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Ricky Chen, Vijay M. Ravindra, Adam L. Cohen, Randy L. Jensen, Karen L. Salzman, Andrew P. Prescot and Howard Colman

The preferred management of suspected low-grade gliomas (LGGs) has been disputed, and the implications of molecular changes for medical and surgical management of LGGs are important to consider. Current strategies that make use of molecular markers and imaging techniques and therapeutic considerations offer additional options for management of LGGs. Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes suggest a role for this abnormal metabolic pathway in the pathogenesis and progression of these primary brain tumors. Use of magnetic resonance spectroscopy can provide preoperative detection of IDH-mutated gliomas and affect surgical planning. In addition, IDH1 and IDH2 mutation status may have an effect on surgical resectability of gliomas. The IDH-mutated tumors exhibit better prognosis throughout every grade of glioma, and mutation may be an early genetic event, preceding lineage-specific secondary and tertiary alterations that transform LGGs into secondary glioblastomas. The O6-methylguanine-DNAmethyltransferase (MGMT) promoter methylation and 1p19q codeletion status can predict sensitivity to chemotherapy and radiation in low- and intermediate-grade gliomas. Thus, these recent advances, which have led to a better understanding of how molecular, genetic, and epigenetic alterations influence the pathogenicity of the different histological grades of gliomas, can lead to better prognostication and may lead to specific targeted surgical interventions and medical therapies.

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Jonathan Frandsen, Andrew Orton, Randy Jensen, Howard Colman, Adam L. Cohen, Jonathan Tward, Dennis C. Shrieve and Gita Suneja

OBJECTIVE

The authors compared presenting characteristics and survival for patients with gliosarcoma (GS) and glioblastoma (GBM). Additionally, they performed a survival analysis for patients who underwent GS treatments with the hypothesis that trimodality therapy (surgery followed by radiation and chemotherapy) would be superior to nontrimodality therapy (surgery alone or surgery followed by chemotherapy or radiation).

METHODS

Adults diagnosed with GS and GBM between the years 2004 and 2013 were queried from the National Cancer Database. Chi-square analysis was used to compare presenting characteristics. Kaplan-Meier, Cox regression, and propensity score analyses were employed for survival analyses.

RESULTS

In total, data from 1102 patients with GS and 36,658 patients with GBM were analyzed. Gliosarcoma had an increased rate of gross-total resection (GTR) compared with GBM (19% vs 15%, p < 0.001). Survival was not different for patients with GBM (p = 0.068) compared with those with GS. After propensity score analysis for GS, patients receiving trimodality therapy (surgery followed by radiation and chemotherapy) had improved survival (12.9 months) compared with those not receiving trimodality therapy (5.5 months). In multivariate analysis, GTR, female sex, fewer comorbidities, trimodality therapy, and age < 65 years were associated with improved survival. There was a trend toward improved survival with MGMT promoter methylation (p = 0.117).

CONCLUSIONS

In this large registry study, there was no difference in survival in patients with GBM compared with GS. Among GS patients, trimodality therapy significantly improved survival compared with nontrimodality therapy. Gross-total resection also improved survival, and there was a trend toward increased survival with MGMT promoter methylation in GS. The major potential confounder in this study is that patients with poor functional status may not have received aggressive radiation or chemotherapy treatments, leading to the observed outcome. This study should be considered hypothesis-generating; however, due to its rarity, conducting a clinical trial with GS patients alone may prove difficult.

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Yasunori Nagahama, Alan J. Schmitt, Daichi Nakagawa, Adam S. Vesole, Janina Kamm, Christopher K. Kovach, David Hasan, Mark Granner, Brian J. Dlouhy, Matthew A. Howard III and Hiroto Kawasaki

OBJECTIVE

Intracranial electroencephalography (iEEG) provides valuable information that guides clinical decision-making in patients undergoing epilepsy surgery, but it carries technical challenges and risks. The technical approaches used and reported rates of complications vary across institutions and evolve over time with increasing experience. In this report, the authors describe the strategy at the University of Iowa using both surface and depth electrodes and analyze outcomes and complications.

