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Russell R. Lonser, Katherine E. Warren, John A. Butman, Zenaide Quezado, R. Aaron Robison, Stuart Walbridge, Raphael Schiffman, Marsha Merrill, Marion L. Walker, Deric M. Park, David Croteau, Roscoe O. Brady and Edward H. Oldfield

✓Recent preclinical studies have demonstrated that convection-enhanced delivery (CED) can be used to perfuse the brain and brainstem with therapeutic agents while simultaneously tracking their distribution using coinfusion of a surrogate magnetic resonance (MR) imaging tracer. The authors describe a technique for the successful clinical application of this drug delivery and monitoring paradigm to the brainstem. Two patients with progressive intrinsic brainstem lesions (one with Type 2 Gaucher disease and one with a diffuse pontine glioma) were treated with CED of putative therapeutic agents mixed with Gd–diethylenetriamene pentaacetic acid (DTPA). Both patients underwent frameless stereotactic placement of MR imaging–compatible outer guide–inner infusion cannulae. Using intraoperative MR imaging, accurate cannula placement was confirmed and real-time imaging during infusion clearly demonstrated progressive filling of the targeted region with the drug and Gd-DTPA infusate. Neither patient had clinical or imaging evidence of short- or long-term infusate-related toxicity. Using this technique, CED can be used to safely perfuse targeted regions of diseased brainstem with therapeutic agents. Coinfused imaging surrogate tracers can be used to monitor and control the distribution of therapeutic agents in vivo. Patients with a variety of intrinsic brainstem and other central nervous system disorders may benefit from a similar treatment paradigm.

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Martin A. Baggenstos, John A. Butman, Edward H. Oldfield and Russell R. Lonser

✓Peritumoral cysts (those arising immediately adjacent to the tumor mass) are frequently associated with benign and malignant tumors of the brain and spinal cord (syringomyelia). The cystic component of central nervous system (CNS) tumors and associated peritumoral cysts are often the cause of clinical symptoms. Because of the common occurrence of peritumoral cysts with CNS neoplasms and the morbidity associated with them, advanced imaging, histological, and molecular techniques have been used to determine the mechanism underlying cyst formation and propagation. Based on evidence from such studies, edema appears to be a common precursor to peritumoral cyst formation in the CNS. Mediators of vascular permeability acting locally in the tumor and/or hydrodynamic forces within abnormal tumor vascula-ture appear to drive fluid extravasation. When these forces overcome the ability of surrounding tissue to resorb fluid, edema and subsequent cyst formation occur. These findings support the concept that the tumor itself is the source of the edema that precedes cyst formation and that resection of tumors or medical therapies directed at decreasing their vascular permeability will result in the resolution of edema and cysts.

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Gregory J. A. Murad, Stuart Walbridge, Paul F. Morrison, Nicholas Szerlip, John A. Butman, Edward H. Oldfield and Russell R. Lonser

Object

To determine if the potent antiglioma chemotherapeutic agent gemcitabine could be delivered to the brainstem safely at therapeutic doses while monitoring its distribution using a surrogate magnetic resonance (MR) imaging tracer, the authors used convection-enhanced delivery to perfuse the primate brainstem with gemcitabine and Gd–diethylenetriamine pentaacetic acid (DTPA).

Methods

Six primates underwent convective brainstem perfusion with gemcitabine (0.4 mg/ml; two animals), Gd-DTPA (5 mM; two animals), or a coinfusion of gemcitabine (0.4 mg/ml) and Gd-DTPA (5 mM; two animals), and were killed 28 days afterward. These primates were observed over time clinically (six animals), and with MR imaging (five animals), quantitative autoradiography (one animal), and histological analysis (all animals). In an additional primate, 3H-gemcitabine and Gd-DTPA were coinfused and the animal was killed immediately afterward.

In the primates there was no histological evidence of infusate-related tissue toxicity. Magnetic resonance images obtained during infusate delivery demonstrated that the anatomical region infused with Gd-DTPA was clearly distinguishable from surrounding noninfused tissue. Quantitative autoradiography confirmed that Gd-DTPA tracked the distribution of 3H-gemcitabine and closely approximated its volume of distribution (mean volume of distribution difference 13.5%).

Conclusions

Gemcitabine can be delivered safely and effectively to the primate brainstem at therapeutic concentrations and at volumes that are higher than those considered clinically relevant. Moreover, MR imaging can be used to track the distribution of gemcitabine by adding Gd-DTPA to the infusate. This delivery paradigm should allow for direct therapeutic application of gemcitabine to brainstem gliomas while monitoring its distribution to ensure effective tumor coverage and to maximize safety.

