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Robert J. Plunkett, Agnieszka Lis, Tara A. Barone, Mary Duffy Fronckowiak, and Steven J. Greenberg

Object. The authors studied the effect of gender and hormonal status on survival in nude rats implanted with human glioblastoma multiforme (GBM) cell lines.

Methods. Nude rats received intracerebral implants of either wild-type U87MG cells or U87MG cells transfected with the gene for endothelin-1 (U87/ET-1). In the initial study, survival was compared in males and females for each of the two cell lines. The six second-phase study groups were composed of: 1) males; 2) females; 3) ovariectomized females; 4) sham ovariectomized females; 5) ovariectomized rats given 10 µg/day estradiol benzoate for 21 days; and 6) ovariectomized rats given 20 mg/kg/day progesterone for 21 days. All rats in the second phase were implanted with U87/ET-1 cells. Animals were killed when they exhibited initial signs of neurological deterioration. Female nude rats survived longer than male rats implanted with either U87 or U87/ET-1 cells. In the second phase, ovariectomized, male, and progesterone-treated rats died at approximately 19 days, whereas the female, sham-treated, and estrogen-treated animals died 23 to 25 days after tumor cell implantation.

Conclusions. The authors demonstrate that female nude rats implanted with human GBM cells have a survival advantage over male rats and that estrogen provides the advantage.

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Ajay K. Wakhloo, Baruch B. Lieber, Stephen Rudin, Mary Duffy Fronckowiak, Robert A. Mericle, and L. Nelson Hopkins

Successful therapeutic embolization of arteriovenous malformations (AVMs) of the brain with liquid polymers (glues) requires precise knowledge of highly variable AVM structure and flow velocities and transit times of blood through the AVM nidus. The goal of this study was to improve AVM flow measurement and visualization by the substitution of the insoluble Ethiodol (ethiodized oil) contrast agent for the soluble contrast media normally used in angiographic studies.

Before enbucrilate embolization of 24 AVM feeding pedicles in 13 patients, standard contrast medium was superselectively injected into each target pedicle, followed by infusion of 20 μl of Ethiodol microdroplets. Transport of contrast material was assessed using high-speed biplane pulsed digital subtraction angiography (DSA) operating at 15 frames per second.

The mean blood flow transit times through AVMs after administration of Ethiodol were found to be approximately half as long as in those measured after injection of soluble contrast materials (0.22 ± 0.10 seconds compared with 0.46 ± 0.19 seconds [mean ± standard deviation]; p < 0.0001). The discrete Ethiodol microdroplets travel with the core flow, more closely approximating the dynamic behavior of enbucrilate, allowing the AVM structure to be traced with high spatial and temporal resolution. There were no inadvertent vessel occlusions or pulmonary complications related to the use of Ethiodol for DSA.

Because of diffusion and convection, forces that decrease concentration, visualization of the contrast front is reduced, often resulting in deceptively long transit times when soluble contrast materials are used. Overestimation may prove dangerous when planning embolizations. The Ethiodol droplet DSA method provides accurate transit time measurements and precise, detailed, and dynamic AVM visualization. Further development of this method will improve the safety and precision of AVM treatments.

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Ajay K. Wakhloo, Baruch B. Lieber, Stephen Rudin, Mary Duffy Fronckowiak, Robert A. Mericle, and L. Nelson Hopkins

Object. Successful therapeutic embolization of arteriovenous malformations (AVMs) of the brain with liquid polymers (glues) requires precise knowledge of highly variable AVM structure and flow velocities and transit times of blood through the AVM nidus. The goal of this study was to improve AVM flow measurement and visualization by the substitution of the insoluble Ethiodol (ethiodized oil) contrast agent for the soluble contrast media normally used in angiographic studies.

Methods. Before enbucrilate embolization of 24 AVM feeding pedicles in 13 patients, standard contrast medium was superselectively injected into each target pedicle, followed by infusion of 20 µl of Ethiodol microdroplets. Transport of contrast material was assessed using high-speed biplane pulsed digital subtraction angiography (DSA) operating at 15 frames per second.

The mean blood flow transit times through AVMs after administration of Ethiodol were found to be approximately half as long as in those measured after injection of soluble contrast materials (0.22 ± 0.10 seconds compared with 0.46 ± 0.19 seconds [mean ± standard deviation]; p < 0.0001). The discrete Ethiodol microdroplets travel with the core flow, more closely approximating the dynamic behavior of enbucrilate, allowing the AVM structure to be traced with high spatial and temporal resolution. There were no inadvertent vessel occlusions or pulmonary complications related to the use of Ethiodol for DSA.

