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William T. Couldwell, Parakrama T. Chandrasoma, and Martin H. Weiss

✓ A case of prostatic carcinoma metastasis to the pituitary gland is reported. The presentation and rarity of such a lesion is addressed. The literature review yielded only isolated case reports of symptomatic brain metastases unassociated with bone disease from adenocarcinoma of the prostate. The management options of such a lesion are discussed.

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William T. Couldwell and Michael L. J. Apuzzo

✓ Initial experience with a new arc-radius design of stereotactic frame that interfaced with the existing components of the Brown-Roberts-Wells instrument is reported. Over a 6-month period, 32 procedures were performed on 23 males and nine female patients (mean age 32 years); these included 27 stereotactic biopsy procedures, two stereotactic implantations of cyst catheter reservoirs, two ventriculoscopic aspirations of third ventricular colloid cysts, and one stereotactic aspiration of a craniopharyngioma. In all cases successful targeting was achieved and verified by postoperative computerized tomography. There were no operation-related complications. This new frame offers rapid and accurate targeting and is a useful adjunct to the stereotactic armamentarium.

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William T. Couldwell, Jack P. Antel, Michael L. J. Apuzzo, and Voon Wee Yong

✓ The protein kinase-C (PKC) second messenger system contributes to regulation of cell growth and differentiation. This study was undertaken to examine the effects of modulators of the PKC enzyme system on the state of differentiation and proliferation rates of human gliomas in vitro. The administration of the PKC-activating phorbol esters 4-beta-phorbol-12,13-dibutyrate (PDB) and phorbol-12-myristate-13-acetate (PMA) resulted in a dose-related inhibition of growth of human glioma cell lines in vitro as measured by 3H-thymidine uptake. The synthetic nonphorbol PKC activator (SC-9) produced an even more pronounced decrease of 3H-thymidine uptake. Diacylglycerol, an endogenous activator of the system, applied externally, transiently decreased the proliferation, in concordance with its short-lived existence in vivo. Conversely, the administration of 4-alpha-phorbol-12,13-didecanoate (α-PDD), a phorbol ester that binds but does not activate the enzyme, had no effect on the proliferation rate. At the dosages that maximally decreased proliferation, there was no evidence of direct glioma cell lysis induced by these agents as measured by a chromium-release assay. Immunocytochemical analysis and cytofluorometric measurement of glial fibrillary acidic protein (GFAP) staining in the treated cultures revealed an increase in GFAP staining over control cultures. In contrast to the response of glioma cells, nonmalignant human adult astrocytes treated with the PKC activators responded by increasing their proliferation rate.

The authors postulate that the diametrically opposed effects of PKC activators on nonmalignant astrocytes versus glioma growth may be due to a high intrinsic PKC activity in glioma cells, with resultant down-regulation of enzyme activity following the administration of the pharmacological activators.

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William T. Couldwell, Nicolas de Tribolet, Jack P. Antel, Thierry Gauthier, and Maria C. Kuppner

✓ Adhesion molecules, a family of cell-surface molecules, are likely to be of central importance in mediating cell-extracellular matrix and specific cell-cell interactions within both neoplastic and inflammatory sites. The recently discovered expression of adhesion molecules on glioma cells, tumor-infiltrating lymphocytes, and endothelial cells within the tumor offers insight into the molecular basis of the interactions both between the glioma cell and surrounding heterologous cell types within the tumor environment, and between the tumor cell and the extracellular matrix. Such interactions suggest that these molecules may play roles in the homing of immune cells to these tumors and in regulating the extent of local tumor invasion. The ability to modulate adhesion molecule expression on either immune cells or their respective ligands on gliomas provides an approach to modify cell-cell interactions that may be used to increase tumor kill by the immune system. A similar approach in the modulation of adhesion molecules involved in tumor cell adhesion to the extracellular matrix or endothelial cells may be a method to limit local invasion in these lesions.

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John H. Schneider, Martin H. Weiss, and William T. Couldwell

✓ The Los Angeles County General Hospital has played an integral role in the development of medicine and neurosurgery in Southern California. From its fledgling beginnings, the University of Southern California School of Medicine has been closely affiliated with the hospital, providing the predominant source of clinicians to care for and to utilize as a teaching resource the immense and varied patient population it serves.

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William T. Couldwell and Takanori Fukushima

✓ The authors describe a cosmetic mastoidectomy technique for use when performing a combined supra/infratentorial craniotomy and transtemporal exposure. The technique involves a single temporal suboccipital bone flap and cosmetic mastoidectomy, removing the outer table of bone for later replacement. Replacement of the outer table of mastoid bone enables tamponade of a fat graft against the dura to reduce the risk of postoperative cerebrospinal fluid leaks. The technique has been performed in eight patients treated for petroclival meningiomas with excellent cosmetic results.

