The Development of Skull Base Surgery as a Discipline: Remembrances of Dr Jon H. Robertson.

Skull base surgery is a young surgical subspecialty currently led by its second generation of surgeons. At present, there is no literature that narrates the connection of the present to the past. An extended interview was held with Dr Jon H. Robertson, who helped establish the subspecialty in Memphis, TN, to aid in identifying and connecting sentinel events and key figures in the development of the discipline. The field drastically evolved during his era of practice (1975-present), with the advent of advanced imaging and technology, as well as the emergence of multidisciplinary skull base surgical teams. The intersection of the careers of Jon H. Robertson, James T. Robertson, Gale Gardner, Edwin Cocke, John Shea, Jr., and Jerrall Crook in Memphis catalyzed the standardization of a multidisciplinary approach to cranial base pathology. We report the findings of Dr Jon H. Robertson's extended interview, told against the backdrop of the history of the subspecialty. The story of the development of skull base surgery is told from the unique perspective of one who lived and shaped a pivotal segment in this historical timeline.

Mechanism of anti-glioma activity and in vivo efficacy of the cannabinoid ligand KM-233.

Glioblastoma multiforme (GBM) is the most common and devastating form of primary central nervous system malignancy. The prognosis for patients diagnosed with GBM is poor, having a median survival rate of 12-15 months. Despite modern advances in the development of antineoplastic agents, the efficacy of newer anti-cancer agents in the treatment of GBM is yet to be determined. Thus, there remains a significant unmet need for new therapeutic strategies against GBM. A promising chemotherapeutic intervention has emerged from studies of cannabinoid receptor agonists wherein tetrahydrocannabinol has been the most extensively studied. The novel cannabinoid ligand KM-233 was developed as a lead platform for future optimization of biopharmaceutical properties of classical based cannabinoid ligands. Treatment of U87MG human GBM cells with KM-233 caused a time dependent change in the phosphorylation profiles of MEK, ERK1/2, Akt, BAD, STAT3, and p70S6K. Almost complete mitochondrial depolarization was observed 6 h post-treatment followed by a rapid increase in cleaved caspase 3 and significant cytoskeletal contractions. Treatment with KM-233 also resulted in a redistribution of the Golgi-endoplasmic reticulum structures. Dose escalation studies in the orthotopic model using U87MG cells revealed an 80 % reduction in tumor size after 12 mg/kg daily dosing for 20 days. The evaluation of KM-233 against primary tumor tissue in the side flank model revealed a significant decrease in the rate of tumor growth. These findings indicate that structural refinement of KM-233 to improve its biopharmaceutical properties may lead to a novel and efficacious treatment for GBM.

A far-lateral approach for removal of a C1-2 extradural neurofibroma.

A young man with type 1 neurofibromatosis presented with progressive myelopathy. Imaging revealed an anterolateral mass within the spinal canal at C1-2, with severe compression of the spinal cord. A far-lateral approach was used to remove the mass, which proved to be an extradural neurofibroma. This narrated stereoscopic video details the important steps of the operation. The video can be found here: http://youtu.be/td4MjLtiMbk .

Simplifying the Surgical Classification and Approach to the Posterolateral Skull Base and Jugular Foramen Using Anatomical Triangles.

Introduction Lesions of the jugular foramen (JF) and postero-lateral skull base are difficult to expose and exhibit complex neurovascular relationships. Given their rarity and the increasing use of radiosurgery, neurosurgeons are becoming less experienced with their surgical management. Anatomical factors are crucial in designing the approach to achieve a maximal safe resection. Methods and methods Six cadaveric heads (12 sides) were dissected via combined post-auricular infralabyrinthine and distal transcervical approach with additional anterior transstyloid and posterior far lateral exposures. Contiguous surgical triangles were measured, and contents were analyzed. Thirty-one patients (32 lesions) were treated surgically between 2000 and 2016 through different variations of the retro-auricular distal cervical transtemporal approaches. Results We anatomically reviewed the carotid, stylodigastric, jugular, condylar, suboccipital, deep condylar, mastoid, suprajugular, suprahypoglossal (infrajugular), and infrahypoglossal triangles. Tumors included glomus jugulare, lower cranial nerve schwannomas or neurofibromas, meningiomas, chondrosarcoma, adenocystic carcinoma, plasmacytoma of the occipitocervical joint, and a sarcoid lesion. We classified tumors into extracranial, intradural, intraosseous, and dumbbell-shaped, and analyzed the approach selection for each. Conclusion Jugular foramen and posterolateral skull base lesions can be safely resected through a retro-auricular distal cervical lateral skull base approach, which is customizable to anatomical location and tumor extension by tailoring the involved osteo-muscular triangles.