Conclusions. Because of diffusion and convection, forces that decrease concentration, visualization of the contrast front is reduced, often resulting in deceptively long transit times when soluble contrast materials are used. Overestimation may prove dangerous when planning embolizations. The Ethiodol droplet DSA method provides accurate transit time measurements and precise, detailed, and dynamic AVM visualization. Further development of this method will improve the safety and precision of AVM treatments.

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Rabih G. Tawk, Mary Duffy-Fronckowiak, Bryan E. Scott, Ronald A. Alberico, Aidnag Z. Diaz, Matthew B. Podgorsak, Robert J. Plunkett, and Robert A. Fenstermaker

Object. The purpose of this study was to assess the durability and completeness of pain relief in patients treated using stereotactic gamma knife surgery (GKS) for trigeminal neuralgia (TN).

Methods. Thirty-eight patients with refractory TN were treated with stereotactic GKS. All patients received a prescription radiation dose of 35, 40, or 45 Gy to the 50% isodose surface through a 4-mm collimator helmet. The group was assessed regularly based on physician-directed interviews for a median follow up of 24 months (range 6–27 months). Pain relief was classified as excellent (no pain without medication), good (well-controlled pain with continued medication), fair (decreased but residual pain with continued medication), or poor (unimproved or increased pain with the same or increased medication).

Three months after treatment, pain relief was good or excellent in 71% of patients. By 24 months post-GKS, 50% of the original cohort had poor pain relief, 21% continued to have either excellent or good relief, 3% had fair relief, and 26% had not reached the 24-month follow up. Based on their status at the last follow up, 29% of patients had excellent and 16% had good pain relief. Thirty-seven percent experienced facial numbness, which was dose related. In addition, there was a significantly higher rate of complete pain relief in patients who had facial numbness following treatment (p = 0.003).

Conclusions. Stereotactic GKS is an effective treatment in patients with TN; however, the durability of pain relief and the time to treatment response are limiting factors. As with other types of ablative treatment, facial numbness is strongly associated with better treatment response.

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Elad I. Levy, Ricardo A. Hanel, Jay U. Howington, Balazs Nemes, Alan S. Boulos, Fermin O. Tio, Ann Marie Paciorek, Shoaib Amlani, Kathleen S. Kagan-Hallett, Mary Duffy Fronckowiak, Lee R. Guterman, and L. Nelson Hopkins

Object. Use of the sirolimus-eluting stent has led to a reduction of in-stent stenosis following treatment of coronary atherosclerosis, whereas treatment of intracranial atherosclerosis with bare-metal stents results in excessive restenosis rates of approximately 40%. Neurotoxicity effects and vessel injury are unknown in the cerebral vasculature. To assess the safety profile and vascular effects of sirolimus-coated stents, the authors conducted a prospective comparative study in which drug-eluting and bare-metal stents were implanted in the canine basilar artery (BA).

Methods. Sixteen mongrel dogs were randomized (eight animals per group) to receive either bare-metal 1.5 × 8—mm (six-cell) stents or sirolimus-eluting stents of the same dimensions. Interventionists, histopathologists, and histopathology technicians who participated in the study were blinded to the stent characteristics. Stents were implanted in the canine BA. Serial peripheral blood samples were obtained during the 1st week after implantation to determine the time-dependent serum concentration of sirolimus. Follow-up angiographic studies were performed 30 days after stent implantation to assess the effects of stent placement on the BA and brainstem perforating vessels. Explantation of the stent and BA was performed immediately after angiography by using a pressurized formalin fixation procedure. Histological and computer-assisted morphometric analyses of specimens obtained in each animal were performed.

Sirolimus could not be detected in peripheral blood samples obtained later than 24 hours posttreatment. On follow-up angiography, all perforating vessels observed on initial angiograms remained patent, and no evidence of parent vessel damage or pseudoaneurysm formation was observed. Explanted vessels and brainstem sections did not demonstrate evidence of histological neurotoxicity, such as gliosis or infarction. No significant differences were found in the time to endothelialization of bare-metal and sirolimus-coated stents. Smooth-muscle cell (SMC) proliferation, the putative agent for restenosis, was lower in animals receiving sirolimus-coated stents (p = 0.003). Additionally, intimal fibrin density was increased in the dogs treated with sirolimus-coated stents (p < 0.0001). Histological evidence of an inflammatory response demonstrated a trend toward a reduced response in the sirolimus group (mean 0.58) compared with the bare-metal group (mean 0.83, p = 0.33).

Conclusions. No neurotoxic effects were observed in the intracranial vessel walls or brainstem tissue in which sirolimus-coated stents were implanted. Compared with bare-metal stents, the sirolimus-coated devices did not impair endothelialization and, furthermore, tended to reduce the proliferation of SMCs. These findings indicate that sirolimus-coated devices may inhibit in-stent stenosis. Further studies with longer-term follow up are required to assess the restenosis rates of sirolimus-coated stents implanted in the intracranial vasculature.

