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Ryan Smith, Kris A. Smith, Christopher A. Biggs and Adrienne C. Scheck

Object

The goal of this study was to develop an assay that makes possible the assessment of the glioma cell response to single-fraction high-dose Gamma Knife surgery. In this assay, the isolation of radioresistant cell subpopulations facilitates mechanistic studies of radioresistance.

Methods

A tissue-equivalent paraffin phantom with an aperture capable of holding an Opticell cell culture cassette was developed for treatment with the Leksell Gamma Knife model C. A second apparatus, which the authors also created, uses the manufacturer-supplied polystyrene phantom, thereby allowing this assay to be performed in the Leksell Gamma Knife Perfexion. After treatment, the cells were morphologically assessed to determine their response to radiation treatment. Two specific parameters were used to determine radiosensitivity: 1) the diameter of the clearing zone, defined as the central region of cell death; and 2) the number of surviving colonies within this central high-dose clearing zone.

Results

Radioresistance was compared in 2 different cell lines from glioblastomas. The first cell line, ME, was established from a primary tumor before its treatment, and the second cell line, DIV, was established from a tumor that recurred after treatment with chemotherapy and fractionated radiotherapy. The ME cell line had the most robust response to radiosurgery, as characterized by a consistently larger clearing zone (28.33 ± 1.1 mm). In contrast, the clearing zone produced when the DIV cell line was used was 24.0 ± 1 mm, indicating an approximate response difference of 5 Gy. The mean number of surviving colonies within the clearing zone for the ME cell line was 1.33 ± 1 compared with that for the DIV cell line, which was 66.67 ± 2.

Conclusions

The authors developed a biological dosimeter to model the response of cells from glioblastomas to single-fraction high-dose radiation. This system also allows the identification and isolation of radioresistant cells.

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Kathryn E. Fenton, Nikolay L. Martirosyan, Mohammed G. Abdelwahab, Stephen W. Coons, Mark C. Preul and Adrienne C. Scheck

Object

For patients with glioblastoma multiforme, median survival time is approximately 14 months. Longer progression-free and overall survival times correlate with gross-total resection of tumor. The ability to identify tumor cells intraoperatively could result in an increased percentage of tumor resected and thus increased patient survival times. Available labeling methods rely on metabolic activity of tumor cells; thus, they are more robust in high-grade tumors, and their utility in low-grade tumors and metastatic tumors is not clear. The authors demonstrate intraoperative identification of tumor cells by using labeled tumor-specific antibodies.

Methods

GL261 mouse glioma cells exhibit high expression of a membrane-bound protein called second tyrosinase-related protein (TRP-2). The authors used these cells to establish an intracranial, immunocompetent model of malignant glioma. Antibodies to TRP-2 were labeled by using Alexa Fluor 488 fluorescent dye and injected into the tail vein of albino C57BL/6 mice. After 24 hours, a craniotomy was performed and the tissue was examined in vivo by using an Optiscan 5.1 handheld portable confocal fiber-optic microscope. Tissue was examined ex vivo by using a Pascal 5 scanning confocal microscope.

Results

Labeled tumor cells were visible in vivo and ex vivo under the respective microscopes.

Conclusions

Fluorescently labeled tumor-specific antibodies are capable of binding and identifying tumor cells in vivo, accurately and specifically. The development of labeled markers for the identification of brain tumors will facilitate the use of intraoperative fluorescence microscopy as a tool for increasing the extent of resection of a broad variety of intracranial tumors.

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Wolfgang K. Pfisterer, Ronald A. Nieman, Adrienne C. Scheck, Stephen W. Coons, Robert F. Spetzler and Mark C. Preul

Object

The goal in this study was to determine if proton (1H) MR spectroscopy can differentiate meningioma grade and is associated with interpretations of biological behavior; the study was performed using ex vivo high-resolution spectra indicating metabolic characteristics.