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Joshua M. Ammerman, Russell R. Lonser, James Dambrosia, John A. Butman and Edward H. Oldfield

Object

In the course of their lives most patients with von Hippel–Lindau (VHL) disease require treatment for several symptom-producing hemangioblastomas of the cerebellum, brainstem, or spinal cord. However, many tumors never produce symptoms and do not require treatment. Detection at an early stage of lesions that will later produce symptoms and ultimately require treatment would allow for earlier excision of hemangioblastomas of the spinal cord, brainstem, or cerebellum, and may identify cerebellar hemangioblastomas that can be treated with radiosurgery at a stage before treatment is contraindicated because of tumor size or the presence of an associated cyst.

Methods

To identify features predictive of symptom development that might allow for earlier treatment of smaller, presymptomatic hemangioblastomas in patients with VHL disease, the authors reviewed and analyzed the serial clinical and imaging findings in all patients with VHL disease who were followed up at the National Institutes of Health for more than 10 years. Features predictive of symptom formation were determined by recursive partition and regression analyses.

Nineteen patients (10 men and nine women; mean age 32.6 ± 11.6 years) harboring a total of 143 hemangioblastomas were identified (mean follow-up duration 12.4 ± 1.4 years). Hemangioblastomas were located in the cerebellum (68 hemangioblastomas, 48% of patients), brainstem (17 hemangioblastomas, 12% of patients), and spinal cord (58 hemangioblastomas, 40% of patients). Despite measurable growth in almost all hemangioblastomas (138 lesions, 97% of patients), only 58 (41% of patients) became symptomatic. Hemangioblastomas grew in a stuttering pattern. (mean growth period 13 ± 15 months, mean quiescent period 25 ± 19 months). Twenty-six (45%) of the hemangioblastomas that eventually produced symptoms were not among the tumors that were apparent on the initial MR imaging study. Depending on location, the hemangioblastoma size and/or tumor and cyst growth rates predicted symptom development and the need for treatment (p < 0.05). Cerebellar hemangioblastomas growing faster than 112 mm3/ month or larger than 69 mm3 with associated tumor and cyst growth rates greater than 14 mm3/month became symptomatic (100% sensitivity, 72% specificity). Brainstem hemangioblastomas larger than 245 mm3 with growth rates greater than 0.1 mm3/month became symptomatic (75% sensitivity, 89% specificity). Spinal hemangioblastomas larger than 22 mm3 became symptomatic (79% sensitivity, 94% specificity).

Conclusions

Because hemangioblastomas exhibit a stuttering growth pattern, frequently remain asymptomatic, and do not require treatment for long intervals, unqualified radiographic progression is not an indication for treatment. Basing the decision to intervene in individual tumors solely on radiographic progression would have resulted in approximately four additional procedures per patient during the 10-year study period. Threshold values are presented for tumor size and/or tumor and cyst growth rates that can be used to predict symptom formation and future need for treatment.

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S. Taylor Jarrell, Alexander O. Vortmeyer, W. Marston Linehan, Edward H. Oldfield and Russell R. Lonser

Object

Patients with hereditary cancer syndromes may be at increased risk for the development of tumor-to-tumor metastases. To gain insight into the biological nature of these lesions in the central nervous system (CNS), to determine their prevalence in a familial neoplasia syndrome, and to better define their management, the authors retrospectively examined a series of cases in which metastatic lesions developed within hemangioblastomas in patients with von Hippel–Lindau (VHL) disease.

Methods

The study included all cases of VHL disease in which patients underwent resection of a CNS hemangioblastoma that contained a metastasis or were found at autopsy to have a metastasis to a hemangioblastoma between January 2002 and December 2005 at the National Institute of Neurological Disorders and Stroke (NINDS). Clinical, histopathological, imaging, and surgical and/or autopsy findings were analyzed.

