To determine the relationship between blood glucose levels (mg/dL) and occurrence of symptomatic ... more To determine the relationship between blood glucose levels (mg/dL) and occurrence of symptomatic vasospasm (VSP) and clinical outcomes after aneurysmal subarachnoid hemorrhage. Retrospective observational study of 352 patients with subarachnoid hemorrhage admitted within 48 hrs of ictus between January 1995 and June 2002. Neurointensive care unit. Adult patients admitted after subarachnoid hemorrhage. None. Variables included age; Hunt-Hess classification score; Fisher group; insulin use; infectious disease status; history of diabetes mellitus; and blood glucose values. Poor clinical outcome was defined by a modified Rankin score > or =3, and hyperglycemia was defined by a blood glucose level >140 mg/dL. Mean daily blood glucose values were assessed from admission to development of VSP or day 14. Mean admission blood glucose value, mean inpatient blood glucose value, insulin use, infectious disease status, Hunt-Hess classification score, Fisher group, and history of diabetes mellitus were entered in a Cox proportional hazards model. VSP occurred in 103 (29.2%) of 352 patients. Mean admission blood glucose values (176.6 +/- 40.3 mg/dL vs. 162.3 +/- 47.8 mg/dL; p = .01) and mean inpatient blood glucose values (166.2 +/- 24.7 mg/dL vs. 155.8 +/- 29.7 mg/dL; p = .001) were significantly higher in patients with VSP. Mean inpatient blood glucose value (relative risk, 1.01; 95% confidence interval, 1.0-1.03; p = .04), Hunt-Hess classification score > or =3 (relative risk, 2.23; 95% confidence interval, 1.21-3.99; p = .02), and Fisher group score of 3 (relative risk, 1.28; 95% confidence interval, 1.15-3.1; p = .05) increased the risk for VSP. Hyperglycemia was associated with longer length of stay in the neurointensive care unit (14.5 +/- 7.1 days vs. 11.6 +/- 5.4 days; p < .001) and poor outcome at discharge (modified Rankin score > or =3: 58.9% vs. 18.8%; p < .001). Mean inpatient blood glucose value is associated with the development of VSP and may represent a target for therapy to prevent VSP and improve clinical outcomes.
The aim of this study was to assess the diagnostic yield of imaging tests performed in patients i... more The aim of this study was to assess the diagnostic yield of imaging tests performed in patients in whom the cause of subarachnoid hemorrhage (SAH) had not been demonstrated on initial angiography. By reviewing medical records of 806 patients with SAH who had been admitted during a 6.5-year period, the authors identified 86 in whom initial transfemoral catheter angiography failed to reveal the cause of SAH. Clinical and radiological data were analyzed to determine the diagnostic yield of subsequent catheter angiography, computerized tomography (CT) angiography, magnetic resonance (MR) angiography, and MR imaging of the brain and spine for various subtypes of SAH (bleeding not visualized on CT studies [CT-negative SAH], perimesencephalic SAH, and nonperimesencephalic SAH). Of 41 patients with nonperimesencephalic SAH, 36, 32, and 21 underwent repeated catheter angiography, CT angiography, and MR angiography, respectively; brain MR imaging was performed in 23 patients (18 with Gd and 15 with susceptibility contrast sequences), and spine MR imaging in 17. Of 36 patients with perimesencephalic SAH, 31, 23, and 17 underwent repeated catheter angiography, CT angiography, and MR angiography, respectively; brain MR imaging was performed in 18 patients (17 with Gd and 11 with susceptibility contrast sequences), and spine MR imaging in 14. Of nine patients with SAH not visualized on CT scanning, three, one, and six underwent repeated catheter angiography, CT angiography, and MR angiography, respectively; brain MR imaging was performed in eight patients (five with Gd and three with susceptibility contrast sequences), and spine MR imaging in seven. The cause of SAH could be determined in only four patients, all with nonperimesencephalic SAH. The only test that yielded a diagnosis was catheter angiography (three aneurysms on the second and one on the third angiography, all surgically secured). Diffusion-weighted MR imaging demonstrated small, deep infarcts in five patients. Repeated catheter angiography remains the most sensitive test to determine the cause of SAH that is not demonstrated on initial angiography, particularly in the subtype of nonperimesencephalic SAH. Newer, noninvasive imaging techniques provide little diagnostic yield.
Neurosurgery Clinics of North America, Jan 1, 2002
There are several medical therapies available to lower unacceptable ICP. We advocate the stepwise... more There are several medical therapies available to lower unacceptable ICP. We advocate the stepwise institution of these therapies to maintain adequate CPP. At every step in the process, consideration of definitive surgical intervention (e.g., hemicraniectomy, clot evacuation) should be entertained. At this time, we cannot recommend hypothermia as a routine last step of therapy given the complications and lack of clinical effect described previously. Research into this therapy continues, however. The next several years may show us when, how, and in what situations this strategy can be applied.
