Dynamic Susceptibility Contrast-Enhanced MR Perfusion Imaging in Assessing Recurrent Glioblastoma Response to Superselective Intra-Arterial Bevacizumab Therapy.

BACKGROUND AND PURPOSE: Recurrent glioblastoma currently has no established standard of care. We evaluated the response of recurrent glioblastoma to superselective intra-arterial cerebral infusion of bevacizumab by using dynamic susceptibility contrast-enhanced MR perfusion imaging. We hypothesized that treatment response would be associated with decreased relative CBV and relative CBF. MATERIALS AND METHODS: Patients were accrued for this study from larger ongoing serial Phase I/II trials. Twenty-five patients (14 men, 11 women; median age, 55 years) were analyzed. Four distinct ROIs were chosen: 1) normal-appearing white matter on the contralateral side, 2) the location of the highest T1 enhancement in the lesion (maximum enhancing), 3) the location of highest relative CBV in the lesion (maximum relative CBV), and 4) nonenhancing T2 hyperintense signal abnormality surrounding the tumor (nonenhancing T2 hyperintensity). RESULTS: There was a statistically significant median percentage change of -32.34% (P = .001) in relative CBV in areas of maximum relative CBV following intra-arterial bevacizumab therapy. There was also a statistically significant median percentage decrease in relative CBF of -30.67 (P = .001) and -27.25 (P = .037) in areas of maximum relative CBV and maximum tumor enhancement, respectively. Last, a trend toward statistical significance for increasing relative CBV in nonenhancing T2 hyperintense areas (median percent change, 30.04; P = .069) was noted. CONCLUSIONS: Dynamic susceptibility contrast-enhanced MR perfusion imaging demonstrated a significant decrease in tumor perfusion metrics within recurrent glioblastomas in response to superselective intra-arterial cerebral infusion of bevacizumab; however, these changes did not correlate with time to progression or overall survival.

Short-term clinico-radiographic response to super-selective intra-arterial cerebral infusion of Bevacizumab for the treatment of vestibular schwannomas in Neurofibromatosis type 2.

Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome with a prevalence of approximately 1 in 30,000. NF 2 is characterized by bilateral vestibular schwannomas, as well as meningiomas, ependymomas and gliomas. Currently, surgical resection and radiotherapy represent the mainstay of treatment, although new studies suggest a role for certain chemotherapeutic agents. Intravenous administration of Bevacizumab (Avastin, Genetech Pharmaceuticals) has been shown to be active in the treatment of vestibular schwannomas. The IV route of administration, however, carries a risk of known systemic side-effects such as bowel perforation, wound dehiscence and pulmonary embolism. In addition, the percentage of drug that reaches the tumor site may be restricted by the blood tumor barrier. This report describes the super-selective intra-arterial infusion of Bevacizumab following blood brain barrier disruption for the treatment of vestibular schwannomas in three patients with Neurofibromatosis type 2. It represents the first time such a technique has been performed for this disease. Additionally, this method of drug delivery may have important implications in the treatment of patients with vestibular schwannomas associated with Neurofibromatosis type 2.

Metabolic response of glioblastoma to superselective intra-arterial cerebral infusion of bevacizumab: a proton MR spectroscopic imaging study.

BACKGROUND AND PURPOSE: SIACI of bevacizumab has emerged as a promising novel therapy in the treatment of recurrent GB. This study assessed the potential of (1)H-MRS as an adjunctive technique in detecting metabolic changes reflective of antiproliferative effects of targeted infusion of bevacizumab in the treatment of GB. MATERIALS AND METHODS: Eighteen patients enrolled in a phase I/II study of SIACI of bevacizumab for treatment of recurrent GB were included. Concurrent MR imaging and (1)H-MRS scans were performed before and after treatment. Five distinct morphologic ROIs were evaluated for structural and metabolic changes on MR imaging and (1)H-MRS, which included enhancing, nonenhancing T2 hyperintense signal abnormality, and multiple control regions. Pre- and post-SIACI of bevacizumab peak areas for NAA, tCho, tCr, as well as tCho/tCr and tCho/NAA ratios, were derived for all 5 ROIs and compared using the Wilcoxon signed-rank test. RESULTS: A significant median decrease of 25.99% (range -55.76 to 123.94; P = .006) in tCho/NAA was found post-SIACI of bevacizumab relative to pretreatment values in regions of enhancing disease. A trend-level significant median decrease of 6.45% (range -23.71 to 37.67; P = .06) was noted in tCho/NAA posttreatment in regions of nonenhancing T2-hyperintense signal abnormality. CONCLUSIONS: The results of this (1)H-MRS analysis suggest that GB treatment with SIACI of bevacizumab may be associated with a direct antiproliferative effect, as demonstrated by significant reductions of tCho/NAA after the intervention.