Metastasis to a CNS hemangioblastoma was found in six resected tumors (8% of all hemangioblastomas resected from patients with VHL disease at the NINDS during the study period) from six patients (five women, one man; mean age at surgery 42.5 years). The primary site of metastatic disease was the kidney in five patients (renal cell carcinoma) and the pancreas in one (a pancreatic neuroendocrine tumor). Only one patient had systemic metastases at the time of resection of the hemangioblastoma containing the metastasis. Neurologically, all patients had remained at baseline or were improved at last clinical follow-up examination (mean follow-up duration 16.5 months, range 3–40 months). In all cases, postoperative imaging revealed that the hemangioblastoma resection was complete, and there was no evidence of recurrence in any of the patients at the last follow up. Two patients (including one who was also in the surgical group) were found at autopsy to have CNS metastases exclusively to spinal hemangioblastomas.

Conclusions

Hemangioblastomas are an early and preferred site for metastasis in VHL disease. Emerging histopathological techniques may lead to recognition of an increasing number of cases of tumor-to-hemangioblastoma metastasis. Management of cases involving tumor-to-hemangioblastoma metastases in VHL disease should be based on the histological characteristics of the primary tumor, extent of the primary disease, and completeness of the resection.

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Russell R. Lonser, John A. Butman and Edward H. Oldfield

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Alfredo Pompili, Andrea Pace and Emanuele Occhipinti

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Edward H. Oldfield and Alexander O. Vortmeyer

Object

The presence of a histological pseudocapsule around pituitary tumors was noted in the early 1900s. Since that time there has been no emphasis on the sequence of the stages of its development or on the relationship between these stages and the capacity to identify very small pituitary tumors at surgery in patients in whom preoperative imaging has been nondiagnostic. In addition, limited emphasis has been given to the pseudocapsule’s use for selective and complete resection of pituitary adenomas.

Methods

The development of the pseudocapsule was examined by performing histological analysis of portions of pituitary glands removed during 805 operations for Cushing disease.

Twenty-five adenomas, each measuring between 0.25 and 4 mm in maximum diameter, were detected in the excised specimens; 17 were adenocorticotropic hormone–positive adenomas and eight were incidental tumors (four prolactin-secreting and four nonsecreting lesions). In 16 tumors the size of the adenoma could be established. The distribution of tumor size in relation to the presence of a histological pseudocapsule indicates a transition from the absence of a reticulin capsule (tumor diameter ≤ 1 mm) through the initial compression of surrounding tissue (tumor diameter 1–2 mm) to the presence of a multilayered reticulin capsule observed when adenomas become larger (tumor diameter 2–3 mm).

Conclusions

The absence of a reticulin capsule in cases of very small tumors may contribute to limited localization of these lesions during surgical exploration of the pituitary gland. In this article the authors describe surgical techniques in which the histological pseudocapsule is used as a surgical capsule during pituitary surgery. In their experience, recognition of this surgical capsule and its use at surgery has contributed to the identification of microadenomas buried in the pituitary gland, aided the recognition of subtle invasion of the pituitary capsule and contiguous dura mater, and enhanced the consistency of complete tumor excision with small and large tumors.

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Edward R. Laws Jr.

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John D. Heiss, Stuart Walbridge, Paul Morrison, Robert R. Hampton, Susumu Sato, Alexander Vortmeyer, John A. Butman, James O'Malley, Param Vidwan, Robert L. Dedrick and Edward H. Oldfield

Object. The activity of γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter, is reduced in the hippocampus in patients with complex partial seizures from mesial temporal sclerosis. To provide preliminary safety and distribution data on using convection-enhanced delivery of agents to treat complex partial seizures and to test the efficacy and safety of regional selective neuronal suppression, the authors infused muscimol, a GABA-A receptor agonist, directly into the hippocampus of nonhuman primates using an integrated catheter electrode.

Methods. Ten rhesus monkeys were divided into three groups: 1) use of catheter electrode alone (four monkeys); 2) infusion of escalating concentrations of muscimol followed by vehicle (three monkeys); and 3) infusion of vehicle and subsequent muscimol mixed with muscimol tracer (three monkeys). Infusions were begun 5 days after catheter electrode placement and continued for 5.6 days before switching to the other agent. Head magnetic resonance (MR) images and electroencephalography recordings were obtained before and during the infusions. Brain histological studies and quantitative autoradiography were performed.

Neurological function was normal in controls and when muscimol concentrations were 0.125 mM or less, whereas higher concentrations (0.5 and 1 mM) produced reversible apathy and somnolence. Fluid distribution was demonstrated on MR images and muscimol distribution was demonstrated on autoradiographs throughout the hippocampus and adjacent white matter.

Conclusions. Targeted modulation of neuronal activity is a reasonable research strategy for the investigation and treatment of medically intractable epilepsy.