METHODS

The authors performed a retrospective review and analysis of all patients who underwent craniotomy and electrode implantation from January 2006 through December 2015 at the University of Iowa Hospitals and Clinics. The basic demographic and clinical information was collected, including electrode coverage, monitoring results, outcomes, and complications. The correlations between clinically significant complications with various clinical variables were analyzed using multivariate analysis. The Fisher exact test was used to evaluate a change in the rate of complications over the study period.

RESULTS

Ninety-one patients (mean age 29 ± 14 years, range 3–62 years), including 22 pediatric patients, underwent iEEG. Subdural surface (grid and/or strip) electrodes were utilized in all patients, and depth electrodes were also placed in 89 (97.8%) patients. The total number of electrode contacts placed per patient averaged 151 ± 58. The duration of invasive monitoring averaged 12.0 ± 5.1 days. In 84 (92.3%) patients, a seizure focus was localized by ictal onset (82 cases) or inferred based on interictal discharges (2 patients). Localization was achieved based on data obtained from surface electrodes alone (29 patients), depth electrodes alone (13 patients), or a combination of both surface and depth electrodes (42 patients). Seventy-two (79.1%) patients ultimately underwent resective surgery. Forty-seven (65.3%) and 18 (25.0%) patients achieved modified Engel class I and II outcomes, respectively. The mean follow-up duration was 3.9 ± 2.9 (range 0.1–10.5) years. Clinically significant complications occurred in 8 patients, including hematoma in 3 (3.3%) patients, infection/osteomyelitis in 3 (3.3%) patients, and edema/compression in 2 (2.2%) patients. One patient developed a permanent neurological deficit (1.1%), and there were no deaths. The hemorrhagic and edema/compression complications correlated significantly with the total number of electrode contacts (p = 0.01), but not with age, a history of prior cranial surgery, laterality, monitoring duration, and the number of each electrode type. The small number of infectious complications precluded multivariate analysis. The number of complications decreased from 5 of 36 cases (13.9%) to 3 of 55 cases (5.5%) during the first and last 5 years, respectively, but this change was not statistically significant (p = 0.26).

CONCLUSIONS

An iEEG implantation strategy that makes use of both surface and depth electrodes is safe and effective at identifying seizure foci in patients with medically refractory epilepsy. With experience and iterative refinement of technical surgical details, the risk of complications has decreased over time.

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Yasunori Nagahama, Christopher K. Kovach, Michael Ciliberto, Charuta Joshi, Ariane E. Rhone, Adam Vesole, Phillip E. Gander, Kirill V. Nourski, Hiroyuki Oya, Matthew A. Howard III, Hiroto Kawasaki and Brian J. Dlouhy

Musicogenic epilepsy (ME) is an extremely rare form of the disorder that is provoked by listening to or playing music, and it has been localized to the temporal lobe. The number of reported cases of ME in which intracranial electroencephalography (iEEG) has been used for seizure focus localization is extremely small, especially with coverage of the superior temporal plane (STP) and specifically, Heschl’s gyrus (HG). The authors describe the case of a 17-year-old boy with a history of medically intractable ME who underwent iEEG monitoring that involved significant frontotemporal coverage as well as coverage of the STP with an HG depth electrode anteriorly and a planum temporale depth electrode posteriorly. Five seizures occurred during the monitoring period, and a seizure onset zone was localized to HG and the STP. The patient subsequently underwent right temporal neocortical resection, involving the STP and including HG, with preservation of the mesial temporal structures. The patient remains seizure free 1 year postoperatively. To the authors’ knowledge, this is the first reported case of ME in which the seizure focus has been localized to HG and the STP with iEEG monitoring. The authors review the literature on iEEG findings in ME, explain their approach to HG depth electrode placement, and discuss the utility of STP depth electrodes in temporal lobe epilepsy.

