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Thomas C. Chen

In this article the author reviews outcomes of thoracic disc surgery reported in the literature. Care was taken to include only series in which none or a few patients underwent laminectomy for the treatment of thoracic disc lesions. The author found that thoracic discectomy may be performed in an efficacious and safe manner via the transthoracic, lateral extracavitary, transpedicular, or endoscopic approach. In the vast majority of patients, preoperative symptoms of pain (radiculopathy or axial loading pain) and myelopathy were improved after surgery. Measurements of operative time, blood loss, length of hospital stay, and patient satisfaction were often inadequately reported. Complications (systemic and neurological) were well documented and were not common. A plea is made for uniformity in documenting outcome in future series so that today's procedures for thoracic discectomy may be more accurately compared with future cases regardless of the inevitable advances in surgical techniques for removal of thoracic discs.

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Thomas C. Chen

The author reviewed five hereditary neurological tumor syndromes associated with gliomas: Li-Fraumeni cancer syndrome, neurofibromatosis type 1 (NF1) and type 2 (NF2), tuberous sclerosis (TS), and Turcot syndrome. In each case, clinical manifestation, genetic localization, and protein function were identified. Correlation with glioma oncogenesis demonstrated the following associations: 1) p53 mutation (Li-Fraumeni) with astrocytoma progression; 2) NF1 mutation (NF1) with pilocytic astrocytomas; and 3) NF2 mutation (NF2) with ependymoma formation. The role of the TS gene and the adenomatous polypopsis coli gene (Turcot syndrome) in glioma oncogenesis is not clear. Because tumorigenesis is a multistep process, it would be premature to equate a specific germline mutation with the multiple somatic mutations required for glioma formation. However, identification of specific germline genetic mutations provides a model for the multiple tumor suppressor genes involved in glioma pathogenesis.

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Thomas C. Chen

The marriage of basic scientific research and clinical application often leads to profound advances in our understanding of various disease processes and how they may be ameliorated. One such fortuitous combination has been the discovery of bone morphogenetic proteins (BMPs) and their potential application in spinal fusions. The goal of this article is to introduce the neurosurgeon to the basic biology of this protein family, current experimental data (in vitro and in vivo models) demonstrating their effectiveness in enhancing bony fusions, and preliminary clinical trials utilizing BMP in long bone fusions. Using this information, a proposal for the use of BMP in spinal fusions under various clinical scenarios will be discussed.

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Thomas C. Chen and Marc C. Chamberlain

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Thomas C. Chen and Lauren E. Abrey

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James B. Elder and Thomas C. Chen

✓ Early diagnosis is central to proper management of primary central nervous system lymphomas (PCNSLs). Surgical intervention hinges on initial entertainment of a diagnosis of a PCNSL, based on acute neurological presentation and neuroimaging findings. Unless there is an urgent need for surgical decompression, a biopsy to obtain a diagnosis of PCNSL is the first step in surgical management. Repeated biopsy may be necessary in patients who have received pre-operative steroid therapy. Patients with PCNSL may also present with leptomeningeal involvement, resulting in the need for an Ommaya reservoir for intrathecal chemotherapy. In cases in which hydrocephalus develops, placement of a ventriculoperitoneal shunt may be necessary. Two case studies are presented to highlight the role of surgical intervention in PCNSL.

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Thomas C. Chen and Gregory A. Helm

Gene therapy is an exciting new discipline in which neurosurgery and neurosurgeons can have a direct impact on both patient care and emerging scientific developments. Unlike other organs, the brain is unique in that it has a blood–brain barrier, often preventing efficient systemic gene delivery to the area of interest. Therefore, not only is gene delivery required, but it will often need to be accomplished in a local and specific manner. Although brain neoplasms have been the most commonly studied application of genetic therapeutics in neurological surgery, there are many other potential applications of this technology to neurosurgical disorders, including spinal instability, neurodegenerative disease, neurogenetic diseases, central nervous system (CNS) injury, aneurysms, trauma, stroke, and epilepsy. As the field of gene therapy for the CNS develops from the preclinical setting to clinical trials to mainstream therapy, the need for safe and specific gene delivery will be increasingly apparent. Neurosurgeons are in an enviable position as there is nobody more qualified to address the issue of how a gene can be delivered to the central nervous system. Not only do we have the training to operate on the nervous system and its coverings, but we have the ability to recognize and take care of complications that may arise from these procedures. However, the neurosurgeon's role in gene therapy for the brain and spine should not be confined to gene delivery only. Instead, we also need to understand and have a role in deciding what genes could have therapeutic utility in our patients. Herein lies our challenge in gene therapy: how can we as neurosurgeons interface with our basic science colleagues to address rapidly all of the problems that are blocking the advancement of nucleic acid therapeutics into the clinical setting.

