Gregory J. A. Murad

Real-time, Image-Guided, Convection-Enhanced Delivery of Interleukin 13 Bound to Pseudomonas Exotoxin

Purpose: To determine if the tumor-targeted cytotoxin interleukin 13 bound to Pseudomonas exotoxin (IL13-PE) could be delivered to the brainstem safely at therapeutic doses while monitoring its distribution in real-time using a surrogate magnetic resonance imaging tracer, we used convection-enhanced delivery to perfuse rat and primate brainstems with IL13-PE and gadolinium-bound albumin (Gd-albumin). Experimental Design: Thirty rats underwent convective brainstem perfusion of IL13-PE (0.25, 0.5, or 10 μg/mL) or vehicle. Twelve primates underwent convective brainstem perfusion of either IL13-PE (0.25, 0.5, or 10 μg/mL; n = 8), co-infusion of 125I-IL13-PE and Gd-albumin (n = 2), or co-infusion of IL13-PE (0.5 μg/mL) and Gd-albumin (n = 2). The animals were permitted to survive for up to 28 days before sacrifice and histologic assessment. Results: Rats showed no evidence of toxicity at all doses. Primates showed no toxicity at 0.25 or 0.5 μg/mL but showed clinical and histologic toxicity at 10 μg/mL. Quantitative autoradiography confirmed that Gd-albumin precisely tracked IL13-PE anatomic distribution and accurately showed the volume of distribution. Conclusions: IL13-PE can be delivered safely and effectively to the primate brainstem at therapeutic concentrations and over clinically relevant volumes using convection-enhanced delivery. Moreover, the distribution of IL13-PE can be accurately tracked by co-infusion of Gd-albumin using real-time magnetic resonance imaging.

Mixed Reality Ventriculostomy Simulation: Experience in Neurosurgical Residency

BACKGROUND: Medicine and surgery are turning toward simulation to improve on limited patient interaction during residency training. Many simulators today use virtual reality with augmented haptic feedback with little to no physical elements. In a collaborative effort, the University of Florida Department of Neurosurgery and the Center for Safety, Simulation & Advanced Learning Technologies created a novel “mixed” physical and virtual simulator to mimic the ventriculostomy procedure. The simulator contains all the physical components encountered for the procedure with superimposed 3-D virtual elements for the neuroanatomical structures. OBJECTIVE: To introduce the ventriculostomy simulator and its validation as a necessary training tool in neurosurgical residency. METHODS: We tested the simulator in more than 260 residents. An algorithm combining time and accuracy was used to grade performance. Voluntary postperformance surveys were used to evaluate the experience. RESULTS: Results demonstrate that more experienced residents have statistically significant better scores and completed the procedure in less time than inexperienced residents. Survey results revealed that most residents agreed that practice on the simulator would help with future ventriculostomies. CONCLUSION: This mixed reality simulator provides a real-life experience, and will be an instrumental tool in training the next generation of neurosurgeons. We have now implemented a standard where incoming residents must prove efficiency and skill on the simulator before their first interaction with a patient. ABBREVIATIONS: AANS, American Association of Neurological Surgeons EVD, external ventricular drain PGY, postgraduate year SNS, Society Neurological Surgeons

Early history of the stereotactic apparatus in neurosurgery

Stereotactic neurosurgery has a rich history, beginning with the first stereotactic frame described by Horsley and Clarke in 1908. It is now widely used for delivery of radiation, surgical targeting of electrodes, and resection to treat tumors, epilepsy, vascular malformations, and pain syndromes. These treatments are now available due to the pioneering efforts of neurosurgeons and scientists in the beginning of the 20th century. Their efforts focused on the development of stereotactic instruments for accurate lesion targeting. In this paper, the authors review the history of the stereotactic apparatus in the early 20th century, with a focus on the fascinating people key to its development.

Mixed-reality simulation for neurosurgical procedures.