Glioblastoma multiforme (GBM) is characterized by neovascularization, raising the question of whe... more Glioblastoma multiforme (GBM) is characterized by neovascularization, raising the question of whether angiogenic blockade may be a useful therapeutic strategy for this disease. It has been suggested, however, that, to be useful, angiogenic blockade must be persistent and at levels sufficient to overcome proangiogenic signals from tumor cells. In this report, the authors tested the hypothesis that sustained high concentrations of 2 different antiangiogenic proteins, delivered using a systemic gene therapy strategy, could inhibit the growth of established intracranial U87 human GBM xenografts in nude mice. Mice harboring established U87 intracranial tumors received intravenous injections of adenoviral vectors encoding either the extracellular domain of vascular endothelial growth factor receptor-2-Fc fusion protein (Ad-VEGFR2-Fc) alone, soluble endostatin (Ad-ES) alone, a combination of Ad-VEGFR2-Fc and Ad-ES, or immunoglobulin 1-Fc (Ad-Fc) as a control. Three weeks after treatment, magnetic resonance imaging-based determination of tumor volume showed that treatment with Ad-VEGFR2-Fc, Ad-ES, or Ad-VEGFR2-Fc in combination with Ad-ES, produced 69, 59, and 74% growth inhibition, respectively. Bioluminescent monitoring of tumor growth revealed growth inhibition in the same treatment groups to be 62, 74, and 72%, respectively. Staining with proliferating cell nuclear antigen and with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling showed reduced tumor cell proliferation and increased apoptosis in all antiangiogenic treatment groups. These results suggest that systemic delivery and sustained production of endostatin and soluble VEGFR2 can slow intracranial glial tumor growth by both reducing cell proliferation and increasing tumor apoptosis. This work adds further support to the concept of using antiangiogenesis therapy for intracranial GBM.
A systematic approach to the consideration of various factors on outcome demands a comprehensive ... more A systematic approach to the consideration of various factors on outcome demands a comprehensive grading system for patients with intracranial aneurysms. We have previously identified potential patient- and lesion-specific factors that correlate strongly with outcome after treatment for intracranial aneurysms, and we have developed a comprehensive grading system based on these factors. In this study, we evaluate this grading system in a large series of aneurysm patients treated by surgery and endovascular therapy.
Neurosurgeons, working as surgical scientists, can have a prominent role in developing and implem... more Neurosurgeons, working as surgical scientists, can have a prominent role in developing and implementing genetic and cellular therapies for cerebral ischemia. The rapid emergence of both genetic and cellular therapies for neural regeneration warrants a careful analysis before implementation of human studies to understand the pitfalls and promises of this strategy. In this article, we review the topic of genetic and cellular therapy for stroke to provide a foundation for practicing neurosurgeons and clinical scientists who may become involved in this type of work. In Part 1, we review preclinical approaches with gene transfer, such as 1) improved energy delivery, 2) reduction of intracellular calcium availability, 3) abrogation of effects of reactive oxygen species, 4) reduction of proinflammatory cytokine signaling, 5) inhibition of apoptosis mediators, and 6) restorative gene therapy, that are paving the way to develop new strategies to treat cerebral infarction. In Part 2, we discuss the results of studies that address the possibility of using cellular therapies for stroke in animal models and in human trials by reviewing 1) the basics of stem cell biology, 2) exogenous and 3) and endogenous cell sources for therapy, and 4) clinical considerations in cell therapy applications. These emerging technologies based on the advancements made in recent years in the fields of genetics, therapeutic cloning, neuroscience, stem cell biology, and gene therapy provide significant potential for new therapies for stroke.
To evaluate the effect of angiopoietin-1, an angiogenic growth factor, on lung capillary leakage ... more To evaluate the effect of angiopoietin-1, an angiogenic growth factor, on lung capillary leakage and survival in a murine model of acute lung injury. Laboratory investigation. Research laboratory at New York University School of Medicine and Department of Veterans Affairs, NY Harbor Healthcare System. C57BL/6 mice weighing 18-20 g, susceptible to endotoxin-induced acute lung injury. Acute lung injury was induced in C57BL/6 mice by the intraperitoneal administration of endotoxin. The effects of angiopoietin-1, expressed from a nonreplicating E1a-deleted adenovirus containing the angiopoietin-1 complementary DNA (AdAng1), on survival and lung injury were evaluated. An E1a-deleted adenovirus that does not contain a transgene (Ad312) and phosphate-buffered saline were used as controls. Angiopoietin-1 protein was detected by immunoblotting in the serum of mice that received an intraperitoneal injection of AdAng1 but not in mice that received the control virus Ad312. When compared with control groups, mice that received AdAng1 5 days before endotoxin administration had improved survival and significantly less protein leakage from the circulation into the lungs, as detected by quantitative spectrophotometric measurements of Evans blue dye. Furthermore, when compared with controls, histopathology and immunostaining of lungs against CD31 and smooth muscle actin suggested preservation of vascular integrity and decreased tissue damage in mice pretreated with AdAng1. When endotoxin administration preceded infection with AdAng1 by 3 hrs, no benefit was observed. These data show that adenoviral mediated expression of angiopoietin-1 can protect against the development of lung capillary protein leak and decrease the mortality induced by endotoxin. However, the timing of AdAng1 administration in relation to the onset of lung injury may be critical.
