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Bradley N. Bohnstedt, Mary Ziemba-Davis, Rishabh Sethia, Troy D. Payner, Andrew DeNardo, John Scott and Aaron A. Cohen-Gadol

OBJECTIVE

The deep and difficult-to-reach location of basilar apex aneurysms, along with their location near critical adjacent perforating arteries, has rendered the perception that microsurgical treatment of these aneurysms is risky. As a result, these aneurysms are considered more suitable for treatment by endovascular intervention. The authors attempt to compare the immediate and long-term outcomes of microsurgery versus endovascular therapy for this aneurysm subtype.

METHODS

A prospectively maintained database of 208 consecutive patients treated for basilar apex aneurysms between 2000 and 2012 was reviewed. In this group, 161 patients underwent endovascular treatment and 47 were managed microsurgically. The corresponding records were analyzed for presenting characteristics, postoperative complications, discharge status, and Glasgow Outcome Scale (GOS) scores up to 1 year after treatment and compared using chi-square and Student t-tests.

RESULTS

Among these 208 aneurysms, 116 (56%) were ruptured, including 92 (57%) and 24 (51%) of the endovascularly and microsurgically managed aneurysms, respectively. The average Hunt and Hess grade was 2.4 (2.4 in the endovascular group and 2.2 in the microsurgical group; p = 0.472). Postoperative complications of cranial nerve deficits and hemiparesis were more common in patients treated microsurgically than endovascularly (55.3% vs 16.2%, p < 0.05; and 27.7% vs 10.6%, p < 0.05, respectively). However, aneurysm remnants and need for retreatment were more common in the endovascular than the microsurgical group (41.3% vs 2.3%, p < 0.05; and 10.6% vs 0.0%, p < 0.05, respectively). Stent placement significantly reduced the need for retreatment. Rehemorrhage rates and average GOS score at discharge and 1 year after treatment were not statistically different between the two treatment groups.

CONCLUSIONS

Patients with basilar apex aneurysms were significantly more likely to be treated via endovascular management, but compared with those treated microsurgically, they had higher rates of recurrence and need for retreatment. The current study did not detect an overall difference in outcomes at discharge and 1 year after either treatment modality. Therefore, in a select group of patients, microsurgical treatment continues to play an important role.

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Ryan P. Morton, Louis J. Kim and Laligam N. Sekhar

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Khadijeh Bijangi-Vishehsaraei, M. Reza Saadatzadeh, Haiyan Wang, Angie Nguyen, Malgorzata M. Kamocka, Wenjing Cai, Aaron A. Cohen-Gadol, Stacey L. Halum, Jann N. Sarkaria, Karen E. Pollok and Ahmad R. Safa

OBJECTIVE

Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)—a constituent of cruciferous vegetables with a multitargeted effect—as a therapeutic agent for GBM.

METHODS

The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSC-derived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphere-forming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models.

RESULTS

SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFN-triggered cell death was ROS dependent. Comet assays revealed that SFN increased single- and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of γ-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell–induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN administration at 100 mg/kg for 5-day cycles repeated for 3 weeks significantly decreased the growth of ectopic xenografts that were established from the early passage of primary cultures of GBM10.

CONCLUSIONS

These results suggest that SFN is a potent anti-GBM agent that targets several apoptosis and cell survival pathways and further preclinical and clinical studies may prove that SFN alone or in combination with other therapies may be potentially useful for GBM therapy.

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Osamu Akiyama, Ken Matsushima, Abuzer Gungor, Satoshi Matsuo, Dylan J. Goodrich, R. Shane Tubbs, Paul Klimo Jr., Aaron A. Cohen-Gadol, Hajime Arai and Albert L. Rhoton Jr.

OBJECTIVE

Approaches to the pulvinar remain challenging because of the depth of the target, surrounding critical neural structures, and complicated arterial and venous relationships. The purpose of this study was to compare the surgical approaches to different parts of the pulvinar and to examine the efficacy of the endoscope as an adjunct to the operating microscope in this area.

METHODS

The pulvinar was examined in 6 formalin-fixed human cadaveric heads through 5 approaches: 4 above and 1 below the tentorium. Each approach was performed using both the surgical microscope and 0° or 45° rigid endoscopes.

RESULTS

The pulvinar has a lateral ventricular and a medial cisternal surface that are separated by the fornix and the choroidal fissure, which wrap around the posterior surface of the pulvinar. The medial cisternal part of the pulvinar can be further divided into upper and lower parts. The superior parietal lobule approach is suitable for lesions in the upper ventricular and cisternal parts. Interhemispheric precuneus and posterior transcallosal approaches are suitable for lesions in the part of the pulvinar forming the anterior wall of the atrium and adjacent cisternal part. The posterior interhemispheric transtentorial approach is suitable for lesions in the lower cisternal part and the supracerebellar infratentorial approach is suitable for lesions in the inferior and medial cisternal parts.

The microscope provided satisfactory views of the ventricular and cisternal surfaces of the pulvinar and adjacent neural and vascular structures. The endoscope provided multi-angled and wider views of the pulvinar and adjacent structures.

CONCLUSIONS

A combination of endoscopic and microsurgical techniques allows optimal exposure of the pulvinar.

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Mahdi Malekpour, Charles Kulwin, Bradley N. Bohnstedt, Golnar Radmand, Rishabh Sethia, Stephen K. Mendenhall, Jonathan Weyhenmeyer, Benjamin K. Hendricks, Thomas Leipzig, Troy D. Payner, Mitesh V. Shah, John Scott, Andrew DeNardo, Daniel Sahlein and Aaron A. Cohen-Gadol

OBJECTIVE

Aneurysmal rebleeding before definitive obliteration of the aneurysm is a cause of mortality and morbidity. There are limited data on the role of short-term antifibrinolytic therapy among patients undergoing endovascular intervention.

