Jeffrey Greenfield - Academia.edu (original) (raw)

Papers by Jeffrey Greenfield

Nature Communications, 2015

A central mechanism of tumour progression and metastasis involves the generation of an immunosupp... more A central mechanism of tumour progression and metastasis involves the generation of an immunosuppressive 'macroenvironment' mediated in part through tumour-secreted factors.

Neurosurgery, 2008

Deep-seated supratentorial intraparenchymal and intraventricular brain lesions can be difficult t... more Deep-seated supratentorial intraparenchymal and intraventricular brain lesions can be difficult to access without causing significant trauma to the overlying cortex and intervening white matter tracts. Traditional brain retractors use multiple blades, which do not exert pressure in an equally distributed fashion. Tubular retractors offer an advantage. Although a commercially available frame-based tubular retractor system is on the market (COMPASS; Compass, Inc., Rochester, MN), we modified existing off-the-shelf equipment at our institution into a frameless tubular brain retractor. We used 14- to 22-mm METRx (Medtronic, Minneapolis, MN) tubular retractors in combination with a frameless stereotactic navigation system to remove 10 deep lesions. Histological findings included 6 periventricular metastases, 1 insular glioblastoma multiforme, 1 periventricular glioblastoma multiforme, 1 intraventricular meningioma, and 1 hippocampal cavernous malformation. Radiographic gross total resect...

Stereotactic and functional neurosurgery, 2008

Infusion of intraventricular chemotherapy requires precise ventricular catheter placement in onco... more Infusion of intraventricular chemotherapy requires precise ventricular catheter placement in oncology patients to avoid intraparenchymal infusion. We assessed the safety and precision of using frameless surgical navigation for the placement of Ommaya reservoir catheters. In 20 consecutive patients who required Ommaya reservoirs for the administration of intrathecal chemotherapy, the catheters were positioned with the guidance of frameless stereotaxy. Precision of catheter placement, operative time, operative complications, and postoperative complications were assessed. All catheters were completely within cerebrospinal fluid and 90% were within 5 mm of the intended target, the ipsilateral foramen of Monro. The average operative time was 47 min, and there were no intraoperative complications. There were no reports of leukoencephalopathy, and 3 patients had minor delayed complications. Frameless surgical navigation is a useful and efficient method for ensuring accurate catheter placem...

Neurosurgical focus, Jan 15, 2005

Endoscopic fenestration has been recognized as an accepted treatment choice for patients with sym... more Endoscopic fenestration has been recognized as an accepted treatment choice for patients with symptomatic arachnoid cysts. The success of this procedure, however, is greatly influenced by individual cyst anatomy and location as well as the endoscopic technique used. This review was conducted to assess what variables influence the treatment success for different categories of arachnoid cysts. Thirty-three consecutive patients who underwent endoscopic fenestration for treatment of an intracranial arachnoid cyst were identified from a prospective database. The surgical indications and techniques were reviewed, and surgical success rates and patient outcomes were assessed. Specific examples of each cyst category are included to illustrate the technical aspects of endoscopic cyst fenestration. Endoscopic fenestration of arachnoid cysts was successful when judged by cyst decompression, and symptom resolution was noted in 32 (97%) of 33 cases. The one patient with short-term treatment fail...

The Journal of biological chemistry, Jan 5, 2002

Estrogen reduces the risk of Alzheimer's disease in post-menopausal women, beta-amyloid (Abet... more Estrogen reduces the risk of Alzheimer's disease in post-menopausal women, beta-amyloid (Abeta) burden in animal models of Alzheimer's disease, and secretion of Abeta from neuronal cultures. The biological basis for these effects remains unknown. Here, utilizing cell-free systems derived from both neuroblastoma cells and primary neurons, we demonstrate that 17beta-estradiol (17beta-E2) stimulates formation of vesicles containing the beta-amyloid precursor protein (betaAPP) from the trans-Golgi network (TGN). Accelerated betaAPP trafficking precludes maximal Abeta generation within the TGN. 17beta-E2 appears to modulate TGN phospholipid levels, particularly those of phosphatidylinositol, and to recruit soluble trafficking factors, such as Rab11, to the TGN. Together, these results suggest that estrogen may exert its anti-Abeta effects by regulating betaAPP trafficking within the late secretory pathway. These results suggest a novel mechanism through which 17beta-E2 may act in...