Intracranial residual and recurrent aneurysms can occur after surgical clipping, with risks of gr... more Intracranial residual and recurrent aneurysms can occur after surgical clipping, with risks of growth and rupture. In the past, surgical reoperation, which can be associated with higher risk than the initial operation, was the only available treatment. A combined neurovascular team that uses both surgical and endovascular therapies could maximize efficacy and outcomes while minimizing risks in these difficult cases. The indications for which surgical or endovascular treatment should be used to treat patients with residual or recurrent aneurysms, however, have not been elucidated well. We have reviewed the 10-year experience of our combined neurovascular team to determine in a retrospective manner which factors were important to treatment modality selection for patients with these residual and recurrent lesions. From 1991 to 2001, the combined neurovascular unit at the Massachusetts General Hospital treated 25 residual and recurrent previously clipped aneurysms (15 had been clipped at other centers). Only patients in whom a clip had been placed were included in the study; patients who did not have a clip placed or whose aneurysms were wrapped or coated were excluded. The radiographic studies and clinical data were reviewed retrospectively to determine the efficacy, outcomes, and factors important to the selection of treatment strategy in these patients. The patients' clinical presentations were radiographic follow-up, 17 patients; rehemorrhage, 3; mass effect, 3; and thromboembolism, 2. The mean aneurysm recurrence or residual size was 11 mm (range, 4-26 mm). The mean interval until representation was 6.6 years (range, 1 wk-25 yr). Treatment consisted of: coiling, 11 patients; reclipping, 8; proximal parent vessel balloon occlusion, 2; extracranial-intracranial bypass with coil occlusion of aneurysm and parent vessel, 2; extracranial-intracranial bypass with clip trapping, 1; and extracranial-intracranial bypass with proximal clip occlusion of parent vessel, 1. The mean radiographic follow-up period was 11 months. Complete angiographic occlusion was found in 19 aneurysms (76%), at least 90% occlusion was found in 4 aneurysms (16%), intentional partial coil obliteration was found in 1 fusiform lesion (4%), and intentional retrograde flow was found in 1 fusiform lesion (4%). Clinical outcomes were excellent or good in 19 patients (76%). Twenty-one patients (84%) were neurologically the same after retreatment (13 remained neurologically intact, and 8 had preexisting neurological deficits that did not change). Three patients (12%) had new neurological deficits after retreatment, and one patient (4%) died. There were four complications of retreatment (16%), one of which was a fatal hemorrhage in a patient 1 month after intentional partial coil obliteration of a fusiform vertebrobasilar junction aneurysm. Factors important to the selection of treatment modality were recurrence or residual location (all posterior circulation lesions were treated endovascularly), lesion size (lesions larger than 10 mm were treated endovascularly or with the use of combined techniques), and aneurysm morphology (fusiform and wide-necked lesions were treated endovascularly or with the use of combined techniques). The proper selection of surgical or endovascular treatment for residual and recurrent previously clipped aneurysms can achieve excellent radiographic efficacy with low mortality. Factors important to the selection of treatment by this combined neurovascular team were posterior circulation location, aneurysm size larger than 10 mm, and fusiform morphology, which were treated endovascularly or with the use of combined techniques because of the higher surgical risk associated with these factors. For aneurysms with lower surgical risk, such as some anterior circulation aneurysms and aneurysms smaller than 10 mm, we prefer to perform a reoperation because of superior radiographic cure without compromising the outcome.
We have previously described an approach that employs retroviral receptor-ligand bridge proteins ... more We have previously described an approach that employs retroviral receptor-ligand bridge proteins to target retroviral vectors to specific cell types. To determine whether targeted retroviral entry can also be achieved using a retroviral receptor–single-chain antibody bridge protein, the TVA-MR1 fusion protein was generated. TVA-MR1 is comprised of the extracellular domain of the TVA receptor for subgroup A avian leukosis viruses (ALV-A), fused to the MR1 single-chain antibody that binds specifically to EGFRvIII, a tumor-specific form of the epidermal growth factor receptor. We show that TVA-MR1 binds specifically to a murine version of EGFRvIII and promotes ALV-A entry selectively into cells that express this cell surface marker. These studies demonstrate that it is possible to target retroviral vectors to specific cell types through the use of a retroviral receptor–single-chain antibody fusion protein.
To explore the epidemiology of the size distribution of intracranial bifurcation aneurysms at dif... more To explore the epidemiology of the size distribution of intracranial bifurcation aneurysms at different locations and to specifically test the hypothesis that distal vessels develop, on average, smaller aneurysms.