Super-selective basilar artery infusion of bevacizumab and cetuximab for multiply recurrent pediatric ependymoma.

Ependymoma is a central nervous system tumor associated with a poor prognosis due to limited efficacy of current medical treatment modalities, often resulting in multiple surgical re-resections with each tumor recurrence. As traditional chemotherapeutic regimens have proved unsuccessful in long-term control of subtotally resected ependymoma, other agents targeting the tumor microenvironement including the angiogenic factors supplying neovascularization have recently been used. Anti-angiogenic agents such as bevacizumab are routinely used in adult patients with recurrent glioma. Selective intra-arterial cerebral infusion (SIACI) of biological agents within tumor-supplying cerebral vasculature has recently been re-examined as a means to avoid the systemic side-effects associated with intravenous use of bevacizumab. This technical paper describes the first reported use of SIACI for delivery of two targeted biologic agents, bevacizumab and cetuximab in a pediatric patient utilizing the basilar artery to selectively administer the drugs to the tumor microenvironment. We believe this method for therapeutic delivery will both broaden treatment options and better refine treatment methodology as the multi-modality treatment approach often required to treat patients with pediatric ependymomas and other intracranial malignancies evolves.

Intra-arterial chemotherapy for malignant gliomas: a critical analysis.

Intra-arterial (IA) chemotherapy for malignant gliomas including glioblastoma multiforme was initiated decades ago, with many preclinical and clinical studies having been performed since then. Although novel endovascular devices and techniques such as microcatheter or balloon assistance have been introduced into clinical practice, the question remains whether IA therapy is safe and superior to other drug delivery modalities such as intravenous (IV) or oral treatment regimens. This review focuses on IA delivery and surveys the available literature to assess the advantages and disadvantages of IA chemotherapy for treatment of malignant gliomas. In addition, we introduce our hypothesis of using IA delivery to selectively target cancer stem cells residing in the perivascular stem cell niche.

Balloon-assisted superselective intra-arterial cerebral infusion of bevacizumab for malignant brainstem glioma. A technical note.

Malignant brainstem gliomas (BSG) are rare tumors in adults, associated with a grim prognosis and limited treatment options. Currently, radiotherapy represents the mainstay of treatment, although new studies suggest an increased role for certain chemotherapeutic agents. Intravenous (IV) administration of bevacizumab (Avastin, Genentech Pharmaceuticals) has been shown to be active in the treatment of some enhancing malignant brainstem gliomas. The IV route of administration, however, carries a risk of systemic side effects such as bowel perforation, wound disrepair and pulmonary embolism. In addition, the percentage of IV drug that reaches the tumor site is restricted by the blood brain barrier (BBB).Weill Cornell Brain Tumor Center, Department of Neurosurgery, Weill Cornell Medical College of Cornell University: New York, NY, USA. This technical report describes our protocol in performing superselective intra-arterial cerebral infusion (SIACI) of bevacizumab using endovascular balloon-assistance in the top of the basilar artery in a patient with a recurrent malignant brainstem glioma. It represents the first time such a technique has been performed for this disease. This method of drug delivery may have important implications in the treatment of both adult and pediatric brainstem gliomas.

Combined supraciliary and endoscopic endonasal approach for resection of frontal sinus mucoceles: technical note.

OBJECTIVE: Mucoceles are progressive, slow-growing lesions of the paranasal sinuses that, left untreated, can erode into surrounding structures. Complete obliteration and exenteration of the frontal sinus via a bicoronal skin incision and frontal craniotomy is the standard neurosurgical approach to treat these lesions. TECHNIQUE: We describe two patients who underwent a combined supraciliary "keyhole" craniotomy and endonasal endoscopic resection of mucoceles with frontal sinus obliteration. The technique takes advantage of a smaller incision, while preserving adequate visualization and the ability for surgical instrumentation. Through the craniotomy, the frontal sinus mucosa is fully exenterated, the posterior table of the sinus is removed to establish communication with the intracranial space, and the nasal frontal ducts are packed with autologous tissue. The endoscopic endonasal route allows a minimally invasive access to the frontal nasal duct to ensure its blockage from the intracranial compartment. Additionally, the endoscope can be used from above through the supraciliary approach to allow for contralateral frontal sinus exposure and mucosal exenteration. CONCLUSION: The combined supraciliary-endoscopic endonasal approach provides a minimally invasive access for the treatment of sinonasal disease with frontal sinus mucoceles that invade the intracranial cavity.

Endoscopic endonasal transsphenoidal surgery using a skull reference array and laser surface scanning.