BACKGROUND: Surgical education is moving rapidly to the use of simulation for technical training of residents and maintenance or upgrading of surgical skills in clinical practice. To optimize the learning exercise, it is essential that both visual and haptic cues are presented to best present a real-world experience. Many systems attempt to achieve this goal through a total virtual interface. OBJECTIVE: To demonstrate that the most critical aspect in optimizing a simulation experience is to provide the visual and haptic cues, allowing the training to fully mimic the real-world environment. METHODS: Our approach has been to create a mixed-reality system consisting of a physical and a virtual component. A physical model of the head or spine is created with a 3-dimensional printer using deidentified patient data. The model is linked to a virtual radiographic system or an image guidance platform. A variety of surgical challenges can be presented in which the trainee must use the same anatomic and radiographic references required during actual surgical procedures. RESULTS: Using the aforementioned techniques, we have created simulators for ventriculostomy, percutaneous stereotactic lesion procedure for trigeminal neuralgia, and spinal instrumentation. The design and implementation of these platforms are presented. CONCLUSION: The system has provided the residents an opportunity to understand and appreciate the complex 3-dimensional anatomy of the 3 neurosurgical procedures simulated. The systems have also provided an opportunity to break procedures down into critical segments, allowing the user to concentrate on specific areas of deficiency.BACKGROUND Surgical education is moving rapidly to the use of simulation for technical training of residents and maintenance or upgrading of surgical skills in clinical practice. To optimize the learning exercise, it is essential that both visual and haptic cues are presented to best present a real-world experience. Many systems attempt to achieve this goal through a total virtual interface. OBJECTIVE To demonstrate that the most critical aspect in optimizing a simulation experience is to provide the visual and haptic cues, allowing the training to fully mimic the real-world environment. METHODS Our approach has been to create a mixed-reality system consisting of a physical and a virtual component. A physical model of the head or spine is created with a 3-dimensional printer using deidentified patient data. The model is linked to a virtual radiographic system or an image guidance platform. A variety of surgical challenges can be presented in which the trainee must use the same anatomic and radiographic references required during actual surgical procedures. RESULTS Using the aforementioned techniques, we have created simulators for ventriculostomy, percutaneous stereotactic lesion procedure for trigeminal neuralgia, and spinal instrumentation. The design and implementation of these platforms are presented. CONCLUSION The system has provided the residents an opportunity to understand and appreciate the complex 3-dimensional anatomy of the 3 neurosurgical procedures simulated. The systems have also provided an opportunity to break procedures down into critical segments, allowing the user to concentrate on specific areas of deficiency.

The future of glioma treatment: stem cells, nanotechnology and personalized medicine

The development of novel therapies, imaging techniques and insights into the processes that drive growth of CNS tumors have allowed growing enthusiasm for the treatment of CNS malignancies. Despite this energized effort to investigate and treat brain cancer, clinical outcomes for most patients continue to be dismal. Recognition of diverse tumor subtypes, behaviors and outcomes has led to an interest in personalized medicine for the treatment of brain tumors. This new paradigm requires evaluation of the tumor phenotype at the time of diagnosis so that therapy can be specifically tailored to each individual patient. Investigating novel therapies involving stem cells, nanotechnology and molecular medicine will allow diversity of therapeutic options for patients with brain cancer. These exciting new therapeutic strategies for brain tumors are reviewed in this article.

Disrupting abnormal electrical activity with deep brain stimulation: is epilepsy the next frontier?

Given the tremendous success of deep brain stimulation (DBS) for the treatment of movement and neuropsychiatric disorders, clinicians have begun to open up to the possible use of electrical stimulation for the treatment of patients with uncontrolled seizures. This process has resulted in the discovery of a wide array of DBS targets, including the cerebellum, hypothalamus, hippocampus, basal ganglia, and various thalamic nuclei. Despite the ambiguity of the mechanism of action and the unknowns surrounding potentially ideal stimulation settings, several recent trials have empirically demonstrated reasonable efficacy in selected cases of medication-refractory seizures. These exciting results have fueled a number of studies aimed at firmly establishing DBS as an effective treatment for selected cases of intractable epilepsy, and many companies are aiming at Food and Drug Administration approval. We endeavor to review the studies in the context of the various DBS targets and their relevant circuitry for epilepsy. Based on the unfolding research, DBS has the potential to play an important role in treating refractory epilepsy. The challenge, as in movement disorders, is to assemble interdisciplinary teams to screen, implant, and follow patients, and to clarify patient selection. The future will undoubtedly be filled with optimization of targets and stimulation parameters and the development of best practices. With tailored therapeutic approaches, epilepsy patients have the potential to improve with DBS.