Chronicling the philanthropic arm of neurological surgery: a review of the growth and development of the Neurosurgery Research & Education Foundation.

OBJECTIVE: The Neurosurgery Research & Education Foundation (NREF), previously known as the Research Foundation of the American Association of Neurological Surgeons (AANS), was established in 1980 to encourage and facilitate innovation through financial support to young neurosurgeons in the process of honing their competencies in neurosciences and neurological surgery. This article provides a historical overview of NREF, its mission, and charitable contributions and the ever-expanding avenues for neurosurgeons, neurosurgical residents and fellows, and medical students to supplement clinical training and to further neurosurgical research advances. METHODS: Data were collected from the historical archives of the AANS and NREF website. Available data included tabulated revenue, geographic and institutional records of funding, changes in funding for fellowships and awards, advertising methods, and sources of funding. RESULTS: Since 1984, NREF has invested more than $23 million into the future of neurosurgery. To date, NREF has provided more than 500 fellowship opportunities which have funded neurosurgeons' education and research efforts at all stages of training and practice. CONCLUSIONS: NREF is designed to serve as the vehicle through which the neurosurgical community fosters the continued excellence in the care of patients with neurosurgical diseases.

Deconstruction of the Surgical Approach to the Jugular Foramen Region: Anatomical Study.

Introduction The jugular foramen occupies a complex and deep location between the skull base and the distal-lateral-cervical region. We propose a morphometric anatomical model to deconstruct its surgical anatomy and offer various quantifiable target-guided exposures and angles-of-attack. Methods Six cadaveric heads (12 sides) were dissected using a combined postauricular infralabyrinthine and distal transcervical approach with additional anterior transstyloid and posterior far lateral exposures. We identified anatomical landmarks and combined new and previously described contiguous triangles to expose the region; we defined the jugular and deep condylar triangles. Angles-of-attack to the jugular foramen were measured after removing the digastric muscle, styloid process, rectus capitis lateralis, and occipital condyle. Results Removing the digastric muscle and styloid process allowed 86.4° laterally and 85.5° anteriorly, respectively. Resecting the rectus capitis lateralis and jugular process provided the largest angle-of-attack (108.4° posteriorly). The occipital condyle can be drilled in the deep condylar triangle only adding 30.4° medially. A purely lateral approach provided a total of 280.3°. Cutting the jugular ring and mobilizing the vein can further expand the medial exposure. Conclusion The microsurgical anatomy of the jugular foramen can be deconstructed using a morphometric model, permitting a surgical approach customized to the pathology of interest.

Neurosurgery and industry.

The primary purpose of the relationship between neurosurgery and industry must be to improve patient care and advance medical knowledge. This relationship is desirable and can be mutually beneficial. Strict adherence to established ethical and legal guidelines is necessary to avoid financial conflicts of interest that may occur between neurosurgery and industry. The Code of Ethics established by the American Association of Neurological Surgeons (AANS) in 1986 emphasizes the physician's responsibility to always act in the best interest of his or her patients. The AANS Guidelines for Corporate Relations were developed in 2004 to address the concern of the potential growing influence of industry in the activities of our neurosurgical organization. Recognizing a need to clarify the proper relationships between neurosurgeons and industry, Guidelines on Neurosurgeon-Industry Conflicts of Interest were recently established. The AANS is committed to the highest ethical and legal standards in future relations with our industry partners. Members of the AANS are encouraged to adhere to the voluntary guidelines established by our organization.

Comparative Neurologic Outcomes of Salvage and Definitive Gamma Knife Radiosurgery for Glomus Jugulare: A 20-Year Experience.

