Brandon S. Imber

Global and regional functional connectivity maps of neural oscillations in focal epilepsy

Intractable focal epilepsy is a devastating disorder with profound effects on cognition and quality of life. Epilepsy surgery can lead to seizure freedom in patients with focal epilepsy; however, sometimes it fails due to an incomplete delineation of the epileptogenic zone. Brain networks in epilepsy can be studied with resting-state functional connectivity analysis, yet previous investigations using functional magnetic resonance imaging or electrocorticography have produced inconsistent results. Magnetoencephalography allows non-invasive whole-brain recordings, and can be used to study both long-range network disturbances in focal epilepsy and regional connectivity at the epileptogenic zone. In magnetoencephalography recordings from presurgical epilepsy patients, we examined: (i) global functional connectivity maps in patients versus controls; and (ii) regional functional connectivity maps at the region of resection, compared to the homotopic non-epileptogenic region in the contralateral hemisphere. Sixty-one patients were studied, including 30 with mesial temporal lobe epilepsy and 31 with focal neocortical epilepsy. Compared with a group of 31 controls, patients with epilepsy had decreased resting-state functional connectivity in widespread regions, including perisylvian, posterior temporo-parietal, and orbitofrontal cortices (P < 0.01, t-test). Decreased mean global connectivity was related to longer duration of epilepsy and higher frequency of consciousness-impairing seizures (P < 0.01, linear regression). Furthermore, patients with increased regional connectivity within the resection site (n = 24) were more likely to achieve seizure postoperative seizure freedom (87.5% with Engel I outcome) than those with neutral (n = 15, 64.3% seizure free) or decreased (n = 23, 47.8% seizure free) regional connectivity (P < 0.02, chi-square). Widespread global decreases in functional connectivity are observed in patients with focal epilepsy, and may reflect deleterious long-term effects of recurrent seizures. Furthermore, enhanced regional functional connectivity at the area of resection may help predict seizure outcome and aid surgical planning.

Epileptogenic zone localization using magnetoencephalography predicts seizure freedom in epilepsy surgery

The efficacy of epilepsy surgery depends critically upon successful localization of the epileptogenic zone. Magnetoencephalography (MEG) enables noninvasive detection of interictal spike activity in epilepsy, which can then be localized in three dimensions using magnetic source imaging (MSI) techniques. However, the clinical value of MEG in the presurgical epilepsy evaluation is not fully understood, as studies to date are limited by either a lack of long‐term seizure outcomes or small sample size.

Ventriculoperitoneal Shunting for Glioblastoma: Risk Factors, Indications, and Efficacy.

BACKGROUND Glioblastoma patients can develop hydrocephalus, either obstructive, typically at diagnosis as a result of mass effect, or communicating, usually later in the disease. OBJECTIVE To characterize the indications and efficacy of ventriculoperitoneal (VP) shunting for patients with glioblastoma-associated hydrocephalus. METHODS Retrospective review was conducted of 841 glioblastoma patients diagnosed from 2004 to 2014, 64 (8%) of whom underwent VP shunting for symptomatic hydrocephalus, to analyze symptoms and outcomes after shunting. Overall survival and postshunt survival were analyzed with Kaplan-Meier methods, with predictors evaluated by use of Cox proportional hazards. RESULTS Of the 64 patients who underwent shunting, 42 (66%) had communicating hydrocephalus (CH) and 22 (34%) had obstructive hydrocephalus (OH). CH patients underwent more preshunt craniotomies than those with noncommunicating hydrocephalus, with a mean of 2.3 and 0.7 surgeries, respectively ( P < .001). Ventricular entry during craniotomy occurred in 52% of CH patients vs 59% of those with OH ( P = .8). After shunting, 61% of all patients achieved symptomatic improvement, which was not associated with hydrocephalus variant ( P > .99). Hydrocephalus symptom improvement rates were as follows: headache, 77%; lethargy, 61%; and altered cognition or memory, 54%. Symptomatic improvement was more likely in patients who were younger at shunt placement (hazard ratio, 0.96; P = .045). Symptomatic improvement, shorter time between glioblastoma diagnosis and shunt placement, and CH rather than OH led to improved postshunt survival (hazard ratio = 0.24-0.99; P = .01-.04). CONCLUSION VP shunting improves symptoms in most glioblastoma patients with suspected CH or OH, specifically younger patients. Symptomatic improvement, shorter duration between glioblastoma diagnosis and shunt placement, and CH rather than OH improve postshunt survival.