Stereotactic radiosurgery and the linear accelerator: accelerating electrons in neurosurgery

The search for efficacious, minimally invasive neurosurgical treatment has led to the development of the operating microscope, endovascular treatment, and endoscopic surgery. One of the most minimally invasive and exciting discoveries is the use of targeted, high-dose radiation for neurosurgical disorders. Radiosurgery is truly minimally invasive, delivering therapeutic energy to an accurately defined target without an incision, and has been used to treat a wide variety of pathological conditions, including benign and malignant brain tumors, vascular lesions such as arteriovenous malformations, and pain syndromes such as trigeminal neuralgia. Over the last 50 years, a tremendous amount of knowledge has been garnered, both about target volume and radiation delivery. This review covers the intense study of these concepts and the development of linear accelerators to deliver stereotactic radiosurgery. The fascinating history of stereotactic neurosurgery is reviewed, and a detailed account is given of the development of linear accelerators and their subsequent modification for radiosurgery.

Evaluation of a Transition to Practice Program for Neurosurgery Residents: Creating a Safe Transition From Resident to Independent Practitioner

BACKGROUND In 2004, the Department of Neurosurgery at the University of Florida implemented a major curriculum innovation called the Transition to Practice program. This program was established to prepare residents to more safely transition to the role of independent practitioner. METHODS A qualitative and quantitative evaluation of the program was conducted after its fifth year using online surveys and interviews. Study participants included Transition to Practice graduates, faculty, and current residents. RESULTS Of the 26 respondents, 89% of faculty and all graduates were very satisfied with the program. Strengths identified included an independent yet mentored broad operative experience, the development of self-confidence, and a real sense of responsibility for patients. Medical billing and coding instruction and career mentoring were areas of the program that required additional attention. CONCLUSION Overall, this program is meeting the stated objectives and is well received by the graduates and faculty. Based on the results of this evaluation, curricular changes such as instructions in practice management and implementation of a career-mentoring program have occurred. The Transition to Practice program is a unique curricular response to change that other surgical specialties may find useful in addressing the current-day stresses on graduate medical education.

Helmet use and cervical spine injury: a review of motorcycle, moped, and bicycle accidents at a level 1 trauma center.

Helmet use in two-wheeled vehicle accidents is widely reported to decrease the rates of death and traumatic brain injury. Previous reports suggest that there exists a trade off with helmet use consisting of an increased risk of cervical spine injuries. Recently, a review of a national trauma database demonstrated the opposite, with reduction in cervical spinal cord injuries in motorcycle crashes (MCC). In 2000, the State of Florida repealed its mandatory helmet law to make helmet use optional for individuals older than 21 with

ACR appropriateness criteria® pre-irradiation evaluation and management of brain metastases

10,000 of health insurance coverage. To better ascertain the risks of cervical spine injury with non-helmet use in all two-wheeled vehicles, we analyzed the University of Florida level one trauma center experience. We reviewed the Traumatic injury database over a five-year period (January 1, 2005, to July 1, 2010) for all patients involved in two-wheeled vehicle accidents. Patients were stratified according to vehicle type (motorcycle, scooter, and bicycle), helmet use, and the presence or absence of a cervical spine injury. Outcomes were compared for injury severity, cervical spine injury, cervical spinal cord injury, and presence of cervical spine injuries requiring surgery. Population means were compared using paired t-test. A total of 1331 patients were identified: 995 involved in motorcycle accidents, 87 involved in low-powered scooter accidents, and 249 involved in bicycle accidents. Helmet use was variable between each group. One hundred thirty-five total cervical spine injuries were identified. No evidence was found to suggest an increased risk of cervical spine injury or increased severity of cervical spine injury with helmet use. This fact, in combination with our previous findings, suggest that the laws age and insurance exemption should be revoked and a universal helmet law be reinstated in the state of Florida.