Objective This case series investigates management of glomus jugulare (GJ) tumors utilizing definitive and salvage Gamma Knife stereotactic radiosurgery (GKSRS). Methods A retrospective chart review was performed to collect data. Statistical analysis included patient, tumor, and treatment information. Results From 1996 to 2013, 17 patients with GJ received GKSRS. Median age was 64 years (range, 27-76). GKSRS was delivered for definitive treatment in eight (47%) and salvage in nine (53%) patients. Median tumor volume was 9.8 cm 3 (range, 2.8-42 cm 3 ). Median dose was 15 Gy (range, 13-18 Gy). Median follow-up was 123 months (range, 38-238 months). Tumor size decreased in 10 (59%), stabilized in 6 (35%), and increased in 1 patient (6%). Overall neurological deficit improved in 53%, stabilized in 41%, and worsened in 6% of patients. Overall cause-specific survival was 100%, and actuarial local control was 94%. Eighty-eight percent of patients without prior resection experienced neurologic deficit improvement, while 25% of patients with prior resection experienced neurologic improvement ( p = 0.02). Conclusion Gamma Knife radiosurgery provides effective long-term control of GJ and overall improvement or stabilization of neurological deficit in most patients. Patients with prior resection are less likely to experience improvement of neurologic deficit.

cDNA cloning and characterization of a novel gene encoding the MLF1-interacting protein MLF1IP.

Myelodysplasia/acute myeloid leukemia (MDS/AML) is characterized by a t(3;5)(q25.1;q34) chromosomal translocation that forms a fusion gene between nucleophosmin (NPM) and MDS/myeloid leukemia factor 1 (MLF1). We identified a novel protein, MLF1-interacting protein (MLF1IP), that specifically associates with MLF1 by yeast two-hybrid analysis and in pulldown assays, and colocalizes with it in both the nuclei and cytoplasm of cells. The MLF1IP gene locus is at chromosome 4q35.1 and is composed of 14 exons spanning 75.8 kb of genomic DNA. The MLF1IP cDNA encodes a 46-kDa protein that contains two bipartite and two classical nuclear localization signals, two nuclear receptor-binding motifs (LXXLL), two leucine zippers, two PEST residues and several potential phosphorylation sites. MLF1IP transcripts are expressed in a variety of tissues (e.g. fetal liver, bone marrow, thymus and testis). MLF1IP appears to be a lineage-specific gene whose expression is confined exclusively to the CFU-E erythroid precursor cells, but not in mature erythrocytes. These observations, together with previous data demonstrating a role for MLF1 in suppressing red cell maturation, suggest a possible role for MLF1IP and MLF1 deregulation in the genesis of erythroleukemias.

Regulation of myeloid leukemia factor-1 interacting protein (MLF1IP) expression in glioblastoma.

The myelodysplasia/myeloid leukemia factor 1-interacting protein MLF1IP is a novel gene which encodes for a putative transcriptional repressor. It is localized to human chromosome 4q35.1 and is expressed in both the nuclei and cytoplasm of cells. Northern and Western blot analyses have revealed MLF1IP to be present at very low amounts in normal brain tissues, whereas a number of human and rat glioblastoma (GBM) cell lines demonstrated a high level expression of the MLF1IP protein. Immunohistochemical analysis of rat F98 and C6 GBM tumor models showed that MLF1IP was highly expressed in the tumor core where it was co-localized with MLF1 and nestin. Moreover, MLF1IP expression was elevated in the contralateral brain where no tumor cells were detected. These observations, together with previous data demonstrating a role for MLF1IP in erythroleukemias, suggest a possible function for this protein in glioma pathogenesis and potentially in other types of malignancies.

Recombinant vesicular stomatitis virus vectors as oncolytic agents in the treatment of high-grade gliomas in an organotypic brain tissue slice-glioma coculture model.