METHODS

All consecutive patients receiving endovascular therapy for their ruptured saccular aneurysm at the authors' institution between 2000 and 2011 were included in this study. These patients underwent endovascular coiling of their aneurysm within 72 hours of admission. In patients receiving ε-aminocaproic acid (EACA), the EACA administration was continued until the time of the endovascular procedure. Complications and clinical outcomes of endovascular treatment after aneurysmal subarachnoid hemorrhage (aSAH) were compared between EACA-treated and untreated patients.

RESULTS

During the 12-year study period, 341 patients underwent endovascular coiling. Short-term EACA treatment was administered in 146 patients and was withheld in the other 195 patients. EACA treatment did not change the risk of preinterventional rebleeding in this study (OR 0.782, 95% CI 0.176–3.480; p = 0.747). Moreover, EACA treatment did not increase the rate of thromboembolic events. On the other hand, patients who received EACA treatment had a significantly longer duration of hospital stay compared with their counterparts who were not treated with EACA (median 19 days, interquartile range [IQR] 12.5–30 days vs median 14 days, IQR 10–23 days; p < 0.001). EACA treatment was associated with increased odds of shunt requirement (OR 2.047, 95% CI 1.043–4.018; p = 0.037) and decreased odds of developing cardiac complications (OR 0.138, 95% CI 0.031–0.604; p = 0.009) and respiratory insufficiency (OR 0.471, 95% CI 0.239–0.926; p = 0.029). Short-term EACA treatment did not affect the Glasgow Outcome Scale score at discharge, 6 months, or 1 year following discharge.

CONCLUSIONS

In this study, short-term EACA treatment in patients who suffered from aSAH and received endovascular aneurysm repair did not decrease the risk of preinterventional rebleeding or increase the risk of thrombotic events. EACA did not affect outcome. Randomized clinical trials are required to provide robust clinical recommendation on short-term use of EACA.

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René Post, Bert A. Coert, W. Peter Vandertop, Dagmar Verbaan and Menno R. Germans

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Mason A. Brown, Jonathan Parish, Cristian F. Guandique, Troy D. Payner, Terry Horner, Thomas Leipzig, Karishma V. Rupani, Richard Kim, Bradley N. Bohnstedt and Aaron A. Cohen-Gadol

OBJECTIVE

With the recent evolution of endovascular therapies, objective evaluation of the efficacy of clip ligation for cerebral aneurysms should be performed. This study was undertaken to evaluate the durability of microsurgical clip ligation, identify risk factors for recurrence, and assess the need for long-term follow-up imaging.

METHODS

A retrospective review of medical records identified 616 consecutive patients (156 male and 460 female patients; mean age 48.4 ± 12.4 years; range 6–90 years) who underwent microsurgical clip ligation and follow-up imaging at least 1 year after discharge between 1990 and 2010 at our institution. Of a total of 926 aneurysms in 616 patients, 758 aneurysms were microsurgically clip-ligated. At presentation, 431 of these aneurysms were ruptured and 327 aneurysms were unruptured. All patients underwent postoperative baseline imaging within the 1st month of their operation. A logistic regression analysis was performed to identify which variables are more likely to predict recurrence.

RESULTS

Late follow-up angiographic imaging was obtained at a mean of 7.2 ± 4.7 years postdischarge (median 5.7 years; range 1–23 years). Of the 699 clipped aneurysms without residua, late follow-up angiography revealed only 1 (0.14%) recurrent aneurysm. Of the 59 residual aneurysms that remained after initial clip ligation on early postoperative imaging, 8 (13.6%) demonstrated growth. All of these aneurysms required treatment. None of the recurrences were due to broken or delayed displacement of clips. A total of 111 patients presented with multiple aneurysms. De novo aneurysm formation occurred in 8 (0.97%) patients, all of whom initially presented with multiple aneurysms.

CONCLUSIONS

This study provides additional evidence to support the long-term efficacy of aneurysm clip ligation. The chance of aneurysm recurrence after complete clip ligation is very small. However, there is a regrowth risk of 1.83% per year for aneurysm remnants after incomplete clip ligation. These findings support the necessity for continued followup, late angiographic imaging, and the potential need for further intervention of incompletely ligated aneurysms. Furthermore, completely clip-ligated aneurysms may not require additional surveillance imaging unless multiple aneurysms were evident at presentation.

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Haiyan Wang, Shanbao Cai, Barbara J. Bailey, M. Reza Saadatzadeh, Jixin Ding, Eva Tonsing-Carter, Taxiarchis M. Georgiadis, T. Zachary Gunter, Eric C. Long, Robert E. Minto, Kevin R. Gordon, Stephanie E. Sen, Wenjing Cai, Jacob A. Eitel, David L. Waning, Lauren R. Bringman, Clark D. Wells, Mary E. Murray, Jann N. Sarkaria, Lawrence M. Gelbert, David R. Jones, Aaron A. Cohen-Gadol, Lindsey D. Mayo, Harlan E. Shannon and Karen E. Pollok

OBJECTIVE

Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM.

METHODS

The combination of TMZ with the MDM2 protein–protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM.

RESULTS

In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nutlin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy.

CONCLUSIONS

Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors' knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein–protein interactions.