Seminars in pediatric neurology, 2014

We review several newer modalities to monitor the brain in children with acute neurologic disease... more We review several newer modalities to monitor the brain in children with acute neurologic disease in the pediatric intensive care unit, such as partial brain tissue oxygen tension (PbtO2), jugular venous oxygen saturation (SjvO2), near infrared spectroscopy (NIRS), thermal diffusion measurement of cerebral blood flow, cerebral microdialysis, and EEG. We then discuss the informatics challenges to acquire, consolidate, analyze, and display the data. Acquisition includes multiple data types: discrete, waveform, and continuous. Consolidation requires device interoperability and time synchronization. Analysis could include pressure reactivity index and quantitative EEG. Displays should communicate the patient's current status, longitudinal and trend information, and critical alarms.

Journal of neurosurgery, 2015

OBJECT The gold-standard surgical approach to the odontoid is via the transoral route. This appro... more OBJECT The gold-standard surgical approach to the odontoid is via the transoral route. This approach necessitates opening of the oropharynx and is associated with risks of infection, and swallowing and breathing complications. The endoscopic endonasal approach has the potential to reduce these complications as the oral cavity is avoided. There are fewer than 25 such cases reported to date. The authors present a consecutive, single-institution series of 9 patients who underwent the endonasal endoscopic approach to the odontoid. METHODS The charts of 9 patients who underwent endonasal endoscopic surgery to the odontoid between January 2005 and August 2013 were reviewed. The clinical presentation, radiographic findings, surgical management, complications, and outcome, particularly with respect to time to extubation and feeding, were analyzed. Radiographic measurements of the distance between the back of the odontoid and the front of the cervicomedullary junction (CMJ) were calculated, ...

Journal of Neurosurgery: Pediatrics, 2008

The authors' aim in this study was to determine if standa... more The authors' aim in this study was to determine if standardizing the evaluation of intraoperative findings during endoscopic third ventriculostomy (ETV) could predict patients with hydrocephalus in whom endoscopic treatment will fail and require ventriculoperitoneal shunt treatment. The creation of a uniform scale with predictive outcomes may reduce returns to the operating room for shunt treatment and reliance on postoperative externalized ventricular monitoring and MR imaging. The authors evaluated the preoperative history, intraoperative findings, and postoperative monitoring and imaging findings in 109 consecutive patients undergoing 112 consecutive attempted ETVs for obstructive hydrocephalus. A 5-grade scale was developed to assess preoperative risk factors and intraoperative evaluation to unify criteria that have been suspected to influence outcome independently. A grade of 0 was assigned to patients with no negative predictors, whereas increasing scores were assigned to patients who had multiple preoperative and intraoperative risks identified. Patients' grades were compared with outcome of the procedure, utility of externalized ventricular monitoring, and results of postoperative MR imaging. Of 112 ETVs, 77 were successful and 35 were unsuccessful. Fifty-nine patients received a grade of 0, 27 received a grade of 1, 11 received a grade of 2, and 15 received a grade of > or = 3. In all 15 patients receiving a grade > or = 3 attempted ETV procedures failed, and the patients required a ventriculoperitoneal shunt. Postoperative monitoring with externalized ventricular drains and MR images demonstrating radiographic evidence of flow was independently less reliable than intraoperative grading in predicting success. Patients with a grade of 0 almost uniformly had successful surgery, independent of MR imaging findings. Patients with a grade of 1 or 2 who had successful surgery almost always lacked negative intraoperative predictive findings. Despite reliance in recent years on post-ETV MR images and externalized ventricular monitoring, these modalities, although often useful adjuncts, appear less reliable as predictive tests than a simple assessment at the time of endoscopic fenestration. By using a uniform grading scale, the authors have introduced a novel means through which intraoperative and postoperative decision making can be aided, with the goal of reducing unnecessary procedures and tests and preventing unnecessary returns to the operating room.

The anterior skull base, in front of the sphenoid sinus, can be approached using a variety of tec... more The anterior skull base, in front of the sphenoid sinus, can be approached using a variety of techniques including extended subfrontal, transfacial, and craniofacial approaches. These methods include risks of brain retraction, contusion, cerebrospinal fluid leak, meningitis, and cosmetic deformity. An alternate and more direct approach is the endonasal, transethmoidal, transcribriform, transfovea ethmoidalis approach. An endoscopic, endonasal approach was used to treat a variety of conditions of the anterior skull base arising in front of the sphenoid sinus and between the orbits in a series of 44 patients. A prospective database was used to detail the corridor of approach, closure technique, use of intraoperative lumbar drainage, operative time, and postoperative complications. Extent of resection was determined by a radiologist using volumetric analysis. Pathology included meningo/encephaloceles (19), benign tumors (14), malignant tumors (9), and infectious lesions (2). Lumbar drains were placed intraoperatively in 20 patients. The CSF leak rate was 6.8% for the whole series and 9% for intradural cases. Leaks were effectively managed with lumbar drainage. Early reoperation for cerebrospinal fluid (CSF) leak occurred in 1 patient (2.2%). There were no intracranial infections. Greater than 98% resection was achieved in 12 of 14 benign and 5 of 9 malignant tumors. The endoscopic, endonasal, transethmoidal, transcribriform, transfovea ethmoidalis approach is versatile and suitable for managing a variety of pathological entities. This minimal access surgery is a feasible alternative to transcranial, transfacial, or combined craniofacial approaches to the anterior skull base and anterior cranial fossa in front of the sphenoid sinus. The risk of CSF leak and infection are reasonably low and decrease with experience. Longer follow-up and larger series of patients will be required to validate the long-term efficacy of this minimally invasive approach.