Cross-activating c-Met/β1 integrin complex drives metastasis and invasive resistance in cancer

Significance Invasion is a major cause of cancer mortality, as exemplified by metastatic spread of peripheral malignancies or local intracranial invasion of glioblastoma. While individual mediators of invasion are identified, functional or structural interactions between these mediators remain undefined. We identified a structural cross-activating c-Met/β1 integrin complex that promotes breast cancer metastases and invasive resistance of glioblastoma to the antiangiogenic therapy bevacizumab. We show that tumor cells adapt to their microenvironmental stressors by usurping c-Met and β1 integrin, with c-Met displacing α5 integrin from β1 integrin to form a c-Met/β1 complex with far greater fibronectin affinity than α5β1 integrin. These findings challenge conventional thinking about integrin–ligand interactions and define a molecular target for disrupting metastases or invasive oncologic resistance. The molecular underpinnings of invasion, a hallmark of cancer, have been defined in terms of individual mediators but crucial interactions between these mediators remain undefined. In xenograft models and patient specimens, we identified a c-Met/β1 integrin complex that formed during significant invasive oncologic processes: breast cancer metastases and glioblastoma invasive resistance to antiangiogenic VEGF neutralizing antibody, bevacizumab. Inducing c-Met/β1 complex formation through an engineered inducible heterodimerization system promoted features crucial to overcoming stressors during metastases or antiangiogenic therapy: migration in the primary site, survival under hypoxia, and extravasation out of circulation. c-Met/β1 complex formation was up-regulated by hypoxia, while VEGF binding VEGFR2 sequestered c-Met and β1 integrin, preventing their binding. Complex formation promoted ligand-independent receptor activation, with integrin-linked kinase phosphorylating c-Met and crystallography revealing the c-Met/β1 complex to maintain the high-affinity β1 integrin conformation. Site-directed mutagenesis verified the necessity for c-Met/β1 binding of amino acids predicted by crystallography to mediate their extracellular interaction. Far-Western blotting and sequential immunoprecipitation revealed that c-Met displaced α5 integrin from β1 integrin, creating a complex with much greater affinity for fibronectin (FN) than α5β1. Thus, tumor cells adapt to microenvironmental stressors induced by metastases or bevacizumab by coopting receptors, which normally promote both cell migration modes: chemotaxis, movement toward concentrations of environmental chemoattractants, and haptotaxis, movement controlled by the relative strengths of peripheral adhesions. Tumor cells then redirect these receptors away from their conventional binding partners, forming a powerful structural c-Met/β1 complex whose ligand-independent cross-activation and robust affinity for FN drive invasive oncologic processes.

Cost-Effectiveness Analysis of Surgical versus Medical Treatment of Prolactinomas

Background Few studies address the cost of treating prolactinomas. We performed a cost‐utility analysis of surgical versus medical treatment for prolactinomas. Materials and Methods We determined total hospital costs for surgically and medically treated prolactinoma patients. Decision‐tree analysis was performed to determine which treatment produced the highest quality‐adjusted life years (QALYs). Outcome data were derived from published studies. Results Average total costs for surgical patients were

Hypophysitis: a single-center case series

19,224 ( ± 18,920). Average cost for the first year of bromocriptine or cabergoline treatment was

Clinical outcome and prognostic factors for central neurocytoma: twenty year institutional experience.

3,935 and

Indications and Efficacy of Gamma Knife Stereotactic Radiosurgery for Recurrent Glioblastoma: 2 Decades of Institutional Experience

6,042, with

ANGI-12. IDENTIFICATION OF A NOVEL TYROSINE KINASE/INTEGRIN COMPLEX THAT DRIVES BRAIN METASTASES

2,622 and

Clinical outcome and prognostic factors for central neurocytoma: twenty year institutional experience

4,729 for each additional treatment year. For a patient diagnosed with prolactinoma at 40 years of age, surgery has the lowest lifetime cost (