Lesions of the skull base are increasingly being resected via the endoscopic, endonasal, transphenoidal approach. We have successfully treated 33 consecutive patients with pituitary lesions using this technique in combination with BrainLAB skull reference array and laser surface scanning for surgical navigation. This technique affords several advantages over neuronavigation based on adhesive-mounted fiducial registration. Rigid fixation in a Mayfield clamp is not required, which allows for flexibility with respect to positioning of the head during the procedure. This is particularly important as extension and flexion of the head provide greater exposure to the clivus and anterior skull base respectively. Also, this technique obviates the need for additional preoperative MRI, thereby reducing cost and delays.

Cervical spinal stenosis and sports-related cervical cord neurapraxia in children.

STUDY DESIGN: Congenital spinal stenosis has been demonstrated to contribute to cervical cord neurapraxia after cervical spinal cord injury in adult athletes. A sagittal canal diameter <14 mm and/or a Torg ratio (sagittal diameter of the spinal canal: midcervical sagittal vertebral body diameter) of <0.8 are indicative of significant cervical spinal stenosis. Although sports-related cervical spine injuries are common in children, the role of congenital cervical stenosis in the etiology of these injuries remains unclear. OBJECTIVES: The authors measured the sagittal canal diameter and the Torg ratio in children presenting with cervical cord neurapraxia resulting from sports-related cervical spinal cord injuries to determine the presence of congenital spinal stenosis. METHODS: A total of 13 children (9 male, 4 female) presented with cervical cord neurapraxia after a sports-related cervical spinal cord injury. Age ranged from 7 to 15 years (mean +/- SD, 11.5 +/- 2.7 years). The sports involved were football (n = 4), wrestling (n = 2), hockey (n = 2), and soccer, gymnastics, baseball, kickball, and pogosticking (n = 1 each). Lateral cervical spine radiographs were used to determine the sagittal canal diameter and the Torg ratio at C4. RESULTS: The sagittal canal diameter (mean +/- SD, 17.58 +/- 1.63 mm) and the Torg ratio (mean +/- SD, 1.20 +/- 0.24) were normal in all of these children. CONCLUSION: Using the sagittal canal diameter and the Torg ratio as a measurement of congenital spinal stenosis, the authors did not find evidence of congenital cervical spinal stenosis in a group of children with sports-related cervical spinal cord neurapraxia. The occurrence of cervical cord neurapraxia in pediatric patients can be attributed to the mobility of the pediatric spine rather than to congenital cervical spinal stenosis.

Development of the Spitz-Holter valve in Philadelphia.

The history of the treatment for hydrocephalus dates back to the Fertile Crescent thousands of years ago. Despite three millennia of management, significant advances in the surgical treatment of the disease have been infrequent. During the 1950s, a milestone occurred at the Children's Hospital of Philadelphia, with the successful development of the first working shunt valve for the treatment of hydrocephalus. In this historical vignette, based on recent interviews with John Holter, D.Sc. (Hon) and Eugene Spitz. M.D., and on a review of the available literature, the authors narrate the exciting story of the development of the Spitz-Holter valve, which took place in Philadelphia during the early 1950s.

Results and risk factors for anterior cervicothoracic junction surgery.

OBJECT: Stabilization of the cervicothoracic junction (CTJ) requires special attention to the operative approach and biomechanical requirements of the fixation construct. In this study the authors assess the morbidity associated with the anterior approach to the CTJ and define risks that may lead to construct failure after anterior CTJ surgery. METHODS: Data obtained for 14 patients (six men and eight women, mean age 50.1 years) who underwent surgical stabilization of the CTJ via an anterior cervical approach were retrospectively reviewed to assess the anterior approach-related morbidity and the risks of construct failure. The mean follow-up period was 21.1 months. Four patients (29%) had previously undergone CTJ surgery; in 11 patients (64%) more than one motion segment was involved (two levels, six patients; three levels, four patients; four levels, one patient); allograft was placed in three (21%) of 14 graft sites; and anterior plates were used for reconstruction augmentation in eight patients (57%). Postoperatively all patients improved, although four patients had residual deficits or pain. Graft/plate failure, requiring surgical revision and/or halo placement, occurred in five patients (36%). One patient experienced transient recurrent laryngeal nerve palsy. Postoperatively, the authors classified patients into one of two groups: those in whom surgery was successful (nine cases) and those in whom it had failed (five cases). Analysis of the characteristics of these two groups revealed that male sex (p < 0.0365), multiple levels of involvement (p < 0.0378), and the use of allograft as compared with autograft (p < 0.0088) were significant risk factors for construct failure. Prior CTJ surgery (p < 0.053) tended to be associated with graft failure. CONCLUSIONS: Findings of this study, in the setting of these factors, indicate that anterior reconstruction alone may not meet the biomechanical needs of this spinal region and that supplementary fixation may be considered to augment stabilization for fusion success.