Hypertensive hypervolemic therapy for vasospasm is widely practiced. It is not clear, however, wh... more Hypertensive hypervolemic therapy for vasospasm is widely practiced. It is not clear, however, whether the use of hypertension and hypervolemia as a treatment for vasospasm risks hemorrhage from an unsecured, unruptured aneurysm. From 1991 to 2000, the neurovascular unit at the Massachusetts General Hospital treated 1908 aneurysms, of which 966 were ruptured. Forty patients with ruptured aneurysms had unsecured, unruptured aneurysms and underwent hypertensive hypervolemic therapy for vasospasm. Hypertension was induced by intravenously administered phenylephrine, norepinephrine, and/or dopamine, and hypervolemia was achieved by intravenously administered crystalloid and colloid solutions. The 24-hour mean arterial systolic blood pressure (SBP) and the 24-hour mean central venous pressure were calculated on the basis of hourly measurements during hypertensive hypervolemic treatment. The 40 study patients harbored 124 aneurysms, of which 51 aneurysms were treated (clipping, 37; coiling, 14) by the time hypertensive hypervolemic therapy began, leaving 73 unsecured aneurysms at risk. The mean size of the unsecured aneurysms was 4.45 mm. Nineteen patients were treated with mild hypertension (SBP, 140-180 mmHg), 12 patients were treated with moderate hypertension (SBP, 180-200 mmHg), and 9 patients were treated with severe hypertension (SBP, >200 mmHg). The 24-hour mean SBP readings were 166.81 +/- 8.19, 187.57 +/- 5.79, and 204.01 +/- 3.75 mmHg for the mild, moderate, and severe hypertension groups, respectively. The mean central venous pressure was 10.43 +/- 3.89 mmHg. The mean course of hypertensive hypervolemic therapy was 7.25 days, and therapy began on mean post-subarachnoid hemorrhage Day 6.73. Twenty-eight aneurysms were eventually treated in later procedures (clipping, 25; coiling, 3). The mean interval to treatment was 6.93 months. In a treatment and follow-up period of 121.75 aneurysm-years of risk, there was no instance of hemorrhage. Hypertension and hypervolemia do not seem to increase the risk of hemorrhage from unsecured, unruptured aneurysms in the acute setting or in their short-term natural history.
The goal of this study was to determine the risk of adverse outcomes after contemporary surgical ... more The goal of this study was to determine the risk of adverse outcomes after contemporary surgical treatment of meningiomas in the US and trends in patient outcomes and patterns of care. The authors performed a retrospective cohort study by using the Nationwide Inpatient Sample covering the period of 1988 to 2000. Multivariate regression models with disposition end points of death and hospital discharge were used to test patient, surgeon, and hospital characteristics, including volume of care, as outcome predictors. Multivariate analyses revealed that larger-volume centers had lower mortality rates for patients who underwent craniotomy for meningioma (odds ratio [OR] 0.74, 95% confidence interval [CI] 0.59-0.93, p = 0.01). Adverse discharge disposition was also less likely at high-volume hospitals (OR 0.71, 95% CI 0.62-0.80, p < 0.001). With respect to the surgeon caseload, there was a trend toward a lower rate of mortality after surgery when higher-caseload providers were involved, and a significantly less frequent adverse discharge disposition (OR 0.71, 95% CI 0.62-0.80, p < 0.001). The annual meningioma caseload in the US increased 83% between 1988 and 2000, from 3900 patients/year to 7200 patients/year. In-hospital mortality rates decreased 61%, from 4.5% in 1988 to 1.8% in 2000. Reductions in the mortality rates were largest at high-volume centers (a 72% reduction in the relative mortality rate at largest-volume-quintile centers, compared with a 6% increase in the relative mortality rate at lowest-volume-quintile centers). The number of US hospitals where craniotomies were performed for meningiomas increased slightly. Fewer centers hosted one meningioma resection annually, whereas the largest centers had disproportionate increases in their caseloads, indicating a modest centralization of meningioma surgery in the US during this interval. The mortality and adverse hospital discharge disposition rates were lower when meningioma surgery was performed by high-volume providers. The annual US caseload increased, whereas the mortality rates decreased, especially at high-volume centers.
For many complex surgical procedures, larger hospital or surgeon caseload is associated with bett... more For many complex surgical procedures, larger hospital or surgeon caseload is associated with better patient outcome. We examined the volume-outcome relationship for surgical excision of acoustic neuromas. Retrospective cohort study. The Nationwide Inpatient Sample (1996 to 2000) was used. Multivariate regression analyses were adjusted for age, sex, race, payer, geographic region, procedure timing, admission type and source, medical comorbidities, and neurofibromatosis status. At 265 hospitals, 2643 operations were performed by 352 identified primary surgeons. Outcome was measured on a four-level scale at hospital discharge: death (0.5%) and discharge to long-term care (1.2%), to short-term rehabilitation (4.4%), and directly to home (94%). Outcomes were significantly better after surgery at higher-volume hospitals (OR 0.47 for fivefold-larger caseload, P <.001) or by higher-volume surgeons (OR 0.46, P <.001). Of patients who had surgery at lowest-volume-quartile hospitals, 12.3% were not discharged directly home, compared with 4.1% at highest-volume-quartile hospitals. There was a trend toward lower mortality for higher-volume hospitals (P =.1) and surgeons (P =.06). Of patients who had surgery at lowest-caseload-quartile hospitals, 1.1% died, compared with 0.6% at highest-volume-quartile hospitals. Postoperative complications (including neurological complications, mechanical ventilation, facial palsy, and transfusion) were less likely with high-volume hospitals and surgeons. Length of stay was significantly shorter with high-volume hospitals (P =.01) and surgeons (P =.009). Hospital charges were lower for high-volume hospitals (by 6% [P =.006]) and surgeons (by 6% [P =.09]). For acoustic neuroma excision, higher-volume hospitals and surgeons provided superior short-term outcomes with shorter lengths of stay and lower charges.