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William T. Couldwell, Thomas C. Chen, Martin H. Weiss, Takanori Fukushima, and William Dougherty

✓ The authors describe the use of a porous polyethylene Flexblock implant for cosmetic cranioplasty. The implant may be used to cover any small- or medium-sized (< 8 cm) cranial defect, offering similar cosmetic results to standard alloplast cranioplasty while decreasing operation time. The porous implant design permits ingrowth of soft tissue and bone to increase implant strength and decrease the risk of infection. The Flexblock alloplast has been utilized in 25 cases with excellent cosmetic results and no implant-related complications.

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William T. Couldwell, Martin H. Weiss, Ronald E. Law, and David R. Hinton

✓ The monoclonal antibody Ki-67 recognizes a nuclear antigen expressed in the G1, S, G2, and M phase of the cell cycle and has been used extensively as an indicator of cellular proliferation in malignant gliomas, both in the laboratory and clinically. Recently, protein kinase C (PKC) inhibitors have been demonstrated to inhibit malignant glioma growth both in in vitro and in vivo. This study was undertaken to determine whether Ki-67 could function as an indicator of cellular proliferation rate after PKC inhibition in gliomas and to explore cell cycle specificity of such inhibition. Both established and low-passage malignant glioma cell lines have previously been shown to be sensitive to growth inhibition by the PKC inhibitors staurosporine and tamoxifen in vitro (IC50 in the nanomolar and micromolar ranges, respectively), as measured by cell numbers, [3H]thymidine uptake, and flow-cytometric DNA analysis. However, in the same cells that are inhibited by staurosporine and tamoxifen on these assays, and on the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) assay in the present study, the Ki-67 labeling index paradoxically increased in a dose-related manner with the same treatments, as measured by immunohistochemistry and confirmed by flow cytometry. For example, in established line U-87, a 20.5% decrease in thymidine uptake and a 28.5% decrease in absorbance on the MTT assay produced by tamoxifen at 1 µM was associated with an increase in Ki-67 labeling from 42% to 62%; staurosporine, which produces a 78.8% decrease in thymidine uptake in cell line A-172 at 10 nM, produced an increase in Ki-67 labeling from 19% to 32%. In this regard, Ki-67 labeling of glioblastoma tissue from a patient treated with high-dose tamoxifen yielded results within the range of 10% to 15% (consistent with values seen in untreated glioblastoma), despite tumor regression with treatment. The authors' interpretation of these results is that these PKC inhibitors are halting the cell cycle in the G1 phase or the G1—S transition (beyond G0 but before S-phase), resulting in a paradoxical increase in labeling while arresting growth. Two important implications from these observations are that Ki-67 is not a reliable indicator of cellular proliferation after treatment with PKC inhibitors and that these inhibitors used at the doses given above halt cell growth in a phase-specific manner.

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Charles B. Stillerman, Thomas C. Chen, J. Diaz Day, William T. Couldwell, and Martin H. Weiss

✓ A number of operative techniques have been described for the treatment of herniated thoracic discs. The transfacet pedicle-sparing approach allows for complete disc removal with limited spinal column disruption and soft-tissue dissection. Fifteen cadaveric spinal columns were used for evaluation of exposure, development of thoracic microdiscectomy instrumentation, and establishment of morphometric measurements. This approach was used to remove eight thoracic discs in six patients. Levels of herniation ranged from T-7 through T-11. Preoperatively, all patients had moderate to severe axial pain, and three (50%) of the six had radicular pain. Myelopathy was present in four (67%) of the six patients. Through a 4-cm opening, the ipsilateral paraspinal muscles were reflected, and a partial facetectomy was performed. The disc was then removed using specially designed microscopic instrumentation. Postoperatively, the radiculopathy resolved in all patients. Axial pain and myelopathy were completely resolved or significantly improved in all patients.

The minimal amount of bone resection and muscle dissection involved in the operation allows for: 1) decreased operative time and blood loss; 2) diminished perioperative pain; 3) shorter hospitalization time and faster return to premorbid activity; 4) avoidance of closed chest tube drainage; and 5) preservation of the integrity of the facet—pedicle complex, with potential for improvement in outcome related to axial pain. This technique appears best suited for the removal of all centrolateral discs, although it has been used successfully for treating a disc occupying nearly the entire ventral canal. The initial experience suggests that this approach may be used to safely remove appropriately selected thoracic disc herniations with good results.