The CyberKnife Stereotactic Radiosurgery System: Description, Installation, and an Initial Evaluation of Use and Functionality

Neurosurgery. Nov, 2003  |  Pubmed ID: 14580294

Identification of Differentially Expressed and Developmentally Regulated Genes in Medulloblastoma Using Suppression Subtraction Hybridization

Oncogene. Apr, 2004  |  Pubmed ID: 15064731

To increase our understanding of the molecular pathogenesis of medulloblastoma (MB), we utilized the technique of suppression subtractive hybridization (SSH) to identify genes that are dysregulated in MB when compared to cerebellum. SSH-enriched cDNA libraries from both human and Ptch+/- heterozygous murine MBs were generated by subtracting common cDNAs from corresponding non-neoplastic cerebellum. For the human classic MB library, total human cerebellar RNA was used as control tissue; for the Ptch+/- heterozygous MB, non-neoplastic cerebellum from an unaffected Ptch+/- littermate was used as the control. Through differential screening of these libraries, over 100 upregulated tumor cDNA fragments were isolated, sequenced and identified with the NCBI BLAST program. From these, we selected genes involved in cellular proliferation, antiapoptosis, and cerebellar differentiation for further analysis. Upregulated genes identified in the human MB library included Unc33-like protein (ULIP), SOX4, Neuronatin (NNAT), the mammalian homologue of Drosophila BarH-like 1(BARHL1), the nuclear matix protein NRP/B (ENC1), and the homeobox OTX2 gene. Genes found to be upregulated in the murine MB library included cyclin D2 (Ccnd2), thymopoietin (Tmpo), Musashi-1 (Msh1), protein phosphatase 2A inhibitor-2 (I-2pp2a), and Unc5h4(D). Using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), the mRNA expression levels for these genes were markedly higher in human MBs than in cerebellum. Western blot analysis was used to further confirm the overexpression of a subset of these genes at the protein level. Notch pathway overactivity was demonstrated in the TE671 MB cell line expressing high levels of MSH1 through HES1-Luciferase transfections. This study has revealed a panel of developmentally regulated genes that may be involved in the pathogenesis of MB.

Gamma Knife Radiosurgery for Benign Cavernous Sinus Tumors: Quantitative Analysis of Treatment Outcomes

Neurosurgery. Jun, 2004  |  Pubmed ID: 15157295

We review our 8-year experience with gamma knife radiosurgery (GKRS) for the treatment of patients with benign cavernous sinus tumors and present a quantitative analysis of factors relevant to treatment outcomes.

The Leksell Gamma Knife Model U Versus Model C: a Quantitative Comparison of Radiosurgical Treatment Parameters

Neurosurgery. Jul, 2004  |  Pubmed ID: 15214986

We present a quantitative comparison of radiosurgery treatments for cavernous sinus tumors using the Leksell gamma knife Model U versus the Model C with automatic positioning system (APS) (Elekta Instruments, Norcross, GA).

Pediatric Surgical Neuro-oncology: Current Best Care Practices and Strategies

Journal of Neuro-oncology. Aug-Sep, 2004  |  Pubmed ID: 15527086

Significant advances have been made in the diagnosis and treatment of childhood brain tumors. Gross total surgical resection combined with appropriate adjuvant therapies can achieve a high rate of disease control for low grade gliomas, ependymomas and medulloblastomas. High grade gliomas, tumors involving the optic apparatus or diencepahalic structures, diffuse brainstem lesions, and recurrent or metastatic disease still pose considerable therapeutic challenges. We review the current treatment strategies of the three most common types of pediatric brain tumors: gliomas, medulloblastomas and ependymomas, and discuss current and future diagnostic and therapeutic modalities.

Distribution of Brain Metastases in Relation to the Hippocampus: Implications for Neurocognitive Functional Preservation

International Journal of Radiation Oncology, Biology, Physics. Jul, 2007  |  Pubmed ID: 17446005

With the advent of intensity-modulated radiotherapy, the ability to limit the radiation dose to normal tissue offers an avenue to limit side effects. This study attempted to delineate the distribution of brain metastases with relation to the hippocampus for the purpose of exploring the viability of tomotherapy-guided hippocampal sparing therapy potentially to reduce neurocognitive deficits from radiation.