To determine the relationship between blood glucose levels (mg/dL) and occurrence of symptomatic ... more To determine the relationship between blood glucose levels (mg/dL) and occurrence of symptomatic vasospasm (VSP) and clinical outcomes after aneurysmal subarachnoid hemorrhage. Retrospective observational study of 352 patients with subarachnoid hemorrhage admitted within 48 hrs of ictus between January 1995 and June 2002. Neurointensive care unit. Adult patients admitted after subarachnoid hemorrhage. None. Variables included age; Hunt-Hess classification score; Fisher group; insulin use; infectious disease status; history of diabetes mellitus; and blood glucose values. Poor clinical outcome was defined by a modified Rankin score > or =3, and hyperglycemia was defined by a blood glucose level >140 mg/dL. Mean daily blood glucose values were assessed from admission to development of VSP or day 14. Mean admission blood glucose value, mean inpatient blood glucose value, insulin use, infectious disease status, Hunt-Hess classification score, Fisher group, and history of diabetes mellitus were entered in a Cox proportional hazards model. VSP occurred in 103 (29.2%) of 352 patients. Mean admission blood glucose values (176.6 +/- 40.3 mg/dL vs. 162.3 +/- 47.8 mg/dL; p = .01) and mean inpatient blood glucose values (166.2 +/- 24.7 mg/dL vs. 155.8 +/- 29.7 mg/dL; p = .001) were significantly higher in patients with VSP. Mean inpatient blood glucose value (relative risk, 1.01; 95% confidence interval, 1.0-1.03; p = .04), Hunt-Hess classification score > or =3 (relative risk, 2.23; 95% confidence interval, 1.21-3.99; p = .02), and Fisher group score of 3 (relative risk, 1.28; 95% confidence interval, 1.15-3.1; p = .05) increased the risk for VSP. Hyperglycemia was associated with longer length of stay in the neurointensive care unit (14.5 +/- 7.1 days vs. 11.6 +/- 5.4 days; p < .001) and poor outcome at discharge (modified Rankin score > or =3: 58.9% vs. 18.8%; p < .001). Mean inpatient blood glucose value is associated with the development of VSP and may represent a target for therapy to prevent VSP and improve clinical outcomes.
The aim of this study was to assess the diagnostic yield of imaging tests performed in patients i... more The aim of this study was to assess the diagnostic yield of imaging tests performed in patients in whom the cause of subarachnoid hemorrhage (SAH) had not been demonstrated on initial angiography. By reviewing medical records of 806 patients with SAH who had been admitted during a 6.5-year period, the authors identified 86 in whom initial transfemoral catheter angiography failed to reveal the cause of SAH. Clinical and radiological data were analyzed to determine the diagnostic yield of subsequent catheter angiography, computerized tomography (CT) angiography, magnetic resonance (MR) angiography, and MR imaging of the brain and spine for various subtypes of SAH (bleeding not visualized on CT studies [CT-negative SAH], perimesencephalic SAH, and nonperimesencephalic SAH). Of 41 patients with nonperimesencephalic SAH, 36, 32, and 21 underwent repeated catheter angiography, CT angiography, and MR angiography, respectively; brain MR imaging was performed in 23 patients (18 with Gd and 15 with susceptibility contrast sequences), and spine MR imaging in 17. Of 36 patients with perimesencephalic SAH, 31, 23, and 17 underwent repeated catheter angiography, CT angiography, and MR angiography, respectively; brain MR imaging was performed in 18 patients (17 with Gd and 11 with susceptibility contrast sequences), and spine MR imaging in 14. Of nine patients with SAH not visualized on CT scanning, three, one, and six underwent repeated catheter angiography, CT angiography, and MR angiography, respectively; brain MR imaging was performed in eight patients (five with Gd and three with susceptibility contrast sequences), and spine MR imaging in seven. The cause of SAH could be determined in only four patients, all with nonperimesencephalic SAH. The only test that yielded a diagnosis was catheter angiography (three aneurysms on the second and one on the third angiography, all surgically secured). Diffusion-weighted MR imaging demonstrated small, deep infarcts in five patients. Repeated catheter angiography remains the most sensitive test to determine the cause of SAH that is not demonstrated on initial angiography, particularly in the subtype of nonperimesencephalic SAH. Newer, noninvasive imaging techniques provide little diagnostic yield.
Neurosurgery Clinics of North America, Jan 1, 2002
There are several medical therapies available to lower unacceptable ICP. We advocate the stepwise... more There are several medical therapies available to lower unacceptable ICP. We advocate the stepwise institution of these therapies to maintain adequate CPP. At every step in the process, consideration of definitive surgical intervention (e.g., hemicraniectomy, clot evacuation) should be entertained. At this time, we cannot recommend hypothermia as a routine last step of therapy given the complications and lack of clinical effect described previously. Research into this therapy continues, however. The next several years may show us when, how, and in what situations this strategy can be applied.