ACCUMULATING EVIDENCE SUGGESTS that a better understanding of normal human brain stem cells and t... more ACCUMULATING EVIDENCE SUGGESTS that a better understanding of normal human brain stem cells and tumor stem cells (TSCs) will have profound implications for treating central nervous system disease during the next decade. Neurosurgeons routinely resect excess surgical tissue containing either normal brain stem cells or TSCs. These cells are immediately available for expansion and use in basic biological assays, animal implantation, and comparative analysis studies. Although normal stem cells have much slower kinetics of expansion than TSCs, they are easily expandable and can be frozen for future use in stem cell banks. This nearly limitless resource holds promise for understanding the basic biology of normal brain stem cells and TSCs, which will likely direct the next major shift in therapeutics for brain tumors, brain and spinal cord injury, and neurodegenerative disease. This report reviews the progress that has been made in harvesting and expanding both normal and tumor-derived stem cells and emphasizes the integral role neurosurgeons will play in moving the neural stem cell field forward.

Simultaneous occurrence of dual intracranial pathology is very rare. Most of such reported cases ... more Simultaneous occurrence of dual intracranial pathology is very rare. Most of such reported cases occur in the setting of a genetic or hereditary predisposing condition like neurofibromatosis. Though some cases of coexistence of multiple intracranial pathologies have been reported, occurrence of an arachnoid and epidermoid cyst in the same patient has never been reported. A 16-year-old boy was referred to us with a diagnosis of left temporal arachnoid cyst. Careful review of the MRI showed the presence of 2 different signal intensities with restricted diffusion in the cyst in the ambient cistern and normal diffusion in the cyst anterior to the temporal tip suggesting the presence of an arachnoid cyst adjacent to an epidermoid cyst which was managed using endoscope-assisted microsurgical transcranial surgery. The possibility of such an association could be explained based on the congenital origin of both lesions. Diffusion-weighted imaging can be invaluable in unraveling such a relationship.

Psychophysiology, 1999

Associations between trait dominance and cardiovascular reactivity were examined in previously un... more Associations between trait dominance and cardiovascular reactivity were examined in previously unacquainted healthy men and women. Subjects participated in three mixed-gender dyadic interactions with the same partner while their cardiovascular responses were assessed. Among men, but not women, trait dominance was positively and significantly associated with systolic blood pressure reactivity. For men and women, diastolic blood pressure reactivity was positively and significantly associated with trait dominance while participants prepared to interact and with partner's trait dominance while they interacted. All effects held after controlling for trait hostility. Dominance merits attention as a correlate of cardiovascular reactivity, a finding that parallels emerging patterns in the cardiovascular disease literature. Gender and gender-related social factors as potential moderators of this relationship are discussed.

Neurosurgical FOCUS, 2008

Brain tumor stem cells (TSCs) hypothetically drive the malignant phenotype of glioblastoma multif... more Brain tumor stem cells (TSCs) hypothetically drive the malignant phenotype of glioblastoma multiforme (GBM), and evidence suggests that a better understanding of these TSCs will have profound implications for treating gliomas. When grown in vitro, putative TSCs grow as a solid sphere, making their subsequent characterization, particularly the cells within the center of the sphere, difficult. Therefore, the purpose of this study was to develop a new method to better understand the proteomic profile of the entire population of cells within a sphere. Tumor specimens from patients with confirmed GBM and glioma models in mice were mechanically and enzymatically dissociated and grown in traditional stem cell medium to generate neurospheres. The neurospheres were then embedded in freezing medium, cryosectioned, and analyzed with immunofluorescence. By sectioning neurospheres as thinly as 5 mum, the authors overcame many of the problems associated with immunolabeling whole neurospheres, such as antibody penetration into the core of the sphere and intense background fluorescence that obscures the specificity of immunoreactivity. Moreover, the small quantity of material required and the speed with which this cryosectioning and immunolabeling technique can be performed make it an attractive tool for the rapid assessment of TSC character. This study is the first to show that cryosectioning of neurospheres derived from glioma models in mice and GBM in humans is a feasible method of better defining the stem cell profile of a glioma.