Methods

Sixty-eight resected tissue samples of meningiomas were examined using ex vivo 1H MR spectroscopy. Of these meningiomas, 46 were WHO Grade I, 14 were WHO Grade II, and 8 were WHO Grade III. Fifty-nine were primary meningiomas and 9 were recurrences. Invasion of adjacent tissue (dura mater, bone, venous sinus, brain) was found in 32 cases. Thirty-nine meningiomas did not rapidly recur (as defined by expansion on MR imaging within a 5-year follow-up period), whereas rapid recurrence was confirmed in 24 meningiomas, and follow-up status was unknown in 5 cases.

Results

The absolute concentrations of total alanine and creatine were decreased in high-grade compared with low-grade meningiomas, as was the ratio of glycine to alanine (all p < 0.05). Additionally, alanine and the glycine/alanine ratio distinguished between primary and recurrent meningiomas (all p < 0.05). Finally, the absolute concentrations of alanine and creatine, and the glycine/alanine and choline/glutamate ratios were associated with rapid recurrence (p < 0.05).

Conclusions

. These data indicate that meningioma tissue can be characterized by metabolic parameters that are not typically identified by histopathological analysis alone. Creatine, glycine, and alanine may be used as markers of meningioma grade, recurrence, and the likelihood of rapid recurrence. These data validate a previous study of a separate group of Grade I meningiomas.

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Tejas Sankar, Nina Z. Moore, Joshua Johnson, Lynn S. Ashby, Adrienne C. Scheck, William R. Shapiro, Kris A. Smith, Robert F. Spetzler and Mark C. Preul

Object

Oligodendrogliomas that enhance on MR images are associated with poor prognosis. However, the importance of the volume of enhancing tumor tissue, and the extent of its resection, is uncertain. The authors examined the prognostic significance of preoperative and residual postoperative enhancing tissue volumes in a large single-center series of patients with oligodendroglioma. They also examined the relationship between enhancement and characteristic genetic signatures in oligodendroglial tumors, specifically deletion of 1p and 19q (del 1p/19q).

Methods

The authors retrospectively analyzed 100 consecutive cases of oligodendroglioma involving patients who had undergone T1-weighted gadolinium-enhanced MRI at diagnosis and immediately after initial surgical intervention. The presence of preoperative enhancement was determined by consensus. Preoperative and residual postoperative volumes were measured using a quantitative, semiautomated method by a single blinded observer. Intrarater reliability for preoperative volumes was confirmed by remeasurement in a subset of patients 3 months later. Intrarater and interrater reliability for residual postoperative volumes was confirmed by remeasurement of these volumes by both the original and a second blinded observer. Multivariate analysis was used to assess the influence of contrast enhancement at diagnosis and the volume of pre- and postoperative contrast-enhancing tumor tissue on time to relapse (TTR) and overall survival (OS), while controlling for confounding clinical, pathological, and genetic factors.

Results

Sixty-three of 100 patients had enhancing tumors at initial presentation. Presence of contrast enhancement at diagnosis was related to reduced TTR and OS on univariate analysis but was not significantly related on multivariate analysis. In enhancing tumors, however, greater initial volume of enhancing tissue correlated with shortened TTR (p = 0.00070). Reduced postoperative residual enhancing volume and a relatively greater resection of enhancing tissue correlated with longer OS (p = 0.0012 and 0.0041, respectively). Interestingly, patients in whom 100% of enhancing tumor was resected had significantly longer TTR (174 vs 64 weeks) and OS (392 vs 135 weeks) than those with any residual enhancing tumor postoperatively. This prognostic benefit was not consistently maintained with greater than 90% or even greater than 95% resection of enhancing tissue. There was no relationship between presence or volume of enhancement and del 1p/19q.

Conclusions

In enhancing oligodendrogliomas, completely resecting enhancing tissue independently improves outcome, irrespective of histological grade or genetic status. This finding supports aggressive resection and may impact treatment planning for patients with these tumors.