Glioblastoma multiforme (GBM) is characterized by neovascularization, raising the question of whe... more Glioblastoma multiforme (GBM) is characterized by neovascularization, raising the question of whether angiogenic blockade may be a useful therapeutic strategy for this disease. It has been suggested, however, that, to be useful, angiogenic blockade must be persistent and at levels sufficient to overcome proangiogenic signals from tumor cells. In this report, the authors tested the hypothesis that sustained high concentrations of 2 different antiangiogenic proteins, delivered using a systemic gene therapy strategy, could inhibit the growth of established intracranial U87 human GBM xenografts in nude mice. Mice harboring established U87 intracranial tumors received intravenous injections of adenoviral vectors encoding either the extracellular domain of vascular endothelial growth factor receptor-2-Fc fusion protein (Ad-VEGFR2-Fc) alone, soluble endostatin (Ad-ES) alone, a combination of Ad-VEGFR2-Fc and Ad-ES, or immunoglobulin 1-Fc (Ad-Fc) as a control. Three weeks after treatment, magnetic resonance imaging-based determination of tumor volume showed that treatment with Ad-VEGFR2-Fc, Ad-ES, or Ad-VEGFR2-Fc in combination with Ad-ES, produced 69, 59, and 74% growth inhibition, respectively. Bioluminescent monitoring of tumor growth revealed growth inhibition in the same treatment groups to be 62, 74, and 72%, respectively. Staining with proliferating cell nuclear antigen and with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling showed reduced tumor cell proliferation and increased apoptosis in all antiangiogenic treatment groups. These results suggest that systemic delivery and sustained production of endostatin and soluble VEGFR2 can slow intracranial glial tumor growth by both reducing cell proliferation and increasing tumor apoptosis. This work adds further support to the concept of using antiangiogenesis therapy for intracranial GBM.
A systematic approach to the consideration of various factors on outcome demands a comprehensive ... more A systematic approach to the consideration of various factors on outcome demands a comprehensive grading system for patients with intracranial aneurysms. We have previously identified potential patient- and lesion-specific factors that correlate strongly with outcome after treatment for intracranial aneurysms, and we have developed a comprehensive grading system based on these factors. In this study, we evaluate this grading system in a large series of aneurysm patients treated by surgery and endovascular therapy.
Neurosurgeons, working as surgical scientists, can have a prominent role in developing and implem... more Neurosurgeons, working as surgical scientists, can have a prominent role in developing and implementing genetic and cellular therapies for cerebral ischemia. The rapid emergence of both genetic and cellular therapies for neural regeneration warrants a careful analysis before implementation of human studies to understand the pitfalls and promises of this strategy. In this article, we review the topic of genetic and cellular therapy for stroke to provide a foundation for practicing neurosurgeons and clinical scientists who may become involved in this type of work. In Part 1, we review preclinical approaches with gene transfer, such as 1) improved energy delivery, 2) reduction of intracellular calcium availability, 3) abrogation of effects of reactive oxygen species, 4) reduction of proinflammatory cytokine signaling, 5) inhibition of apoptosis mediators, and 6) restorative gene therapy, that are paving the way to develop new strategies to treat cerebral infarction. In Part 2, we discuss the results of studies that address the possibility of using cellular therapies for stroke in animal models and in human trials by reviewing 1) the basics of stem cell biology, 2) exogenous and 3) and endogenous cell sources for therapy, and 4) clinical considerations in cell therapy applications. These emerging technologies based on the advancements made in recent years in the fields of genetics, therapeutic cloning, neuroscience, stem cell biology, and gene therapy provide significant potential for new therapies for stroke.
To evaluate the effect of angiopoietin-1, an angiogenic growth factor, on lung capillary leakage ... more To evaluate the effect of angiopoietin-1, an angiogenic growth factor, on lung capillary leakage and survival in a murine model of acute lung injury. Laboratory investigation. Research laboratory at New York University School of Medicine and Department of Veterans Affairs, NY Harbor Healthcare System. C57BL/6 mice weighing 18-20 g, susceptible to endotoxin-induced acute lung injury. Acute lung injury was induced in C57BL/6 mice by the intraperitoneal administration of endotoxin. The effects of angiopoietin-1, expressed from a nonreplicating E1a-deleted adenovirus containing the angiopoietin-1 complementary DNA (AdAng1), on survival and lung injury were evaluated. An E1a-deleted adenovirus that does not contain a transgene (Ad312) and phosphate-buffered saline were used as controls. Angiopoietin-1 protein was detected by immunoblotting in the serum of mice that received an intraperitoneal injection of AdAng1 but not in mice that received the control virus Ad312. When compared with control groups, mice that received AdAng1 5 days before endotoxin administration had improved survival and significantly less protein leakage from the circulation into the lungs, as detected by quantitative spectrophotometric measurements of Evans blue dye. Furthermore, when compared with controls, histopathology and immunostaining of lungs against CD31 and smooth muscle actin suggested preservation of vascular integrity and decreased tissue damage in mice pretreated with AdAng1. When endotoxin administration preceded infection with AdAng1 by 3 hrs, no benefit was observed. These data show that adenoviral mediated expression of angiopoietin-1 can protect against the development of lung capillary protein leak and decrease the mortality induced by endotoxin. However, the timing of AdAng1 administration in relation to the onset of lung injury may be critical.
