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Shelly D. Timmons and Steven A. Toms

Comparative effectiveness research (CER) is emerging as a commonly applied technique to determine the usefulness of medical interventions. Such research aims to compare various treatments for specific disease entities for overall effectiveness and potential for harm. According to the Centers for Disease Control, an estimated 1.7 million patients sustain a traumatic brain injury (TBI) annually in the US. In this review the authors examine the existence of CER reports in the area of neurotrauma to date and consider the context in which clinical research and evidence-based guidelines have and will continue to inform such analyses, with special attention to TBI.

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Jorge A. González-Martínez, William E. Bingaman, Steven A. Toms and Imad M. Najm

Object

The normal adult human telencephalon does not reveal evidence of spontaneous neuronal migration and differentiation despite the robust germinal capacity of the subventricular zone (SVZ) astrocyte ribbon that contains neural stem cells. This might be because it is averse to accepting new neurons into an established neuronal network, probably representing an evolutionary acquisition to prevent the formation of anomalous neuronal circuits. Some forms of epilepsy, such as malformations of cortical development, are thought to be due to abnormal corticogenesis during the embryonic and early postnatal periods. The role of postnatal architectural reorganization and possibly postnatal neurogenesis in some forms of epilepsy in humans remains unknown. In this study the authors used resected specimens of epileptic brain to determine whether neurogenesis could occur in the diseased tissue.

Methods

The authors studied freshly resected brain tissue obtained in 47 patients who underwent neurosurgical procedures and four autopsies. Forty-four samples were harvested in patients who underwent resection for the treatment of pharmacoresistant epilepsy.

Results

Using organotypic brain slice preparations cultured with 5-bromodeoxyuridine (a marker for cell proliferation), immunohistochemistry, and cell trackers, the authors demonstrate the presence of spontaneous cell proliferation, migration, and neuronal differentiation in the adult human telencephalon that starts in the SVZ and progresses to the adjacent white matter and neocortex in human neocortical pathological structures associated with epilepsy. No cell migration or neuronal differentiation was found in the control group.

Conclusions

The presence of spontaneous neurogenesis associated with some forms of human neocortical epilepsy may represent an erroneous and maladaptive mechanism for neuronal circuitry repair, or it may be an intrinsic part of the pathogenic process.

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Mahlon D. Johnson, Evelyn Okediji, Ann Woodard, Steven A. Toms and George S. Allen

Object. The intracellular events transducing mitogenic signals from platelet-derived growth factor—β (PDGFβ) receptor tyrosine kinases are not precisely known. In this study the authors evaluated whether the phosphatidylinositol 3-kinase (PI3-K)—Akt—p70S6K pathway is expressed in meningiomas, regulates their growth, and transduces mitogenic signals of PDGF-BB.

Methods. Nine meningioma tumors obtained in humans were evaluated using Western blot analysis for phosphorylated (activated) Akt and phosphorylated p70S6K. Cells cultured from seven of these meningiomas were also screened using Western blot analysis for Akt and for phosphorylated Akt and p70S6K. The authors also evaluated whether PDGF-BB stimulation of meningioma cells was associated with the phosphorylation of Akt and p70S6K known to activate these kinases. In addition, the effects of wortmannin, an inhibitor of PI3-K, on proliferation and activation of Akt and p70S6K in meningioma cells stimulated with PDGF-BB were evaluated.

Western blots of lysates from meningiomas demonstrated phosphorylated Akt and p70S6K. Treatment with PDGF-BB stimulated phosphorylation of Akt and p70S6K in each meningioma cell culture. Wortmannin (500 and 1000 nM) significantly decreased PDGF-BB stimulation of meningioma cells (p < 0.001) while it reduced Akt and p70S6K phosphorylation but not mitogen-activated protein kinase/extracellular signal—regulated kinase (MAPK/ERK) phosphorylation.

Conclusions. These findings indicate that Akt and p70S6K are constitutively expressed and activated in meningioma cells and that the PI3-K—Akt—p70S6K pathway may participate in transduction of mitogenic signals in meningiomas independent of the Raf-1—MEK-1—MAPK/ERK cascade.