Neurosurgery, 2008

OBJECTIVE: Many common neurosurgical procedures, including anterior temporal lobectomy and endosc... more OBJECTIVE: Many common neurosurgical procedures, including anterior temporal lobectomy and endoscopic ventricular puncture, allow neurosurgeons to retrieve portions of the germinal subventricular zone (SVZ). Isolation and maintenance of precursor cells from this zone can be used for hypothesis-driven experiments with a goal of improving our understanding of the basic mechanisms of central nervous system injury or disease and the potential of cell-based therapies to treat them. This article details our ability to reliably harvest, isolate, characterize, and maintain normal adult human brain SVZ precursor cells. METHODS: Normal SVZ specimens were retrieved as part of anterior temporal lobe resections during planned epilepsy surgery. Dissociated SVZ specimens were plated and incubated in epidermal growth factor and basic fibroblast growth factor for more than 1 year to select for and expand normal neural precursor cells. RESULTS: Self-renewal and immunocytochemical experiments proved the feasibility of long-term expansion of a slowly dividing nestin + , vimentin + , and glial fibrillary acidic protein-positive astrocyte capable of generating new neurons and glia. These mitotically active bipotent human precursors generated a large number of progeny and possessed significant self-renewal capacity, demonstrated by their ability to generate neurospheres. Cryopreservation was reliable with no loss of the precursor phenotype. CONCLUSION: We have adapted techniques to allow for the isolation and long-term propagation of human adult neural precursors that are capable of generating both neurons and astrocytes in vitro. We have exploited the cell's self-renewal capacity to significantly and consistently expand human neural precursor cells for as long as 20 months. These findings suggest that cells derived from the SVZ during routine surgery may provide a renewable source of human neural precursor cells to study the biological mechanism of central nervous system disease or for application in cell-based human transplantation paradigms.

Neurosurgery, 2009

The neovascularization of malignant brain tumors is a poorly understood phenomenon. Radiographic ... more The neovascularization of malignant brain tumors is a poorly understood phenomenon. Radiographic and histological evidence of increased vascularity correlate with clinical grade of gliomas. However, a quantitative noninvasive assay to assess glioma vascularity and associated clinical aggressiveness has not been developed. Circulating endothelial progenitor cells are unique vascular precursors recruited from the bone marrow through the circulation to form new tumor blood vessels. These cells were measured in patients undergoing surgery for glioblastoma multiforme (GBM). We hypothesized that this might reflect the extent of tumor vascularity, predict prognosis, or be useful as an assay to assess response to antiangiogenesis therapies. In addition, we report on a novel in vitro assay to assess the proangiogenic activity within the plasma samples obtained from glioma patients. Fifty-six patients with various-grade gliomas had peripheral venous blood collected at the time of surgery and at subsequent visits during the follow-up period. The blood was separated into plasma and cellular fractions. The plasma was utilized in a human umbilical vein endothelial cell-based angiogenic assay. The cellular fraction containing endothelial progenitor cells was isolated, and specific cellular phenotypes were immunologically separated and counted using flow cytometry. Pathological samples were reviewed at the time of initial resection, and each patient's clinical course was monitored until the time of manuscript submission. Plasma derived from peripheral blood of patients with GBM scored significantly higher on the functional angiogenic scale compared with plasma derived from patients with low-grade gliomas and from controls. In addition, all patients with GBM had measurable numbers of bone marrow-derived endothelial precursor cells coexpressing CD133 and vascular endothelial growth factor receptor 2 in their peripheral circulation at the time of tumor resection. These cells range from less than 0.1% to 1.6% of the entire circulating mononuclear white blood cell population, or approximately 200,000 cells in some patients. A statistically significant relationship was observed between the percentage of endothelial progenitor cells in the peripheral blood at the time of initial GBM resection and survival. These studies suggest that plasma and circulating CD133+ vascular endothelial growth factor receptor 2+ proangiogenic cells are present in the peripheral blood of patients with glioma and can be used as a surrogate biomarker to measure tumor angiogenicity. These cells can be measured at the time of diagnosis and monitored in the postoperative period. These assays can be used to predict tumor aggressiveness. Also promising is their potential to identify patients with increased angiogenic activity who might respond maximally to antiangiogenesis therapies or to assess tumor response in patients using those therapies as the use of these adjuvant molecular modalities becomes more prevalent in neuro-oncology.