Unexpected Myxopapillary Ependymoma Within a Filum Terminale Tethering the Spinal Cord

Pediatric Neurosurgery. 2007  |  Pubmed ID: 17627148

We present a 9-month-old neurologically normal infant with cutaneous markers for a closed neural tube defect consisting of two sacral dimples and associated tuft of hair. Magnetic resonance imaging showed that her spinal cord was tethered at S2 and associated with a large syrinx. A myelotomy was performed to address the hydrosyringomyelia and the filum terminale resected to untether the spinal cord. Histopathologic examination of the filum terminale specimen revealed the presence of an unexpected myxopapillary ependymoma. The association of a myxopapillary ependymoma with a closed neural tube defect appears to be coincidental. This patient may have presented at some future date with a clinically symptomatic myxopapillary ependymoma. The presence of microscopic myxopapillary ependymoma cells in this infant's filum supports the concept that these tumors arise from embryonic rests of ependymal cells.

Developmental Signaling Pathways in Brain Tumor-derived Stem-like Cells

Developmental Dynamics : an Official Publication of the American Association of Anatomists. Dec, 2007  |  Pubmed ID: 18000980

Recently, a subpopulation of cells highly efficient in tumor initiation and growth has been isolated from brain tumors. Of interest, these brain tumor initiating cells exhibit many stem-like properties, including self-renewal, extended proliferation, and multipotency, and are both phenotypically and genetically similar to normal neural stem cells (NSCs). Aberrant expression of developmental pathways, such as WNT, Hedgehog, Notch, and transforming growth factor-beta/bone morphogenetic protein, have been demonstrated in brain tumors, and extrinsic regulation of these pathways may be used to target brain tumor stem-like cells (BTSCs) and form the basis of novel biological therapies. Because of regulatory redundancy during normal development, future therapeutic strategies to inhibit BTSC-mediated tumor growth and minimize NSC-related deleterious effects may require detailed understanding and regulation of multiple cellular mechanisms. This review analyzes the role developmental pathways play in brain tumors, focusing on the potential effects of pathway regulation on BTSC-driven tumorigenesis.

Incidental Findings on Brain MRI

The New England Journal of Medicine. Feb, 2008  |  Pubmed ID: 18287610

The CyberKnife Stereotactic Radiosurgery System: Description, Installation, and an Initial Evaluation of Use and Functionality

Neurosurgery. Feb, 2008  |  Pubmed ID: 18596427

The CyberKnife Stereotactic Radiosurgery System is manufactured by Accuray, Inc. (570 Del Rey Avenue, Sunnyvale, CA 94085; telephone 1-888/522-3740 or 1-408/522-3740; http://www.accuray.com). It is currently available for purchase (capital cost of US $3.2 million plus US $0.5 to 0.75 million for site setup), or in a revenue-sharing plan (US $0.5 to 0.75 million setup cost). [Figure: see text].

Tumour Vaccine Approaches for CNS Malignancies: Progress to Date

Drugs. 2009  |  Pubmed ID: 19275269

Despite the many overall advances in understanding cancer biology and therapeutic development in the last 50 years, most CNS malignancies are still clinically difficult, incurable diseases. Current combinations of aggressive surgical resection, radiation therapy and chemotherapy regimens do not significantly improve long-term patient survival for these cancers. Cancer immunotherapy is a potentially promising new therapeutic strategy that primes a patient's immune system to attack neoplastic cells. We review the preclinical and clinical progress in developing vaccination-based therapy for CNS malignancies to date, including peptide-based vaccinations, dendritic cell-based vaccinations and other potential modalities. Some of the challenges for developing an effective vaccination strategy, such as abnormal immune molecules on glioma cells and abnormal lymphocyte populations within a glioma, are also discussed.

Symptomatic Hyperprolactinemia from an Ectopic Pituitary Adenoma Located in the Clivus

Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. Mar, 2009  |  Pubmed ID: 19289326

To report a case of an ectopic pituitary adenoma in the clivus.

Giant Prolactinoma

Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. Mar, 2009  |  Pubmed ID: 19289331

Estimated Risk of Perihippocampal Disease Progression After Hippocampal Avoidance During Whole-brain Radiotherapy: Safety Profile for RTOG 0933

Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Jun, 2010  |  Pubmed ID: 20392503

RTOG 0933 is a phase II clinical trial of hippocampal avoidance during whole-brain radiotherapy (HA-WBRT) to prevent radiation-induced neurocognitive decline. By quantifying baseline incidence of perihippocampal or hippocampal metastasis, we sought to estimate the risk of developing metastases in the hippocampal avoidance region (the hippocampus plus 5mm margin).