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Jonathan R. Slotkin, Alfred S. Casale, Glenn D. Steele Jr. and Steven A. Toms

Comparative effectiveness research (CER) represents an evolution in clinical decision-making research that allows for the study of heterogeneous groups of patients with complex diseases processes. It has foundations in decision science, reliability science, and health care policy research. Health care finance will increasingly rely on CER for guidance in the coming years. There is increasing awareness of the importance of decreasing unwarranted variation in health care delivery. In the past 7 years, Geisinger Health System has performed broad reengineering of its acute episodic and chronic care delivery models utilizing macrosystem-level application of CER principles. These provider-driven process initiatives have resulted in significant improvement across all segments of care delivery, improved patient outcomes, and notable cost containment. These programs have led to the creation of novel pricing models, and when “hardwired” throughout a care delivery system, they can lead to correct medical decision making by 100% of providers in all patient encounters. Neurosurgery as a specialty faces unique challenges and opportunities with respect to broad adoption and application of CER techniques.

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Robert J. Weil, Steven A. Toms, Mahlon D. Johnson and Amanda Mealer

Object. Current methods used to describe the proliferative status of brain tumors rely on labor-intensive, potentially costly procedures. This article provides a description of a rapid, inexpensive, uncomplicated technique used to identify proliferating cells in tissue obtained at the time of resection.

Methods. Touch preparations of 16 fresh astrocytic tumors and four fresh healthy temporal neocortical tissue samples were obtained at the time of surgery. Slides were placed in hypotonic potassium chloride to permeabilize their membranes, incubated in nucleotide precursors, and labeled with bromodeoxyuridine; they were later examined with the aid of a fluorescence microscope. The percentage of tumor cells in the S phase increased in conjunction with the grade of tumor and corresponded with the findings of immunohistochemical staining for the cell-cycle marker MIB-1. These results were confirmed in cell culture by using normal human astrocytes and two glioma cell lines. Slides can be analyzed in as little as 30 minutes after removal of tissue during surgery.

Conclusions. In this study the authors describe a simple method by which cells in the S phase of the cell cycle, which are contained in fresh tumor obtained at the time of surgery, can be labeled. This method may prove a useful adjunct to frozen-section analysis and may permit discrimination of neoplastic tissues from other tissues observed in small specimen samples.

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Steven E. Kornguth, Patrick A. Turski, William H. Perman, Ronald Schultz, Tom Kalinke, Richard Reale and Francois Raybaud

✓ Two different murine monoclonal anti-human T cell antibodies, that were coupled to gadolinium (Gd), bind specifically to human T lymphocyte cells implanted in canine brain. This binding was at a concentration of Gd sufficient to detect the implanted cells and to distinguish them from the surrounding brain tissue with magnetic resonance imaging (MRI) at a field strength of 1.5 Tesla. These Gd-labeled immunoglobulin preparations did not bind bovine T cells at a concentration sufficient to be detected on MRI. A protein solution containing the immunoglobulins (100 µg), gelatin (2 mg), and bovine serum albumin (2.5 mg) was reacted with the dianhydride of diethylenetriaminepenta-acetic acid (DTPA); the DTPA serves as a metal chelator and as a protein crosslinking agent. The DTPA-protein complex was reacted with Gd chloride. There were approximately 10 DTPA residues per protein molecule in the modified protein mixture. Isolated human or bovine monocytes (approximately 12 million cells) were implanted in the brains of anesthetized dogs in a volume of 40 µl. The blood-brain barrier was then disrupted by the intra-arterial injection of hyperosmotic mannitol, and the Gd-labeled antibodies were injected through a catheter placed at the branch of the internal and external carotid arteries. The brains were imaged 48 to 72 hours later. The MRI scans revealed a markedly decreased T1 relaxation time with a high signal intensity (TE = 25 msec, TR = 200 msec) related to the human T cell implants. There was no evidence of decreased T1 at the site of the bovine T cells. Neither control murine gamma globulin coupled to Gd-DTPA nor anti-human T cell antibodies uncoupled to Gd modified the MRI contrast of the human T cells in the brain.