OBJECT: The purpose of this study was to evaluate both replication-competent and replication-restricted recombinant vesicular stomatitis virus (VSV) vectors as therapeutic agents for high-grade gliomas by using an organotypic brain tissue slice-glioma coculture system. METHODS: The coculture system involved growing different brain structures together to allow neurons from these tissues to develop synaptic connections similar to those found in vivo. Rat C6 or human U87 glioma cells were then introduced into the culture to evaluate VSV as an oncolytic therapy. The authors found that recombinant wild-type VSV (rVSV-wt) rapidly eliminated C6 glioma cells from the coculture, but also caused significant damage to neurons, as measured by a loss of microtubule-associated protein 2 immunoreactivity and a failure in electrophysiological responses from neurons in the tissue slice. Nonetheless, pretreatment with interferon beta (IFNbeta) virtually eliminated VSV infection in healthy tissues without impeding any oncolytic effects on tumor cells. Despite the protective effects of the IFNbeta pretreatment, the tissue slices still showed signs of cytopathology when exposed to rVSV-wt. In contrast, pretreatment with IFNbeta and inoculation with a replication-restricted vector with its glycoprotein gene deleted (rVSV-deltaG) effectively destroyed rat C6 and human U87 glioma cells in the coculture, without causing detectable damage to the neuronal integrity and electrophysiological properties of the healthy tissue in the culture. CONCLUSIONS: Data in this study provide in vitro proof-of-principle that rVSV-deltaG is an effective oncolytic agent that has minimal toxic side effects to neurons compared with rVSV-wt and therefore should be considered for development as an adjuvant to surgery in the treatment of glioma.

Role of basic fibroblast growth factor in the course of cerebral vasospasm in an experimental model of subarachnoid hemorrhage.

The goal of this study was to investigate the relationship between basic fibroblast growth factor (bFGF) and the course of cerebral vasospasm after subarachnoid hemorrhage (SAH), using an immunohistochemical method. Female Sprague-Dawley rats were sacrificed by perfusion fixation 10 min, 6 h, 1, 2, 3, 4, 7 or 14 days after a single intracisternal injection of fresh autologous arterial blood. Morphometric analysis of lumen cross-sectional areas of blood vessels were determined by computerized image analysis. Results were expressed as percent lumen patency, defined as the ratio of the area of vessel patency in SAH rats to the area of patency in control rats. An immunohistochemical analysis against bFGF was performed using the avidin-biotin-peroxidase technique. The immuno-reactivity of bFGF was observed with the aid of a light microscope and semiquantitatively graded. Basilar arterial spasm was greatest 10 min after SAH (mean decrease: 67.1% of the control values; p < 0.001). Subsequently, there was a significant degree of spasm of the artery for three days after SAH, followed by full recovery at day 4. A slight increase in immunoreactivity was observed in the intima only at 10 min and one day after SAH. In the media, immunoreactivity showed a biphasic pattern; a significant increase in immunoreactivity was observed at 10 min that persisted for two days after SAH. At three days after SAH, immunoreactivity in the media returned to the control level, but then gradually increased significantly to reach a maximum at 14 days after SAH while the vascular dimensions were normal. Immunohistochemical analysis failed to show a direct relationship between bFGF and the course of cerebral vasospasm in this rat single-hemorrhage model. However, the late phase upregulation of bFGF might lead to the vascular angiopathy, fibrosis or hyperplasia during the chronic stage of SAH.

Glomus jugulare tumors: historical overview of the management of this disease.

The treatment of glomus jugulare tumors presents the surgeon with a significant management problem. Because the neoplasm originates in the region of the jugular bulb, it frequently involves the lower cranial nerves, with occasional extension into the posterior fossa. Despite extensive work on the development of surgical and radiation treatment strategies, considerable controversy still exists regarding the optimal management of these lesions. A historical review of the development of management options for glomus jugulare tumors is presented in an effort to offer a foundation for understanding their contemporary treatment.

A minimal access far-lateral approach to foramen magnum lesions.

Objectives The far-lateral approach is widely used to treat pathology of the ventral foramen magnum. Numerous methods of exposure have been described, most of which utilize long skin incisions and myocutaneous flaps. Here we present our experience with gaining exposure through a small paramedian incision using a muscle-splitting technique. Design A cadaveric anatomical study was first performed to verify the feasibility of the approach. We then describe our experience with using the approach in 13 patients. A retrospective chart review was performed and data regarding pathology, imaging, and complications were collected. Results The cadaveric study confirmed that a small paramedian muscle-splitting approach allows sufficient exposure to approach many foramen magnum lesions. Our case series included 10 patients with meningioma, one brainstem glioblastoma, one posterior inferior cerebellar artery aneurysm, and one odontoid pannus. The exposure was adequate in all cases. For the meningioma patients, six had gross total resections and four had subtotal resection because of tumor adherence to neurovascular structures. Two patients experienced postoperative cardiovascular complications. There were no new neurologic deficits, cerebrospinal fluid leaks, or wound complications. Conclusions A small paramedian incision may be used to gain exposure and perform successful far-lateral approaches. The small exposure is likely to reduce the risk of local complications such as cerebrospinal fluid fistula and pseudomeningocele when compared with larger exposures.

