebral artery (7%) deployments with Flex (p = 0.001). Procedural success was achieved in 96% of classic and 98% of Flex cases (p = 0.078). Major morbidity or death occurred in 3.5% of cases overall: 5.6% of classic cases, and 1.9% of Flex cases (p = 0.019). On multivariate logistic regression, predictors of major complications were in situ thrombosis (OR 4.3, p = 0.006), classic as opposed to Flex device (OR 3.7, p = 0.008), and device deployment in the anterior cerebral artery or middle cerebral artery as opposed to the internal carotid artery (OR 3.5, p = 0.034).CONCLUSIONSFlow diversion of anterior circulation cerebral aneurysms is associated with an overall low rate of major complications. The complication rate is significantly lower since the introduction of the second-generation PED (Flex).

Long-term hemorrhagic risk in pediatric patients with arteriovenous malformations.

OBJECTIVE Compared with the general population, the specific natural history of arteriovenous malformations (AVMs) in pediatric patients is less well understood. Furthermore, few pediatric studies have compared posttreatment hemorrhagic risk and functional outcome across different treatment modalities. The objective of this study was to elucidate these points. METHODS The authors retrospectively reviewed all pediatric patients with AVMs evaluated at their institution between 1990 and 2013. The AVM natural history was represented by hemorrhagic risk during the observation period. For treated patients, the observation period was defined as the interval between diagnosis and treatment. Posttreatment hemorrhagic risk and functional outcomes were also assessed. RESULTS A total of 124 pediatric patients with AVMs were evaluated, and 90 patients (72.6%) were retained through follow-up. The average patient age was 13.3 ± 3.8 years, with a mean follow-up period of 9.95 years. The overall AVM obliteration rate was 59.7%. Radiosurgery had an obliteration rate of 49.0%. Thirteen patients were managed conservatively. Four patients under observation hemorrhaged during a total interval of 429.4 patient-years, translating to an annual risk of 0.9%. Posttreatment hemorrhagic risk by treatment modalities were categorized as follows: surgery ± embolization (0.0%), radiosurgery ± embolization (0.8%), embolization alone (2.8%), surgery + radiosurgery ± embolization (3.5%), and observation (0.8%). A significantly higher risk of posttreatment hemorrhage was observed for patients with hemorrhagic presentation (p = 0.043) in multivariate analysis. Seizure presentation, frontal lobe location, nonheadache presentation, and treatment modality were significantly associated with increased risk of poor functional outcomes. CONCLUSIONS In this study of pediatric patients with AVMs, the natural history of hemorrhage was relatively low at 0.9%. Resection remained the optimal management for hemorrhage control and functional outcome perseverance in these pediatric patients with AVMs. AVM obliteration is a valid treatment goal, especially for patients with ruptured presentation, to prevent further hemorrhages later in life.

Computational Identification of Tumor Anatomic Location Associated with Survival in 2 Large Cohorts of Human Primary Glioblastomas

Preoperative T1 anatomic MR images of 384 patients with glioblastomas were evaluated by an automated computational image-analysis pipeline to determine the anatomic locations of tumor in each patient. Voxel-based differences in tumor location between good and poor survival groups identified in the training cohort were used to classify patients in The Cancer Genome Atlas cohort into 2 brain-location groups, for which clinical features, messenger RNA expression, and copy number changes were compared. Tumors in the right occipitotemporal periventricular white matter were significantly associated with poor survival in both training and test cohorts. Tumors in the right periatrial location were associated with hypoxia pathway enrichment and PDGFRA amplification. The authors conclude that voxel-based location in glioblastoma is associated with patient outcome and may have a potential role for guiding personalized treatment. BACKGROUND AND PURPOSE: Tumor 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 METHODS: Preoperative 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 <11 months) survival groups identified in the training cohort were used to classify patients in The Cancer Genome Atlas cohort into 2 brain-location groups, for which clinical features, messenger RNA expression, and copy number changes were compared to elucidate the biologic basis of tumors located in different brain regions. RESULTS: Tumors in the right occipitotemporal periventricular white matter were significantly associated with poor survival in both training and test cohorts (both, log-rank P < .05) and had larger tumor volume compared with tumors in other locations. Tumors in the right periatrial location were associated with hypoxia pathway enrichment and PDGFRA amplification, making them potential targets for subgroup-specific therapies. CONCLUSIONS: Voxel-based location in glioblastoma is associated with patient outcome and may have a potential role for guiding personalized treatment.

Cavernous Sinus Involvement by Pituitary Adenomas: Clinical Implications and Outcomes of Endoscopic Endonasal Resection

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.