The Cancer Stem Cell Paradigm: a New Understanding of Tumor Development and Treatment

Expert Opinion on Therapeutic Targets. Jun, 2010  |  Pubmed ID: 20426697

Cancer is the second leading cause of death in the United States, and therefore remains a central focus of modern medical research. Accumulating evidence supports a 'cancer stem cell' (CSC) model - where cancer growth and/or recurrence is driven by a small subset of tumor cells that exhibit properties similar to stem cells. This model may provide a conceptual framework for developing more effective cancer therapies that target cells propelling cancer growth.

Hippocampal-sparing Whole-brain Radiotherapy: a "how-to" Technique Using Helical Tomotherapy and Linear Accelerator-based Intensity-modulated Radiotherapy

International Journal of Radiation Oncology, Biology, Physics. Nov, 2010  |  Pubmed ID: 20598457

Sparing the hippocampus during cranial irradiation poses important technical challenges with respect to contouring and treatment planning. Herein we report our preliminary experience with whole-brain radiotherapy using hippocampal sparing for patients with brain metastases.

Turning Everything into Brain?

Neurosurgery. Aug, 2010  |  Pubmed ID: 20644402

The University of Wisconsin Department of Neurological Surgery

Neurosurgery. Aug, 2010  |  Pubmed ID: 20644429

The practice of neurological surgery at the University of Wisconsin has evolved and expanded greatly over the past nearly 70 years. From its beginnings as a 1-man division of general surgery, the Department of Neurosurgery has grown to the current department consisting of 14 neurosurgeons and 12 full-time researchers, along with fellows, residents, nurse practitioners, laboratory personnel, and support staff. The department is able to take advantage of the unique opportunities provided by this large research institution to foster close collaborations between surgeons and researchers, both within and outside of the department. This article chronicles the development of the Department of Neurological Surgery at the University of Wisconsin, directed by its 3 chairmen, in the context of the University, the state of Wisconsin, and the Midwestern United States.

Current Practices of Driving Restriction Implementation for Patients with Brain Tumors

Journal of Neuro-oncology. Jul, 2011  |  Pubmed ID: 20972603

Brain tumors may impair functioning in several neuro-cognitive domains and interfere with sophisticated tasks, such as driving motor vehicles. No formalized national guidelines or recommendations for driving restrictions in patients with brain tumors exist in the US. We created and administered a 24 question survey to 1,157 US medical practitioners, mostly neurosurgeons, radiation oncologists, and medical oncologists, to identify their knowledge of local driving restriction laws and their practice patterns regarding driving restriction instructions to brain tumor patients. Response were collected from 251 (21.7%) and analyzed from 221 (19%) recipients. Seventy-one percent of the respondents indicated they discuss driving recommendations/restrictions with brain tumor patients, with 82% primarily basing this on seizure activity. Approximately 28% of respondents were unsure if they are required by their State's motor vehicle licensing authority to report medically impaired drivers. Respondents felt that longer periods of restriction prior to re-evaluation are warranted in patients with malignant versus benign brain tumors and high versus low grade gliomas. Only 25% of respondents use formal, standardized testing to determine driving eligibility and approximately 31% address driving restrictions in every patient with a brain tumor. This survey highlights the lack of consensus regarding the responsibilities of physicians treating brain tumor patients in designing and enforcing driving restrictions. We propose that a panel of experts generate driving restriction guidelines to be used in conjunction with objective testing of motor and sensory impairment. These would aid practitioners in developing individualized driving restrictions for every brain tumor patient.

