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  • Author or Editor: Eric Holland x
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Marc-Eric Halatsch, Ursula Schmidt, Ingolf C. Bötefür, James F. Holland and Takao Ohnuma

Object. The goal of this study was to evaluate the activity of certain hairpin ribozymes against deletion-mutant epidermal growth factor receptor (ΔEGFR) messenger (m)RNA in glioblastomas multiforme (GBMs). A distinct 801-bp deletion mutation associated with amplification of the EGFR gene is present in a large subgroup of primary GBMs and confers enhanced tumorigenicity in vivo. As a result of the deletion mutation, the fusion junction of the gene is created directly upstream of a GTA triplet, which is subsequently transcribed into a ribozyme target codon (GUA).

Methods. In attempts to intercept ΔEGFR gene expression at the mRNA level, the authors designed three different hairpin ribozymes derived from the negative strands of satellite RNAs in tobacco ringspot virus, chicory yellow mottle virus (sCYMV1), and arabis mosaic virus against this target and evaluated their efficiency and specificity in a cell-free system. The sCYMV1, identified as the most active anti-ΔEGFR hairpin ribozyme motif, was cloned into the retroviral plasmid N2A+tRNAi met. High-titer recombinant retrovirus-containing supernatants (> 105 colony-forming units/ml) derived from an amphotropic GP+envAM 12 packaging cell line transfected with the N2A+tRNAi met-anti-ΔEGFR-sCYMV1 construct were used to introduce the sCYMV1 hairpin ribozyme into U-87MG.ΔEGFR glioblastoma cells, which overexpress exogenous ΔEGFR. Using a virus/target cell ratio of 40:1 in the absence of drug selection, the ribozyme transfer resulted in a greater than 90% reduction of ΔEGFR mRNA levels, a 69% inhibition of ΔEGFR-mediated proliferation advantage, and a greater than 95% decrease of colony formation in soft agar under relative serum starvation conditions in vitro; transfer of a control mutant ribozyme that was rendered incapable of cleaving its target yielded none of these effects.

Conclusions. These findings indicate that the anti-ΔEGFR-sCYMV1 hairpin ribozyme is capable of specifically inhibiting the expression of ΔEGFR and reversing the ΔEGFR-associated malignant phenotype of GBM cells. This strategy may constitute a promising gene therapy approach for a molecularly defined subgroup of GBMs.

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Frederick F. Lang, Nancy E. Olansen, Franco DeMonte, Ziya L. Gokaslan, Eric C. Holland, Christopher Kalhorn and Raymond Sawaya

Object. Surgical resection of tumors located in the insular region is challenging for neurosurgeons, and few have published their surgical results. The authors report their experience with intrinsic tumors of the insula, with an emphasis on an objective determination of the extent of resection and neurological complications and on an analysis of the anatomical characteristics that can lead to suboptimal outcomes.

Methods. Twenty-two patients who underwent surgical resection of intrinsic insular tumors were retrospectively identified. Eight tumors (36%) were purely insular, eight (36%) extended into the temporal pole, and six (27%) extended into the frontal operculum. A transsylvian surgical approach, combined with a frontal opercular resection or temporal lobectomy when necessary, was used in all cases. Five of 13 patients with tumors located in the dominant hemisphere underwent craniotomies while awake. The extent of tumor resection was determined using volumetric analyses. In 10 patients, more than 90% of the tumor was resected; in six patients, 75 to 90% was resected; and in six patients, less than 75% was resected. No patient died within 30 days after surgery. During the immediate postoperative period, the neurological conditions of 14 patients (64%) either improved or were unchanged, and in eight patients (36%) they worsened. Deficits included either motor or speech dysfunction. At the 3-month follow-up examination, only two patients (9%) displayed permanent deficits. Speech and motor dysfunction appeared to result most often from excessive opercular retraction and manipulation of the middle cerebral artery (MCA), interruption of the lateral lenticulostriate arteries (LLAs), interruption of the long perforating vessels of the second segment of the MCA (M2), or violation of the corona radiata at the superior aspect of the tumor. Specific methods used to avoid complications included widely splitting the sylvian fissure and identifying the bases of the periinsular sulci to define the superior and inferior resection planes, identifying early the most lateral LLA to define the medial resection plane, dissecting the MCA before tumor resection, removing the tumor subpially with preservation of all large perforating arteries arising from posterior M2 branches, and performing craniotomy with brain stimulation while the patient was awake.