Nature Communications, 2015

A central mechanism of tumour progression and metastasis involves the generation of an immunosupp... more A central mechanism of tumour progression and metastasis involves the generation of an immunosuppressive 'macroenvironment' mediated in part through tumour-secreted factors.

Neurosurgery, 2008

Deep-seated supratentorial intraparenchymal and intraventricular brain lesions can be difficult t... more Deep-seated supratentorial intraparenchymal and intraventricular brain lesions can be difficult to access without causing significant trauma to the overlying cortex and intervening white matter tracts. Traditional brain retractors use multiple blades, which do not exert pressure in an equally distributed fashion. Tubular retractors offer an advantage. Although a commercially available frame-based tubular retractor system is on the market (COMPASS; Compass, Inc., Rochester, MN), we modified existing off-the-shelf equipment at our institution into a frameless tubular brain retractor. We used 14- to 22-mm METRx (Medtronic, Minneapolis, MN) tubular retractors in combination with a frameless stereotactic navigation system to remove 10 deep lesions. Histological findings included 6 periventricular metastases, 1 insular glioblastoma multiforme, 1 periventricular glioblastoma multiforme, 1 intraventricular meningioma, and 1 hippocampal cavernous malformation. Radiographic gross total resect...

Stereotactic and functional neurosurgery, 2008

Infusion of intraventricular chemotherapy requires precise ventricular catheter placement in onco... more Infusion of intraventricular chemotherapy requires precise ventricular catheter placement in oncology patients to avoid intraparenchymal infusion. We assessed the safety and precision of using frameless surgical navigation for the placement of Ommaya reservoir catheters. In 20 consecutive patients who required Ommaya reservoirs for the administration of intrathecal chemotherapy, the catheters were positioned with the guidance of frameless stereotaxy. Precision of catheter placement, operative time, operative complications, and postoperative complications were assessed. All catheters were completely within cerebrospinal fluid and 90% were within 5 mm of the intended target, the ipsilateral foramen of Monro. The average operative time was 47 min, and there were no intraoperative complications. There were no reports of leukoencephalopathy, and 3 patients had minor delayed complications. Frameless surgical navigation is a useful and efficient method for ensuring accurate catheter placem...

Neurosurgical focus, Jan 15, 2005

Endoscopic fenestration has been recognized as an accepted treatment choice for patients with sym... more Endoscopic fenestration has been recognized as an accepted treatment choice for patients with symptomatic arachnoid cysts. The success of this procedure, however, is greatly influenced by individual cyst anatomy and location as well as the endoscopic technique used. This review was conducted to assess what variables influence the treatment success for different categories of arachnoid cysts. Thirty-three consecutive patients who underwent endoscopic fenestration for treatment of an intracranial arachnoid cyst were identified from a prospective database. The surgical indications and techniques were reviewed, and surgical success rates and patient outcomes were assessed. Specific examples of each cyst category are included to illustrate the technical aspects of endoscopic cyst fenestration. Endoscopic fenestration of arachnoid cysts was successful when judged by cyst decompression, and symptom resolution was noted in 32 (97%) of 33 cases. The one patient with short-term treatment fail...

The Journal of biological chemistry, Jan 5, 2002

Estrogen reduces the risk of Alzheimer's disease in post-menopausal women, beta-amyloid (Abet... more Estrogen reduces the risk of Alzheimer's disease in post-menopausal women, beta-amyloid (Abeta) burden in animal models of Alzheimer's disease, and secretion of Abeta from neuronal cultures. The biological basis for these effects remains unknown. Here, utilizing cell-free systems derived from both neuroblastoma cells and primary neurons, we demonstrate that 17beta-estradiol (17beta-E2) stimulates formation of vesicles containing the beta-amyloid precursor protein (betaAPP) from the trans-Golgi network (TGN). Accelerated betaAPP trafficking precludes maximal Abeta generation within the TGN. 17beta-E2 appears to modulate TGN phospholipid levels, particularly those of phosphatidylinositol, and to recruit soluble trafficking factors, such as Rab11, to the TGN. Together, these results suggest that estrogen may exert its anti-Abeta effects by regulating betaAPP trafficking within the late secretory pathway. These results suggest a novel mechanism through which 17beta-E2 may act in...