Intracranial residual and recurrent aneurysms can occur after surgical clipping, with risks of gr... more Intracranial residual and recurrent aneurysms can occur after surgical clipping, with risks of growth and rupture. In the past, surgical reoperation, which can be associated with higher risk than the initial operation, was the only available treatment. A combined neurovascular team that uses both surgical and endovascular therapies could maximize efficacy and outcomes while minimizing risks in these difficult cases. The indications for which surgical or endovascular treatment should be used to treat patients with residual or recurrent aneurysms, however, have not been elucidated well. We have reviewed the 10-year experience of our combined neurovascular team to determine in a retrospective manner which factors were important to treatment modality selection for patients with these residual and recurrent lesions. From 1991 to 2001, the combined neurovascular unit at the Massachusetts General Hospital treated 25 residual and recurrent previously clipped aneurysms (15 had been clipped at other centers). Only patients in whom a clip had been placed were included in the study; patients who did not have a clip placed or whose aneurysms were wrapped or coated were excluded. The radiographic studies and clinical data were reviewed retrospectively to determine the efficacy, outcomes, and factors important to the selection of treatment strategy in these patients. The patients' clinical presentations were radiographic follow-up, 17 patients; rehemorrhage, 3; mass effect, 3; and thromboembolism, 2. The mean aneurysm recurrence or residual size was 11 mm (range, 4-26 mm). The mean interval until representation was 6.6 years (range, 1 wk-25 yr). Treatment consisted of: coiling, 11 patients; reclipping, 8; proximal parent vessel balloon occlusion, 2; extracranial-intracranial bypass with coil occlusion of aneurysm and parent vessel, 2; extracranial-intracranial bypass with clip trapping, 1; and extracranial-intracranial bypass with proximal clip occlusion of parent vessel, 1. The mean radiographic follow-up period was 11 months. Complete angiographic occlusion was found in 19 aneurysms (76%), at least 90% occlusion was found in 4 aneurysms (16%), intentional partial coil obliteration was found in 1 fusiform lesion (4%), and intentional retrograde flow was found in 1 fusiform lesion (4%). Clinical outcomes were excellent or good in 19 patients (76%). Twenty-one patients (84%) were neurologically the same after retreatment (13 remained neurologically intact, and 8 had preexisting neurological deficits that did not change). Three patients (12%) had new neurological deficits after retreatment, and one patient (4%) died. There were four complications of retreatment (16%), one of which was a fatal hemorrhage in a patient 1 month after intentional partial coil obliteration of a fusiform vertebrobasilar junction aneurysm. Factors important to the selection of treatment modality were recurrence or residual location (all posterior circulation lesions were treated endovascularly), lesion size (lesions larger than 10 mm were treated endovascularly or with the use of combined techniques), and aneurysm morphology (fusiform and wide-necked lesions were treated endovascularly or with the use of combined techniques). The proper selection of surgical or endovascular treatment for residual and recurrent previously clipped aneurysms can achieve excellent radiographic efficacy with low mortality. Factors important to the selection of treatment by this combined neurovascular team were posterior circulation location, aneurysm size larger than 10 mm, and fusiform morphology, which were treated endovascularly or with the use of combined techniques because of the higher surgical risk associated with these factors. For aneurysms with lower surgical risk, such as some anterior circulation aneurysms and aneurysms smaller than 10 mm, we prefer to perform a reoperation because of superior radiographic cure without compromising the outcome.
We have previously described an approach that employs retroviral receptor-ligand bridge proteins ... more We have previously described an approach that employs retroviral receptor-ligand bridge proteins to target retroviral vectors to specific cell types. To determine whether targeted retroviral entry can also be achieved using a retroviral receptor–single-chain antibody bridge protein, the TVA-MR1 fusion protein was generated. TVA-MR1 is comprised of the extracellular domain of the TVA receptor for subgroup A avian leukosis viruses (ALV-A), fused to the MR1 single-chain antibody that binds specifically to EGFRvIII, a tumor-specific form of the epidermal growth factor receptor. We show that TVA-MR1 binds specifically to a murine version of EGFRvIII and promotes ALV-A entry selectively into cells that express this cell surface marker. These studies demonstrate that it is possible to target retroviral vectors to specific cell types through the use of a retroviral receptor–single-chain antibody fusion protein.
To explore the epidemiology of the size distribution of intracranial bifurcation aneurysms at dif... more To explore the epidemiology of the size distribution of intracranial bifurcation aneurysms at different locations and to specifically test the hypothesis that distal vessels develop, on average, smaller aneurysms.