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Robert J. Weil, Gaurav G. Mavinkurve, Samuel T. Chao, Michael A. Vogelbaum, John H. Suh, Matthew Kolar and Steven A. Toms

OBJECT

The authors assessed the feasibility of intraoperative radiotherapy (IORT) using a portable radiation source to treat newly diagnosed, surgically resected, solitary brain metastasis (BrM).

METHODS

In a nonrandomized prospective study, 23 patients with histologically confirmed BrM were treated with an Intrabeam device that delivered 14 Gy to a 2-mm depth to the resection cavity during surgery.

RESULTS

In a 5-year minimum follow-up period, progression-free survival from the time of surgery with simultaneous IORT averaged (± SD) 22 ± 33 months (range 1–96 months), with survival from the time of BrM treatment with surgery+IORT of 30 ± 32 months (range 1–96 months) and overall survival from the time of first cancer diagnosis of 71 ± 64 months (range 4–197 months). For the Graded Prognostic Assessment (GPA), patients with a score of 1.5–2.0 (n = 12) had an average posttreatment survival of 21 ± 26 months (range 1–96 months), those with a score of 2.5–3.0 (n = 7) had an average posttreatment survival of 52 ± 40 months (range 5–94 months), and those with a score of 3.5–4.0 (n = 4) had an average posttreatment survival of 17 ± 12 months (range 4–28 months). A BrM at the treatment site recurred in 7 patients 9 ± 6 months posttreatment, and 5 patients had new but distant BrM 17 ± 3 months after surgery+IORT. Six patients later received whole-brain radiation therapy, 7 patients received radiosurgery, and 2 patients received both treatments. The median Karnofsky Performance Scale scores before and 1 and 3 months after surgery were 80, 90, and 90, respectively; at the time of this writing, 3 patients remain alive with a CNS progression-free survival of > 90 months without additional BrM treatment.

CONCLUSIONS

The results of this study demonstrate the feasibility of resection combined with IORT at a dose of 14 Gy to a 2-mm peripheral margin to treat a solitary BrM. Local control, distant control, and long-term survival were comparable to those of other commonly used modalities. Surgery combined with IORT seems to be a potential adjunct to patient treatment for CNS involvement by systemic cancer.

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Steven A. Toms, Aleck Hercbergs, Jinbo Liu, Seiji Kondo, Talat Haqqi, Graham Casey, Koichi Iwasaki, Gene H. Barnett and Barbara P. Barna

Object. Tamoxifen (TAM) has been found to be effective in inhibiting proliferation of glioblastoma cells in vitro, but clinical studies have been disappointing. The purpose of this study was to determine whether insulin-like growth factor I (IGF-I), a potential autocrine/paracrine mitogen produced by glioblastomas, interferes with the antimitogenic actions of TAM.

Methods. Human glioblastoma cells were treated with or without TAM and/or IGF-I in vitro and evaluated for: viability by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenol tetrazolium bromide cleavage assay; apoptosis by histochemical analysis of nuclear morphology and 3′-OH DNA fragments; and expression of the IGF-I receptor, and the bcl-2, bcl-xL, and bax proteins by immunoblot analysis. In addition, p53 status was determined by DNA sequencing and by transient transfection with luciferase reporter plasmids containing wild-type or mutant p53. Results indicated that after 72 hours of exposure to 2 mg/ml TAM in vitro, 56.3% of WITG3 and 43.8% of U87-MG glioblastoma cells contained apoptotic nuclei (p < 0.01 compared with untreated cells). Apoptosis was independent of the presence of p53 because the WITG3 cells, in contrast to the U87-MG cells, expressed a mutant, nonfunctional p53. The WITG3 cells expressed IGF-I receptor proteins and demonstrated IGF-I binding. Exogenous IGF-I stimulated WITG3 cell proliferation and significantly (p < 0.05) antagonized the cytotoxic effects of TAM in a dose-dependent fashion; IGF-I, but not TAM, enhanced expression of bcl-2 and bcl-xL proteins; however, bax protein expression was unchanged by either treatment.

Conclusions. Because many gliomas secrete large amounts of IGF-I in autocrine/paracrine growth pathways, these data may, in part, explain the failure of TAM to achieve clinical results as dramatic as those in vitro.