Microfluidics-based Devices: New Tools for Studying Cancer and Cancer Stem Cell Migration

Biomicrofluidics. 2011  |  Pubmed ID: 21522502

Cell movement is highly sensitive to stimuli from the extracellular matrix and media. Receptors on the plasma membrane in cells can activate signal transduction pathways that change the mechanical behavior of a cell by reorganizing motion-related organelles. Cancer cells change their migration mechanisms in response to different environments more robustly than noncancer cells. Therefore, therapeutic approaches to immobilize cancer cells via inhibition of the related signal transduction pathways rely on a better understanding of cell migration mechanisms. In recent years, engineers have been working with biologists to apply microfluidics technology to study cell migration. As opposed to conventional cultures on dishes, microfluidics deals with the manipulation of fluids that are geometrically constrained to a submillimeter scale. Such small scales offer a number of advantages including cost effectiveness, low consumption of reagents, high sensitivity, high spatiotemporal resolution, and laminar flow. Therefore, microfluidics has a potential as a new platform to study cell migration. In this review, we summarized recent progress on the application of microfluidics in cancer and other cell migration researches. These studies have enhanced our understanding of cell migration and cancer invasion as well as their responses to subtle variations in their microenvironment. We hope that this review will serve as an interdisciplinary guidance for both biologists and engineers as they further develop the microfluidic toolbox toward applications in cancer research.

Upper Cervical Intramedullary Spinal Metastasis of Ovarian Carcinoma: a Case Report and Review of the Literature

Journal of Medical Case Reports. 2011  |  Pubmed ID: 21756304

ABSTRACT:

What is the Optimal Venous Thromboembolism Prophylaxis for Gynecological Oncology Patients with CNS Metastases?

Gynecologic Oncology. Nov, 2011  |  Pubmed ID: 21807402

Introduction to Induced Pluripotent Stem Cells: Advancing the Potential for Personalized Medicine

World Neurosurgery. Sep-Oct, 2011  |  Pubmed ID: 21986423

Induced pluripotent stem (iPS) cell technology has enormous potential to advance medical therapy by personalizing regenerative medicine and creating novel human disease models for research and therapeutic testing. Before this technology is broadly used in the clinic, we must realistically evaluate its disease modeling and therapeutic potential. Recent advances including the use of iPS cells to successfully model spinal muscular atrophy in vitro, as well as new techniques in generating iPS cells with recombinant proteins have accelerated the prospects of iPS cells for clinical use in regenerative therapy. This review explores the development and limitations of iPS cell technology, presents a critical comparison of iPS cells and embryonic stem cells, and discusses potential clinical applications and future research directions.

A Pilot Study of Fat Allograft Transplantation in Immunocompetent Rabbits for Potential Neurosurgical Applications

Journal of Neurosurgery. Feb, 2011  |  Pubmed ID: 19961319

The authors investigated the feasibility of using fat allografts (chemically treated to reduce the host immune response) for neurosurgical applications.

Chronic Rhinosinusitis with Nasal Polyps: a Proteomic Analysis

The Annals of Otology, Rhinology, and Laryngology. Dec, 2011  |  Pubmed ID: 22279949

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a severe subtype of chronic rhinosinusitis that can affect patients despite medical and surgical interventions. The purpose of this study was to utilize the techniques of proteomics to investigate differences in protein abundance within the sinonasal mucosa of patients with CRSwNP compared to healthy controls.

Differential Expression of 2',3'-cyclic-nucleotide 3'-phosphodiesterase and Neural Lineage Markers Correlate with Glioblastoma Xenograft Infiltration and Patient Survival

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Jul, 2012  |  Pubmed ID: 22589395

Glioblastoma multiforme (GBM) is a poorly treated human brain cancer with few established clinically useful molecular prognostic markers. We characterized glioblastoma stem-like cells (GSC) according to developmental neural lineage markers and correlated their expression with patient survival.

Activation of Multiple ERBB Family Receptors Mediates Glioblastoma Cancer Stem-like Cell Resistance to EGFR-targeted Inhibition

Neoplasia (New York, N.Y.). May, 2012  |  Pubmed ID: 22745588

Epidermal growth factor receptor (EGFR) signaling is strongly implicated in glioblastoma (GBM) tumorigenesis. However, molecular agents targeting EGFR have demonstrated minimal efficacy in clinical trials, suggesting the existence of GBM resistance mechanisms. GBM cells with stem-like properties (CSCs) are highly efficient at tumor initiation and exhibit therapeutic resistance. In this study, GBMCSC lines showed sphere-forming and tumor initiation capacity after EGF withdrawal from cell culture media, compared with normal neural stem cells that rapidly perished after EGF withdrawal. Compensatory activation of related ERBB family receptors (ERBB2 and ERBB3) was observed in GBM CSCs deprived of EGFR signal (EGF deprivation or cetuximab inhibition), suggesting an intrinsic GBM resistance mechanism for EGFR-targeted therapy. Dual inhibition of EGFR and ERBB2 with lapatinib significantly reduced GBM proliferation in colony formation assays compared to cetuximab-mediated EGFR-specific inhibition. Phosphorylation of downstream ERBB signaling components (AKT, ERK1/2) and GBM CSC proliferation were inhibited by lapatinib. Collectively, these findings show that GBM therapeutic resistance to EGFR inhibitors may be explained by compensatory activation of EGFR-related family members (ERBB2, ERBB3) enabling GBM CSC proliferation, and therefore simultaneous blockade of multiple ERBB family members may be required for more efficacious GBM therapy.