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Michael L. Levy, Thomas C. Chen and Martin H. Weiss

✓ A case report of monostotic fibrous dysplasia of the clivus in a postadolescent woman is described. Although fibrous dysplasia of craniofacial structures is well documented, involvement of the clivus has not been reported. Diagnosis by clinical, radiographic, and histopathological features is detailed. Implications for the role of surgery and management are discussed.

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Vinay Gupta, Christian G. Samuleson, Susan Su and Thomas C. Chen

✓ Although most meningiomas are treated surgically, it may not be possible to completely remove atypical, malignant, and surgically inaccessible meningiomas; in the majority of these cases there is tumor recurrence. The authors have already reported initial preclinical results on the efficacy of imatinib in the treatment of meningiomas; however, a recent Phase II trial of imatinib in patients with recurrent meningiomas did not demonstrate significant antitumor activity. To enhance the activity of imatinib, the authors investigated the use of a combination therapy with nelfinavir on primary meningioma cells and meningioma cell lines IOMM-Lee and CH157.

Cytotoxicity was measured using methylthiotetrazole and colony formation assays. In low-dose combination therapy with imatinib, nelfinavir potentiated the antiproliferative and anti–colony formation effects of imatinib. Primary meningioma cells responded better to combination therapy than to imatinib alone. Treatment induced a dose-dependent antiproliferative effect, decreased cell survival, and inhibited colony formation. Western blotting demonstrated decreased levels of survivin protein on combination therapy. Because meningiomas have very high levels of survivin protein, survivin inhibition by nelfinavir may represent a potential mechanism for the additive effect observed with imatinib. Moreover, an increase in the proapoptotic Bax/Bcl-2 protein ratio was demonstrated with the combination of imatinib and nelfinavir.

The authors propose that nelfinavir not only potentiates imatinib efficacy, it also abrogates resistance to imatinib by decreasing survivin protein levels in meningiomas. In an in vivo assay, this combination therapy was found to be more effective than imatinib alone. More preclinical work with in vivo models is needed to determine if this new combination therapy will translate into a viable future therapy for meningiomas.

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Christiana Charalambous, Florence M. Hofman and Thomas C. Chen

Object. Glioblastomas multiforme (GBMs) are hypervascular tumors characterized by endothelial cell (EC) proliferation. There is increasing evidence that ECs that infiltrate systemic tumors are different from normal blood vessel cells; whether this difference is seen in the central nervous system between GBM and normal brain tissue is not known. The goal of this investigation was to characterize and compare the functional and phenotypic properties of GBM-associated ECs and normal brain ECs.

Methods. Human ECs were isolated from fresh tissue specimens, purified using flow cytometry, and characterized by immunostaining. Proliferation was measured by determining bromodeoxyuridine incorporation and Ki-67 staining, and by performing the monotetrazolium assay. The migration rate of the cells was determined using the modified Boyden chamber technique. Apoptosis was evaluated by performing the TUNEL assay, cell death enzyme-linked immunosorbent assay (ELISA), and annexin V staining. Growth factor production was analyzed using the ELISA technique.

The brain tumor ECs differed from normal brain ECs morphologically and by their expression and distribution of specific markers (that is, vascular endothelial cadherin [VE-cadherin] and CD31). Functional differences between the two cell populations were also evident. The brain tumor ECs proliferated more slowly and underwent less apoptosis than normal brain ECs; however, the tumor ECs migrated faster than the normal ECs. The normal ECs were sensitive to growth factors such as vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1), whereas the tumor ECs were not. In addition, the brain tumor ECs constitutively produced higher levels of ET-1 and VEGF, compared with the normal ECs.

Conclusions. The data demonstrated that ECs derived from normal brain and from GBMs have significant phenotypic and functional distinctions. Further characterization of brain tumor ECs is essential for efficient antiangiogenic treatment of gliomas.