Seminars in pediatric neurology, 2014

We review several newer modalities to monitor the brain in children with acute neurologic disease... more We review several newer modalities to monitor the brain in children with acute neurologic disease in the pediatric intensive care unit, such as partial brain tissue oxygen tension (PbtO2), jugular venous oxygen saturation (SjvO2), near infrared spectroscopy (NIRS), thermal diffusion measurement of cerebral blood flow, cerebral microdialysis, and EEG. We then discuss the informatics challenges to acquire, consolidate, analyze, and display the data. Acquisition includes multiple data types: discrete, waveform, and continuous. Consolidation requires device interoperability and time synchronization. Analysis could include pressure reactivity index and quantitative EEG. Displays should communicate the patient's current status, longitudinal and trend information, and critical alarms.

Journal of neurosurgery, 2015

OBJECT The gold-standard surgical approach to the odontoid is via the transoral route. This appro... more OBJECT The gold-standard surgical approach to the odontoid is via the transoral route. This approach necessitates opening of the oropharynx and is associated with risks of infection, and swallowing and breathing complications. The endoscopic endonasal approach has the potential to reduce these complications as the oral cavity is avoided. There are fewer than 25 such cases reported to date. The authors present a consecutive, single-institution series of 9 patients who underwent the endonasal endoscopic approach to the odontoid. METHODS The charts of 9 patients who underwent endonasal endoscopic surgery to the odontoid between January 2005 and August 2013 were reviewed. The clinical presentation, radiographic findings, surgical management, complications, and outcome, particularly with respect to time to extubation and feeding, were analyzed. Radiographic measurements of the distance between the back of the odontoid and the front of the cervicomedullary junction (CMJ) were calculated, ...

Journal of Neurosurgery: Pediatrics, 2008

The authors' aim in this study was to determine if standa... more The authors' aim in this study was to determine if standardizing the evaluation of intraoperative findings during endoscopic third ventriculostomy (ETV) could predict patients with hydrocephalus in whom endoscopic treatment will fail and require ventriculoperitoneal shunt treatment. The creation of a uniform scale with predictive outcomes may reduce returns to the operating room for shunt treatment and reliance on postoperative externalized ventricular monitoring and MR imaging. The authors evaluated the preoperative history, intraoperative findings, and postoperative monitoring and imaging findings in 109 consecutive patients undergoing 112 consecutive attempted ETVs for obstructive hydrocephalus. A 5-grade scale was developed to assess preoperative risk factors and intraoperative evaluation to unify criteria that have been suspected to influence outcome independently. A grade of 0 was assigned to patients with no negative predictors, whereas increasing scores were assigned to patients who had multiple preoperative and intraoperative risks identified. Patients' grades were compared with outcome of the procedure, utility of externalized ventricular monitoring, and results of postoperative MR imaging. Of 112 ETVs, 77 were successful and 35 were unsuccessful. Fifty-nine patients received a grade of 0, 27 received a grade of 1, 11 received a grade of 2, and 15 received a grade of > or = 3. In all 15 patients receiving a grade > or = 3 attempted ETV procedures failed, and the patients required a ventriculoperitoneal shunt. Postoperative monitoring with externalized ventricular drains and MR images demonstrating radiographic evidence of flow was independently less reliable than intraoperative grading in predicting success. Patients with a grade of 0 almost uniformly had successful surgery, independent of MR imaging findings. Patients with a grade of 1 or 2 who had successful surgery almost always lacked negative intraoperative predictive findings. Despite reliance in recent years on post-ETV MR images and externalized ventricular monitoring, these modalities, although often useful adjuncts, appear less reliable as predictive tests than a simple assessment at the time of endoscopic fenestration. By using a uniform grading scale, the authors have introduced a novel means through which intraoperative and postoperative decision making can be aided, with the goal of reducing unnecessary procedures and tests and preventing unnecessary returns to the operating room.

The anterior skull base, in front of the sphenoid sinus, can be approached using a variety of tec... more The anterior skull base, in front of the sphenoid sinus, can be approached using a variety of techniques including extended subfrontal, transfacial, and craniofacial approaches. These methods include risks of brain retraction, contusion, cerebrospinal fluid leak, meningitis, and cosmetic deformity. An alternate and more direct approach is the endonasal, transethmoidal, transcribriform, transfovea ethmoidalis approach. An endoscopic, endonasal approach was used to treat a variety of conditions of the anterior skull base arising in front of the sphenoid sinus and between the orbits in a series of 44 patients. A prospective database was used to detail the corridor of approach, closure technique, use of intraoperative lumbar drainage, operative time, and postoperative complications. Extent of resection was determined by a radiologist using volumetric analysis. Pathology included meningo/encephaloceles (19), benign tumors (14), malignant tumors (9), and infectious lesions (2). Lumbar drains were placed intraoperatively in 20 patients. The CSF leak rate was 6.8% for the whole series and 9% for intradural cases. Leaks were effectively managed with lumbar drainage. Early reoperation for cerebrospinal fluid (CSF) leak occurred in 1 patient (2.2%). There were no intracranial infections. Greater than 98% resection was achieved in 12 of 14 benign and 5 of 9 malignant tumors. The endoscopic, endonasal, transethmoidal, transcribriform, transfovea ethmoidalis approach is versatile and suitable for managing a variety of pathological entities. This minimal access surgery is a feasible alternative to transcranial, transfacial, or combined craniofacial approaches to the anterior skull base and anterior cranial fossa in front of the sphenoid sinus. The risk of CSF leak and infection are reasonably low and decrease with experience. Longer follow-up and larger series of patients will be required to validate the long-term efficacy of this minimally invasive approach.