The history of neurosurgery in Memphis: the Semmes-Murphey Clinic and the Department of Neurosurgery at the University of Tennessee College of Medicine.

Neurological surgery was defined as a separate surgical specialty by Harvey Cushing and a few other surgeons, most of whom were trained and influenced by Cushing. One of these, Raphael Eustace Semmes, became the first neurosurgeon in Memphis, Tennessee, in 1912. After World War II, Semmes and his first associate, Francis Murphey, incorporated the Semmes-Murphey Clinic, which has been primarily responsible for the growth of the Department of Neurosurgery at the University of Tennessee Health Science Center in Memphis, as well as the development of select neurosurgical subspecialties in Memphis area hospitals.

Up-regulation of neuropoiesis generating glial progenitors that infiltrate rat intracranial glioma.

To investigate adult neural stem cell (NSC) biology in relation to glioma, the C6 glioma cell line was tagged with green fluorescent protein (GFP) and inoculated into the brain of adult rats. The in vivo biological response of the brain to glioma was studied using immunohistochemical analysis of the subventricular zone (SVZ), peritumoral areas, and glioma. Nestin immunoreactive cells were found infiltrating glioma, but the distribution of abnormal immunoreactivity was restricted to the dorsal and medial border of the tumor relative to the ipsilateral ventricle. The SVZ was found to be hypertrophic, hypercellular, and up-regulated nestin expression. Furthermore, a dense contiguous population of nestin immunoreactive cells could be found streaming from ipsilateral dorsal tip of the SVZ, tracking along the ventral margin of the corpus callosum, and fanning out to encompass and infiltrate the proximal tumor border. Although most cells were either nestin or glial fibrillary acidic protein (GFAP) immunoreactive in the SVZ and along the ventral margin of the corpus callosum, the number of cells co-expressing both markers increased proportionally as the tumor was approached so that the predominant cell population along the proximal tumor border was GFAP immunoreactive. Finally, we demonstrated that a significant proportion of cells found in areas of abnormal immunoreactivity were proliferating, especially in peritumoral areas. In summary, there is an induction of neuropoietic activity in a rat intracranial glioma model that results in an infiltration and accumulation of abnormal nestin and GFAP expressing cells with proliferative potential along the dorsal and medial border of intracranial C6 glioma.

The treatment of advanced sinonasal malignancies with pre-operative intra-arterial cisplatin and concurrent radiation.

INTRODUCTION: Malignancies of the nasal and paranasal sinuses are uncommon tumors, accounting for only 3% of all aerodigestive tract neoplasms. Despite advances in surgical techniques and continued evolution of adjuvant therapies, the 5-year mortality remains unusually high at greater than 50%. In 1996, we begin utilizing a novel strategy in the treatment of advanced sinonasal carcinomas. This consisted of neoadjuvant selective intra-arterial cisplatin with concurrent radiation therapy (acronym RADPLAT) followed by a conservative craniofacial resection. We now report our results for 11 patients treated with this regimen. METHODS: Between July 1996 and April 2003, 11 patients with advanced sinonasal malignancies underwent treatment utilizing the RADPLAT protocol followed by a planned surgical resection via a craniofacial approach. Patient charts, operative notes, follow-up clinic notes, and pre- and post-operative imaging studies were reviewed in detail for each subject. RESULTS: Histopathological analysis of the tumors revealed seven squamous cell carcinomas (64%), two adenocarcinomas (18%), one adenoid cystic carcinoma (9%), and one sinonasal undifferentiated carcinoma (9%). T4N0M0 disease was present in nine patients (81%), and two patients had T3N0M0 disease (19%). Survival was calculated using the Kaplan-Meier method with an overall survival of 81% at 5 years and a progression-free survival at 5 years of 67%. Mean follow-up is 57.2 months ranging from 12 to 95 months. CONCLUSIONS: The treatment of advanced sinonasal malignancies with pre-operative intra-arterial cisplatin and concurrent radiation results in a significant improvement in survival. This can be done safely with high response rates and excellent loco-regional control in T3 and T4 disease. Although are results are encouraging, there is a need for a cooperative, multi-institutional, prospective study.