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Yasunori Nagahama, Alan J. Schmitt, Brian J. Dlouhy, Adam S. Vesole, Phillip E. Gander, Christopher K. Kovach, Daichi Nakagawa, Mark A. Granner, Matthew A. Howard III and Hiroto Kawasaki

OBJECTIVE

The epileptogenic zones in some patients with temporal lobe epilepsy (TLE) involve regions outside the typical extent of anterior temporal lobectomy (i.e., “temporal plus epilepsy”), including portions of the supratemporal plane (STP). Failure to identify this subset of patients and adjust the surgical plan accordingly results in suboptimum surgical outcomes. There are unique technical challenges associated with obtaining recordings from the STP. The authors sought to examine the clinical utility and safety of placing depth electrodes within the STP in patients with TLE.

METHODS

This study is a retrospective review and analysis of all cases in which patients underwent intracranial electroencephalography (iEEG) with use of at least one STP depth electrode over the 10 years from January 2006 through December 2015 at University of Iowa Hospitals and Clinics. Basic clinical information was collected, including the presence of ictal auditory symptoms, electrode coverage, monitoring results, resection extent, outcomes, and complications. Additionally, cases in which the temporal lobe was primarily or secondarily involved in seizure onset and propagation were categorized based upon how rapidly epileptic activity was observed within the STP following seizure onsets: within 1 second, between 1 and 15 seconds, after 15 seconds, and not involved.

RESULTS

Fifty-two patients underwent iEEG with STP coverage, with 1 STP electrode used in 45 (86.5%) cases and 2 STP electrodes in the other cases. There were no complications related to STP electrode placement. Of 42 cases in which the temporal lobe was primarily or secondarily involved, seizure activity was recorded from the STP in 36 cases (85.7%): in 5 cases (11.9%) within 1 second, in 5 (11.9%) between 1 and 15 seconds, and in 26 (61.9%) more than 15 seconds following seizure onset. Seizure outcomes inversely correlated with rapid ictal involvement of the STP (Engel class I achieved in 25%, 67%, and 82% of patients in the above categories, respectively). All patients without ictal STP involvement achieved seizure freedom. Only 4 (11.1%) patients with STP ictal involvement reported auditory symptoms.

CONCLUSIONS

Ictal involvement of the STP is common even in the absence of auditory symptoms and can be effectively detected by the STP electrodes. These electrodes are safe to implant and provide useful prognostic information.

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Yasunori Nagahama, Alan J. Schmitt, Daichi Nakagawa, Adam S. Vesole, Janina Kamm, Christopher K. Kovach, David Hasan, Mark Granner, Brian J. Dlouhy, Matthew A. Howard III and Hiroto Kawasaki

OBJECTIVE

Intracranial electroencephalography (iEEG) provides valuable information that guides clinical decision-making in patients undergoing epilepsy surgery, but it carries technical challenges and risks. The technical approaches used and reported rates of complications vary across institutions and evolve over time with increasing experience. In this report, the authors describe the strategy at the University of Iowa using both surface and depth electrodes and analyze outcomes and complications.

METHODS

The authors performed a retrospective review and analysis of all patients who underwent craniotomy and electrode implantation from January 2006 through December 2015 at the University of Iowa Hospitals and Clinics. The basic demographic and clinical information was collected, including electrode coverage, monitoring results, outcomes, and complications. The correlations between clinically significant complications with various clinical variables were analyzed using multivariate analysis. The Fisher exact test was used to evaluate a change in the rate of complications over the study period.