Hypertensive hypervolemic therapy for vasospasm is widely practiced. It is not clear, however, wh... more Hypertensive hypervolemic therapy for vasospasm is widely practiced. It is not clear, however, whether the use of hypertension and hypervolemia as a treatment for vasospasm risks hemorrhage from an unsecured, unruptured aneurysm. From 1991 to 2000, the neurovascular unit at the Massachusetts General Hospital treated 1908 aneurysms, of which 966 were ruptured. Forty patients with ruptured aneurysms had unsecured, unruptured aneurysms and underwent hypertensive hypervolemic therapy for vasospasm. Hypertension was induced by intravenously administered phenylephrine, norepinephrine, and/or dopamine, and hypervolemia was achieved by intravenously administered crystalloid and colloid solutions. The 24-hour mean arterial systolic blood pressure (SBP) and the 24-hour mean central venous pressure were calculated on the basis of hourly measurements during hypertensive hypervolemic treatment. The 40 study patients harbored 124 aneurysms, of which 51 aneurysms were treated (clipping, 37; coiling, 14) by the time hypertensive hypervolemic therapy began, leaving 73 unsecured aneurysms at risk. The mean size of the unsecured aneurysms was 4.45 mm. Nineteen patients were treated with mild hypertension (SBP, 140-180 mmHg), 12 patients were treated with moderate hypertension (SBP, 180-200 mmHg), and 9 patients were treated with severe hypertension (SBP, >200 mmHg). The 24-hour mean SBP readings were 166.81 +/- 8.19, 187.57 +/- 5.79, and 204.01 +/- 3.75 mmHg for the mild, moderate, and severe hypertension groups, respectively. The mean central venous pressure was 10.43 +/- 3.89 mmHg. The mean course of hypertensive hypervolemic therapy was 7.25 days, and therapy began on mean post-subarachnoid hemorrhage Day 6.73. Twenty-eight aneurysms were eventually treated in later procedures (clipping, 25; coiling, 3). The mean interval to treatment was 6.93 months. In a treatment and follow-up period of 121.75 aneurysm-years of risk, there was no instance of hemorrhage. Hypertension and hypervolemia do not seem to increase the risk of hemorrhage from unsecured, unruptured aneurysms in the acute setting or in their short-term natural history.
The goal of this study was to determine the risk of adverse outcomes after contemporary surgical ... more The goal of this study was to determine the risk of adverse outcomes after contemporary surgical treatment of meningiomas in the US and trends in patient outcomes and patterns of care. The authors performed a retrospective cohort study by using the Nationwide Inpatient Sample covering the period of 1988 to 2000. Multivariate regression models with disposition end points of death and hospital discharge were used to test patient, surgeon, and hospital characteristics, including volume of care, as outcome predictors. Multivariate analyses revealed that larger-volume centers had lower mortality rates for patients who underwent craniotomy for meningioma (odds ratio [OR] 0.74, 95% confidence interval [CI] 0.59-0.93, p = 0.01). Adverse discharge disposition was also less likely at high-volume hospitals (OR 0.71, 95% CI 0.62-0.80, p < 0.001). With respect to the surgeon caseload, there was a trend toward a lower rate of mortality after surgery when higher-caseload providers were involved, and a significantly less frequent adverse discharge disposition (OR 0.71, 95% CI 0.62-0.80, p < 0.001). The annual meningioma caseload in the US increased 83% between 1988 and 2000, from 3900 patients/year to 7200 patients/year. In-hospital mortality rates decreased 61%, from 4.5% in 1988 to 1.8% in 2000. Reductions in the mortality rates were largest at high-volume centers (a 72% reduction in the relative mortality rate at largest-volume-quintile centers, compared with a 6% increase in the relative mortality rate at lowest-volume-quintile centers). The number of US hospitals where craniotomies were performed for meningiomas increased slightly. Fewer centers hosted one meningioma resection annually, whereas the largest centers had disproportionate increases in their caseloads, indicating a modest centralization of meningioma surgery in the US during this interval. The mortality and adverse hospital discharge disposition rates were lower when meningioma surgery was performed by high-volume providers. The annual US caseload increased, whereas the mortality rates decreased, especially at high-volume centers.
For many complex surgical procedures, larger hospital or surgeon caseload is associated with bett... more For many complex surgical procedures, larger hospital or surgeon caseload is associated with better patient outcome. We examined the volume-outcome relationship for surgical excision of acoustic neuromas. Retrospective cohort study. The Nationwide Inpatient Sample (1996 to 2000) was used. Multivariate regression analyses were adjusted for age, sex, race, payer, geographic region, procedure timing, admission type and source, medical comorbidities, and neurofibromatosis status. At 265 hospitals, 2643 operations were performed by 352 identified primary surgeons. Outcome was measured on a four-level scale at hospital discharge: death (0.5%) and discharge to long-term care (1.2%), to short-term rehabilitation (4.4%), and directly to home (94%). Outcomes were significantly better after surgery at higher-volume hospitals (OR 0.47 for fivefold-larger caseload, P <.001) or by higher-volume surgeons (OR 0.46, P <.001). Of patients who had surgery at lowest-volume-quartile hospitals, 12.3% were not discharged directly home, compared with 4.1% at highest-volume-quartile hospitals. There was a trend toward lower mortality for higher-volume hospitals (P =.1) and surgeons (P =.06). Of patients who had surgery at lowest-caseload-quartile hospitals, 1.1% died, compared with 0.6% at highest-volume-quartile hospitals. Postoperative complications (including neurological complications, mechanical ventilation, facial palsy, and transfusion) were less likely with high-volume hospitals and surgeons. Length of stay was significantly shorter with high-volume hospitals (P =.01) and surgeons (P =.009). Hospital charges were lower for high-volume hospitals (by 6% [P =.006]) and surgeons (by 6% [P =.09]). For acoustic neuroma excision, higher-volume hospitals and surgeons provided superior short-term outcomes with shorter lengths of stay and lower charges.
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