Conclusions. A good understanding of the surgical anatomy and an awareness of potential pitfalls can help reduce neurological complications and maximize surgical resection of insular tumors.

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Ricardo J. Komotar, J. Bryan Iorgulescu, Daniel M. S. Raper, Eric C. Holland, Kathryn Beal, Mark H. Bilsky, Cameron W. Brennan, Viviane Tabar, Jonathan H. Sherman, Yoshiya Yamada and Philip H. Gutin

Object

Atypical (WHO Grade II) meningiomas comprise a heterogeneous group of tumors, with histopathology delineated under the guidance of the WHO and a spectrum of clinical outcomes. The role of postoperative radiotherapy for patients with atypical meningiomas who have undergone gross-total resection (GTR) remains unclear. In this paper, the authors sought to clarify this role by reviewing their experience over the past 2 decades.

Methods

The authors retrospectively analyzed all patients at their institution who underwent GTR between 1992 and 2011 with a final histology demonstrating atypical meningioma. Information regarding patients, tumor characteristics, and postoperative adjuvant therapy was gleaned from medical records. Time to recurrence and overall survival were analyzed using univariate, multivariate, and Kaplan-Meier survival analyses.

Results

Forty-five patients who met the inclusion criteria underwent GTR for atypical meningiomas. By a median follow-up of 44.1 months, 22% of atypical meningiomas had recurred. There was no recurrence in 12 (92%) of 13 patients who received postoperative radiotherapy or in 19 (59%) of 32 patients who did not undergo postoperative radiotherapy (p = 0.085), demonstrating a strong trend toward improved local control with postoperative radiotherapy. No other factors were significantly associated with recurrence in univariate or multivariate analyses.

Conclusions

This retrospective series supports the observation that postoperative radiotherapy likely results in lower recurrence rates of gross totally resected atypical meningiomas. Although a multicenter prospective trial will ultimately be needed to fully define the role of radiotherapy in managing gross totally resected atypical meningiomas, the authors' results contribute to a growing number of series that support routine postoperative radiotherapy as an adjuvant treatment for these lesions.

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Michel Lacroix, Dima Abi-Said, Daryl R. Fourney, Ziya L. Gokaslan, Weiming Shi, Franco DeMonte, Frederick F. Lang, Ian E. McCutcheon, Samuel J. Hassenbusch, Eric Holland, Kenneth Hess, Christopher Michael, Daniel Miller and Raymond Sawaya

Object. The extent of tumor resection that should be undertaken in patients with glioblastoma multiforme (GBM) remains controversial. The purpose of this study was to identify significant independent predictors of survival in these patients and to determine whether the extent of resection was associated with increased survival time.

Methods. The authors retrospectively analyzed 416 consecutive patients with histologically proven GBM who underwent tumor resection at the authors' institution between June 1993 and June 1999. Volumetric data and other tumor characteristics identified on magnetic resonance (MR) imaging were collected prospectively.

Conclusions. Five independent predictors of survival were identified: age, Karnofsky Performance Scale (KPS) score, extent of resection, and the degree of necrosis and enhancement on preoperative MR imaging studies. A significant survival advantage was associated with resection of 98% or more of the tumor volume (median survival 13 months, 95% confidence interval [CI] 11.4–14.6 months), compared with 8.8 months (95% CI 7.4–10.2 months; p < 0.0001) for resections of less than 98%. Using an outcome scale ranging from 0 to 5 based on age, KPS score, and tumor necrosis on MR imaging, we observed significantly longer survival in patients with lower scores (1–3) who underwent aggressive resections, and a trend toward slightly longer survival was found in patients with higher scores (4–5). Gross-total tumor resection is associated with longer survival in patients with GBM, especially when other predictive variables are favorable.