Inhibition of Na(+)-K(+)-2Cl(-) Cotransporter Isoform 1 Accelerates Temozolomide-mediated Apoptosis in Glioblastoma Cancer Cells

Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology. 2012  |  Pubmed ID: 22759954

The hallmark of apoptosis is a significant reduction in cell volume (AVD) resulting from loss of K(+)(i) and Cl(-)(i). Loss of cell volume and lowering of ionic strength of intracellular K(+) and Cl(-) occur before any other detectable characteristics of apoptosis. In the present study, temozolomide (TMZ) triggered loss of K(+)(i) and Cl(-)(i) and AVD in primary glioblastoma multiforme (GBM) cancer cells (GC) and GC cancer stem cells (GSC). We hypothesize that Na(+)-K(+)-2Cl(-) cotransporter isoform 1 (NKCC1) counteracts AVD during apoptosis in GBM cancer cells by regulating cell volume and Cl(-) homeostasis. NKCC1 protein was expressed in both GC and GSC and played an essential role in regulatory volume increase (RVI) in response to hypertonic cell shrinkage and isotonic cell shrinkage. Blocking NKCC1 activity with its potent inhibitor bumetanide abolished RVI. These cells maintained a basal [Cl(-)](i) (~ 68 mM) above the electrochemical equilibrium for Cl(-)(i). NKCC1 also functioned to replenish Cl(-)(i) levels following the loss of Cl(-)(i). TMZ-treated cells exhibited increased phosphorylation of NKCC1 and its up-stream novel Cl(-)/volume-sensitive regulatory kinase WNK1. Inhibition of NKCC1 activity with bumetanide accelerated AVD, early apoptosis, as well as activation of caspase-3 and caspase-8. Taken together, this study strongly suggests that NKCC1 is an essential mechanism in GBM cells to maintain K(+), Cl(-), and volume homeostasis to counteract TMZ-induced loss of K(+), Cl(-) and AVD. Therefore, blocking NKCC1 function augments TMZ-induced apoptosis in glioma cells.

Significant Association of Multiple Human Cytomegalovirus Genomic Loci with Glioblastoma Multiforme Samples

Journal of Virology. Jan, 2012  |  Pubmed ID: 22090104

Viruses are appreciated as etiological agents of certain human tumors, but the number of different cancer types induced or exacerbated by viral infections is unknown. Glioblastoma multiforme (GBM)/astrocytoma grade IV is a malignant and lethal brain cancer of unknown origin. Over the past decade, several studies have searched for the presence of a prominent herpesvirus, human cytomegalovirus (HCMV), in GBM samples. While some have detected HCMV DNA, RNA, and proteins in GBM tissues, others have not. Therefore, any purported association of HCMV with GBM remains controversial. In most of the previous studies, only one or a select few viral targets were analyzed. Thus, it remains unclear the extent to which the entire viral genome was present when detected. Here we report the results of a survey of GBM specimens for as many as 20 different regions of the HCMV genome. Our findings indicate that multiple HCMV loci are statistically more likely to be found in GBM samples than in other brain tumors or epileptic brain specimens and that the viral genome was more often detected in frozen samples than in paraffin-embedded archival tissue samples. Finally, our experimental results indicate that cellular genomes substantially outnumber viral genomes in HCMV-positive GBM specimens, likely indicating that only a minority of the cells found in such samples harbor viral DNA. These data argue for the association of HCMV with GBM, defining the virus as oncoaccessory. Furthermore, they imply that, were HCMV to enhance the growth or survival of a tumor (i.e., if it is oncomodulatory), it would likely do so through mechanisms distinct from classic tumor viruses that express transforming viral oncoproteins in the overwhelming majority of tumor cells.