ACCUMULATING EVIDENCE SUGGESTS that a better understanding of normal human brain stem cells and t... more ACCUMULATING EVIDENCE SUGGESTS that a better understanding of normal human brain stem cells and tumor stem cells (TSCs) will have profound implications for treating central nervous system disease during the next decade. Neurosurgeons routinely resect excess surgical tissue containing either normal brain stem cells or TSCs. These cells are immediately available for expansion and use in basic biological assays, animal implantation, and comparative analysis studies. Although normal stem cells have much slower kinetics of expansion than TSCs, they are easily expandable and can be frozen for future use in stem cell banks. This nearly limitless resource holds promise for understanding the basic biology of normal brain stem cells and TSCs, which will likely direct the next major shift in therapeutics for brain tumors, brain and spinal cord injury, and neurodegenerative disease. This report reviews the progress that has been made in harvesting and expanding both normal and tumor-derived stem cells and emphasizes the integral role neurosurgeons will play in moving the neural stem cell field forward.

Simultaneous occurrence of dual intracranial pathology is very rare. Most of such reported cases ... more Simultaneous occurrence of dual intracranial pathology is very rare. Most of such reported cases occur in the setting of a genetic or hereditary predisposing condition like neurofibromatosis. Though some cases of coexistence of multiple intracranial pathologies have been reported, occurrence of an arachnoid and epidermoid cyst in the same patient has never been reported. A 16-year-old boy was referred to us with a diagnosis of left temporal arachnoid cyst. Careful review of the MRI showed the presence of 2 different signal intensities with restricted diffusion in the cyst in the ambient cistern and normal diffusion in the cyst anterior to the temporal tip suggesting the presence of an arachnoid cyst adjacent to an epidermoid cyst which was managed using endoscope-assisted microsurgical transcranial surgery. The possibility of such an association could be explained based on the congenital origin of both lesions. Diffusion-weighted imaging can be invaluable in unraveling such a relationship.

Psychophysiology, 1999

Associations between trait dominance and cardiovascular reactivity were examined in previously un... more Associations between trait dominance and cardiovascular reactivity were examined in previously unacquainted healthy men and women. Subjects participated in three mixed-gender dyadic interactions with the same partner while their cardiovascular responses were assessed. Among men, but not women, trait dominance was positively and significantly associated with systolic blood pressure reactivity. For men and women, diastolic blood pressure reactivity was positively and significantly associated with trait dominance while participants prepared to interact and with partner's trait dominance while they interacted. All effects held after controlling for trait hostility. Dominance merits attention as a correlate of cardiovascular reactivity, a finding that parallels emerging patterns in the cardiovascular disease literature. Gender and gender-related social factors as potential moderators of this relationship are discussed.

Neurosurgical FOCUS, 2008

Brain tumor stem cells (TSCs) hypothetically drive the malignant phenotype of glioblastoma multif... more Brain tumor stem cells (TSCs) hypothetically drive the malignant phenotype of glioblastoma multiforme (GBM), and evidence suggests that a better understanding of these TSCs will have profound implications for treating gliomas. When grown in vitro, putative TSCs grow as a solid sphere, making their subsequent characterization, particularly the cells within the center of the sphere, difficult. Therefore, the purpose of this study was to develop a new method to better understand the proteomic profile of the entire population of cells within a sphere. Tumor specimens from patients with confirmed GBM and glioma models in mice were mechanically and enzymatically dissociated and grown in traditional stem cell medium to generate neurospheres. The neurospheres were then embedded in freezing medium, cryosectioned, and analyzed with immunofluorescence. By sectioning neurospheres as thinly as 5 mum, the authors overcame many of the problems associated with immunolabeling whole neurospheres, such as antibody penetration into the core of the sphere and intense background fluorescence that obscures the specificity of immunoreactivity. Moreover, the small quantity of material required and the speed with which this cryosectioning and immunolabeling technique can be performed make it an attractive tool for the rapid assessment of TSC character. This study is the first to show that cryosectioning of neurospheres derived from glioma models in mice and GBM in humans is a feasible method of better defining the stem cell profile of a glioma.