RESULTS

Ninety-one patients (mean age 29 ± 14 years, range 3–62 years), including 22 pediatric patients, underwent iEEG. Subdural surface (grid and/or strip) electrodes were utilized in all patients, and depth electrodes were also placed in 89 (97.8%) patients. The total number of electrode contacts placed per patient averaged 151 ± 58. The duration of invasive monitoring averaged 12.0 ± 5.1 days. In 84 (92.3%) patients, a seizure focus was localized by ictal onset (82 cases) or inferred based on interictal discharges (2 patients). Localization was achieved based on data obtained from surface electrodes alone (29 patients), depth electrodes alone (13 patients), or a combination of both surface and depth electrodes (42 patients). Seventy-two (79.1%) patients ultimately underwent resective surgery. Forty-seven (65.3%) and 18 (25.0%) patients achieved modified Engel class I and II outcomes, respectively. The mean follow-up duration was 3.9 ± 2.9 (range 0.1–10.5) years. Clinically significant complications occurred in 8 patients, including hematoma in 3 (3.3%) patients, infection/osteomyelitis in 3 (3.3%) patients, and edema/compression in 2 (2.2%) patients. One patient developed a permanent neurological deficit (1.1%), and there were no deaths. The hemorrhagic and edema/compression complications correlated significantly with the total number of electrode contacts (p = 0.01), but not with age, a history of prior cranial surgery, laterality, monitoring duration, and the number of each electrode type. The small number of infectious complications precluded multivariate analysis. The number of complications decreased from 5 of 36 cases (13.9%) to 3 of 55 cases (5.5%) during the first and last 5 years, respectively, but this change was not statistically significant (p = 0.26).

CONCLUSIONS

An iEEG implantation strategy that makes use of both surface and depth electrodes is safe and effective at identifying seizure foci in patients with medically refractory epilepsy. With experience and iterative refinement of technical surgical details, the risk of complications has decreased over time.

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Weijun Wang, Walavan Sivakumar, Shering Torres, Niyati Jhaveri, Vijaya Pooja Vaikari, Alex Gong, Adam Howard, Encouse B. Golden, Stan G. Louie, Axel H. Schönthal, Florence M. Hofman and Thomas C. Chen

OBJECT

Bevacizumab (Avastin), an antibody to vascular endothelial growth factor (VEGF), alone or in combination with irinotecan (Camptosar [CPT-11]), is a promising treatment for recurrent glioblastoma. However, the intravenous (IV) administration of bevacizumab produces a number of systemic side effects, and the increase in survival it provides for patients with recurrent glioblastoma is still only a few months. Because bevacizumab is an antibody against VEGF, which is secreted into the extracellular milieu by glioma cells, the authors hypothesized that direct chronic intratumoral delivery techniques (i.e., convection-enhanced delivery [CED]) can be more effective than IV administration. To test this hypothesis, the authors compared outcomes for these routes of bevacizumab application with respect to animal survival, microvessel density (MVD), and inflammatory cell distribution.

METHODS

Two human glioma cell lines, U87 and U251, were used as sources of intracranial tumor cells. The glioma cell lines were implanted into the brains of mice in an orthotopic xenograft mouse tumor model. After 7 days, the mice were treated with one of the following: 1) vehicle, 2) CED bevacizumab, 3) IV bevacizumab, 4) intraperitoneal (IP) irinotecan, 5) CED bevacizumab plus IP irinotecan, or 6) IV bevacizumab plus IP irinotecan. Alzet micro-osmotic pumps were used to introduce bevacizumab directly into the tumor. Survival was monitored. Excised tumor tissue samples were immunostained to measure MVD and inflammatory cell and growth factor levels.

RESULTS

The results demonstrate that mice treated with CED of bevacizumab alone or in combination with irinotecan survived longer than those treated systemically; CED-treated animals survived 30% longer than IV-treated animals. In combination studies, CED bevacizumab plus CPT-11 increased survival by more than 90%, whereas IV bevacizumab plus CPT-11 increased survival by 40%. Furthermore, CED bevacizumab-treated tissues exhibited decreased MVD compared with that of IV-treated tissues. In additional studies, the infiltration of macrophages and dendritic cells into CED-treated animals were increased compared with those in IV-treated animals, suggesting a highly active inflammatory response taking place in CED-treated mice.

CONCLUSIONS

The administration of bevacizumab via CED increases survival over that of treatment with IV bevacizumab. Thus, CED of bevacizumab alone or in combination with chemotherapy can be an effective protocol for treating gliomas.