Efficacy of unilateral deep brain stimulation of the thalamic ventralis intermedius nucleus in a patient with bipolar disorder associated with Klinefelter syndrome and essential tremor. Case report.

Deep brain stimulation (DBS) of the ventralis intermedius nucleus (Vim) is a safe and effective treatment for essential tremor. Bipolar disorder and essential tremor had each been reported to occur in association with Klinefelter syndrome but the three diseases have been reported to occur together in only one patient. The genetic basis and natural history of these disorders are not completely understood and may be related rather than coincidental. The authors report on a 23-year-old man with Klinefelter syndrome (47,XXY) and bipolar disorder who was treated successfully with unilateral DBS of the thalamic Vim for essential tremor.

Long-term deep brain stimulation in a patient with essential tremor: clinical response and postmortem correlation with stimulator termination sites in ventral thalamus. Case report.

Essential tremor can be suppressed with chronic, bilateral deep brain stimulation (DBS) of the ventralis intermedius nucleus (Vim), the cerebellar receiving area of the motor thalamus. The goal in this study was to correlate the location of the electrodes with the clinical efficacy of DBS in a patient with essential tremor. The authors report on a woman with essential tremor in whom chronic bilateral DBS directed to the ventral thalamus produced adequate tremor suppression until her death from unrelated causes 16 months after placement of the electrodes. Neuropathological postmortem studies of the brain in this patient demonstrated that both stimulators terminated in the Vim region of the thalamus, and that chronic DBS elicited minor reactive changes confined to the immediate vicinity of the electrode tracks. Although the authors could not identify neuropathological abnormalities specific to essential tremor, they believe that suppression of essential tremor by chronic DBS correlates with bilateral termination of the stimulators in the Vim region of the thalamus.

Neurosurgery at the University of Pennsylvania Medical Center.

The University of Pennsylvania Medical School was the nation's first medical school, and its Department of Neurosurgery is one of the nation's oldest. The history of the Department of Neurosurgery at Penn is recounted, beginning with the pioneer surgeon Charles Harrison Frazier. The evolution of the current department, its contemporary status, and its residency program are described.

Symptomatic lateral ventricular ependymal cysts: criteria for distinguishing these rare cysts from other symptomatic cysts of the ventricles: case report.

OBJECTIVE AND IMPORTANCE: Symptomatic lateral ventricular ependymal cysts are rare. Two previous cases of this lesion have been reported in the literature. We report a third case and provide radiological and histopathological criteria for differentiating this entity from common intracranial cysts. CLINICAL PRESENTATION: A 43-year-old man presented with a 6-year history of seizures and progressive right occipitoparietal headaches. Computed tomography and magnetic resonance imaging demonstrated a 4- x 3- x 3-cm nonenhancing cystic mass, expanding the trigone of the right lateral ventricle. INTERVENTION: The patient underwent a right occipital craniotomy. The cyst was opened, fluid was aspirated, the cyst wall was biopsied, and a cyst-subarachnoid communication was established. The patient did well postoperatively, with no seizures and with resolution of headaches. CONCLUSION: Lateral ventricular ependymal cysts are a rare cause of neurological symptoms, including headache and seizure. Distinctive radiographic characteristics distinguish these cysts at preoperative evaluation. Careful analysis of the histopathology and immunohistochemistry studies correctly identifies these lesions, gives insight into the natural history of ependymal cysts, and guides clinical management decisions.

Subacute paraparesis induced by venous thrombosis of a spinal angiolipoma: a case report.

STUDY DESIGN: A case report of spinal extradural angiolipoma, a rare tumor that can cause spinal cord compression, is presented with a complete review of the literature related to this disorder. OBJECTIVES: To discuss venous thrombosis involving the angiolipoma in the development of subacute paraparesis. SUMMARY OF BACKGROUND DATA: This case shows that venous thrombosis of a spinal angiolipoma can precipitate the subacute onset of paraparesis. METHODS: Medical history, physical findings, and the results of imaging and histopathologic studies were analyzed to elucidate the pathogenesis of the patient's subacute onset of paraparesis. A bilateral T3-T7 laminectomy was performed, and although the tumor was extremely hemorrhagic, it was mobilized easily off the compressed dura to achieve resection. RESULTS: The postoperative course was uneventful. One month after her surgery, the patient's myelopathic symptoms had resolved, and the she was able to return to work. CONCLUSION: Because the prognosis after surgical management of these lesions is favorable, the diagnosis of thrombosis involving a spinal angiolipoma should be considered in the differential diagnosis of subacute spinal cord compression.