Neurosurgery, 2008

OBJECTIVE: Many common neurosurgical procedures, including anterior temporal lobectomy and endosc... more OBJECTIVE: Many common neurosurgical procedures, including anterior temporal lobectomy and endoscopic ventricular puncture, allow neurosurgeons to retrieve portions of the germinal subventricular zone (SVZ). Isolation and maintenance of precursor cells from this zone can be used for hypothesis-driven experiments with a goal of improving our understanding of the basic mechanisms of central nervous system injury or disease and the potential of cell-based therapies to treat them. This article details our ability to reliably harvest, isolate, characterize, and maintain normal adult human brain SVZ precursor cells. METHODS: Normal SVZ specimens were retrieved as part of anterior temporal lobe resections during planned epilepsy surgery. Dissociated SVZ specimens were plated and incubated in epidermal growth factor and basic fibroblast growth factor for more than 1 year to select for and expand normal neural precursor cells. RESULTS: Self-renewal and immunocytochemical experiments proved the feasibility of long-term expansion of a slowly dividing nestin + , vimentin + , and glial fibrillary acidic protein-positive astrocyte capable of generating new neurons and glia. These mitotically active bipotent human precursors generated a large number of progeny and possessed significant self-renewal capacity, demonstrated by their ability to generate neurospheres. Cryopreservation was reliable with no loss of the precursor phenotype. CONCLUSION: We have adapted techniques to allow for the isolation and long-term propagation of human adult neural precursors that are capable of generating both neurons and astrocytes in vitro. We have exploited the cell's self-renewal capacity to significantly and consistently expand human neural precursor cells for as long as 20 months. These findings suggest that cells derived from the SVZ during routine surgery may provide a renewable source of human neural precursor cells to study the biological mechanism of central nervous system disease or for application in cell-based human transplantation paradigms.

Neurosurgery, 2009

The neovascularization of malignant brain tumors is a poorly understood phenomenon. Radiographic ... more The neovascularization of malignant brain tumors is a poorly understood phenomenon. Radiographic and histological evidence of increased vascularity correlate with clinical grade of gliomas. However, a quantitative noninvasive assay to assess glioma vascularity and associated clinical aggressiveness has not been developed. Circulating endothelial progenitor cells are unique vascular precursors recruited from the bone marrow through the circulation to form new tumor blood vessels. These cells were measured in patients undergoing surgery for glioblastoma multiforme (GBM). We hypothesized that this might reflect the extent of tumor vascularity, predict prognosis, or be useful as an assay to assess response to antiangiogenesis therapies. In addition, we report on a novel in vitro assay to assess the proangiogenic activity within the plasma samples obtained from glioma patients. Fifty-six patients with various-grade gliomas had peripheral venous blood collected at the time of surgery and at subsequent visits during the follow-up period. The blood was separated into plasma and cellular fractions. The plasma was utilized in a human umbilical vein endothelial cell-based angiogenic assay. The cellular fraction containing endothelial progenitor cells was isolated, and specific cellular phenotypes were immunologically separated and counted using flow cytometry. Pathological samples were reviewed at the time of initial resection, and each patient's clinical course was monitored until the time of manuscript submission. Plasma derived from peripheral blood of patients with GBM scored significantly higher on the functional angiogenic scale compared with plasma derived from patients with low-grade gliomas and from controls. In addition, all patients with GBM had measurable numbers of bone marrow-derived endothelial precursor cells coexpressing CD133 and vascular endothelial growth factor receptor 2 in their peripheral circulation at the time of tumor resection. These cells range from less than 0.1% to 1.6% of the entire circulating mononuclear white blood cell population, or approximately 200,000 cells in some patients. A statistically significant relationship was observed between the percentage of endothelial progenitor cells in the peripheral blood at the time of initial GBM resection and survival. These studies suggest that plasma and circulating CD133+ vascular endothelial growth factor receptor 2+ proangiogenic cells are present in the peripheral blood of patients with glioma and can be used as a surrogate biomarker to measure tumor angiogenicity. These cells can be measured at the time of diagnosis and monitored in the postoperative period. These assays can be used to predict tumor aggressiveness. Also promising is their potential to identify patients with increased angiogenic activity who might respond maximally to antiangiogenesis therapies or to assess tumor response in patients using those therapies as the use of these adjuvant molecular modalities becomes more prevalent in neuro-oncology.