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Raul A. Rodas, Robert A. Fenstermaker, Paul E. McKeever, Mila Blaivas, Lawrence D. Dickinson, Stephen M. Papadopoulos, Julian T. Hoff, L. Nelson Hopkins, Mary Duffy-Fronckowiak, and Harry S. Greenberg

Object. Thrombotic complications (deep vein thrombosis and/or pulmonary embolization [DVT/PE]) occur in 18 to 50% of patients harboring brain tumors who undergo neurosurgical procedures. Such patients are at risk for DVT/PE because of immobility, paresis, hypovolemia, and lengthy surgery. The present study was undertaken to see whether tumor patients at highest risk for DVT/PE could be identified so that augmentation of prophylactic measures might be used to reduce the incidence of thrombotic complications.

Methods. The authors conducted a retrospective analysis of 488 patients enrolled in their brain tumor registries between 1988 and 1995, identifying 57 patients (12%) with recorded symptomatic DVT, PE, or both postoperatively. In 24 of these 57 cases histological specimens were retrievable for review, allowing an in-depth analysis. Forty-five patients were lost to follow-up review, and the remaining 386 patients had no record of systemic thrombosis. Slides of pathological specimens were retrievable in 50 cases in which there was no DVT/PE. From these 50 cases, 25 were selected at random to represent the control group by a blinded observer. Seventeen (71%) of the 24 brain tumor specimens obtained in patients with DVT/PE stained positively for intraluminal thrombosis (ILT) after hematoxylin and eosin had been applied. The odds ratio associated with the presence of ILT was 17.8, with a confidence interval ranging from 4 to 79.3. No evidence of ILT was found in 22 patients (88%) within the control group (p < 0.0001, Fisher's exact test). Other factors that may predispose patients with brain tumors to DVT/PE—limb paresis, extent of tumor removal, and duration of the surgery—were also analyzed and found not to be statistically significant. Therefore, these factors were not the basis for differences seen between the study and control groups.

Conclusions. These preliminary observations suggest that the presence of ILT within malignant glioma or glioblastoma tumor vessels may represent a marker of tumor-induced hypercoagulability.

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Elad I. Levy, Alan S. Boulos, Ricardo A. Hanel, Fermin O. Tio, Ronald A. Alberico, Mary Duffy Fronckowiak, Balazs Nemes, Ann Marie Paciorek, Lee R. Guterman, and L. Nelson Hopkins

Object. No animal model currently exists for the examination of time-dependent histological changes occurring in intracranial vessels after endoluminal stent placement. The authors' goal was to develop a reproducible in vivo model of stent implantation in intracranial vessels in dogs that was capable of demonstrating stent-related vascular changes after the implantation of coated and uncoated devices.

Methods. The authors implanted heparin-coated or uncoated stents in the basilar arteries (BAs) of 11 mongrel dogs. In a 12th animal, one coated stent was implanted in the BA and a second uncoated one was implanted in the distal anterior spinal artery. All the devices were oversized to induce intimal injury. Surviving animals were observed for 12 weeks, after which they underwent repeated angiography before planned death and removal of the brain. Histological studies and computer-assisted morphometric analyses were conducted on stent-treated and untreated sections of the BAs to assess the percentage of stenosis, neointimal proliferation, vessel injury, and inflammation. Perforating vessels partially covered by stent struts (“jailing”) were studied for evidence of stenosis or occlusion. The pathologist, interventionists, histopathologist, histopathology technicians, and radiologist were blinded to the stent type.

Seven stents (three uncoated and four coated) were removed from the six animals that were observed during the follow-up period. The mean neointimal proliferation was 0.42 mm2 in the group treated with uncoated stents and 0.18 mm2 in the group treated with heparin-coated devices (p = 0.04). Neointimal thickness was significantly increased in the group with uncoated stents (p = 0.04). The mean percentage of occlusion was less (12%) in the group with heparin-coated stents, compared with 22% in the group with uncoated devices (p = 0.07). When comparing results between the heparin-coated and uncoated devices implanted in the five animals that received a single stent only, greater differences (indicating a benefit from heparin-coated stents) were observed in neointimal area (p = 0.009), neointima/media ratio (p = 0.001), neointimal thickness (p = 0.002), and percentage of occlusion (p = 0.009). All brainstem perforating vessels covered by stent struts remained patent.

Conclusions. This in vivo intracranial stent model was developed to assess proliferative and inflammatory responses to endoluminal stent implantation in the cerebrovasculature. The results indicate that a lower percentage of occlusion occurs 12 weeks after implantation of heparin-coated compared with uncoated stents.