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Nikolay L. Martirosyan, Daniel D. Cavalcanti, Jennifer M. Eschbacher, Peter M. Delaney, Adrienne C. Scheck, Mohammed G. Abdelwahab, Peter Nakaji, Robert F. Spetzler and Mark C. Preul

Object

Infiltrative tumor resection is based on regional (macroscopic) imaging identification of tumorous tissue and the attempt to delineate invasive tumor margins in macroscopically normal-appearing tissue, while preserving normal brain tissue. The authors tested miniaturized confocal fiberoptic endomicroscopy by using a near-infrared (NIR) imaging system with indocyanine green (ICG) as an in vivo tool to identify infiltrating glioblastoma cells and tumor margins.

Methods

Thirty mice underwent craniectomy and imaging in vivo 14 days after implantation with GL261-luc cells. A 0.4 mg/kg injection of ICG was administered intravenously. The NIR images of normal brain, obvious tumor, and peritumoral zones were collected using the handheld confocal endomicroscope probe. Histological samples were acquired from matching imaged areas for correlation of tissue images.

Results

In vivo NIR wavelength confocal endomicroscopy with ICG detects fluorescence of tumor cells. The NIR and ICG macroscopic imaging performed using a surgical microscope correlated generally to tumor and peritumor regions, but NIR confocal endomicroscopy performed using ICG revealed individual tumor cells and satellites within peritumoral tissue; a definitive tumor border; and striking fluorescent microvascular, cellular, and subcellular structures (for example, mitoses, nuclei) in various tumor regions correlating with standard clinical histological features and known tissue architecture.

Conclusions

Macroscopic fluorescence was effective for gross tumor detection, but NIR confocal endomicroscopy performed using ICG enhanced sensitivity of tumor detection, providing real-time true microscopic histological information precisely related to the site of imaging. This first-time use of such NIR technology to detect cancer suggests that combined macroscopic and microscopic in vivo ICG imaging could allow interactive identification of microscopic tumor cell infiltration into the brain, substantially improving intraoperative decisions.

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Nikolay L. Martirosyan, Joseph Georges, Jennifer M. Eschbacher, Daniel D. Cavalcanti, Ali M. Elhadi, Mohammed G. Abdelwahab, Adrienne C. Scheck, Peter Nakaji, Robert F. Spetzler and Mark C. Preul

Object

The authors sought to assess the feasibility of a handheld visible-wavelength confocal endomicroscope imaging system (Optiscan 5.1, Optiscan Pty., Ltd.) using a variety of rapid-acting fluorophores to provide histological information on gliomas, tumor margins, and normal brain in animal models.

Methods

Mice (n = 25) implanted with GL261 cells were used to image fluorescein sodium (FNa), 5-aminolevulinic acid (5-ALA), acridine orange (AO), acriflavine (AF), and cresyl violet (CV). A U251 glioma xenograft model in rats (n = 5) was used to image sulforhodamine 101 (SR101). A swine (n = 3) model with AO was used to identify confocal features of normal brain. Images of normal brain, obvious tumor, and peritumoral zones were collected using the handheld confocal endomicroscope. Histological samples were acquired through biopsies from matched imaging areas. Samples were visualized with a benchtop confocal microscope. Histopathological features in corresponding confocal images and photomicrographs of H & E–stained tissues were reviewed.

Results

Fluorescence induced by FNa, 5-ALA, AO, AF, CV, and SR101 and detected with the confocal endomicroscope allowed interpretation of histological features. Confocal endomicroscopy revealed satellite tumor cells within peritumoral tissue, a definitive tumor border, and striking fluorescent cellular and subcellular structures. Fluorescence in various tumor regions correlated with standard histology and known tissue architecture. Characteristic features of different areas of normal brain were identified as well.

Conclusions

Confocal endomicroscopy provided rapid histological information precisely related to the site of microscopic imaging with imaging characteristics of cells related to the unique labeling features of the fluorophores. Although experimental with further clinical trial validation required, these data suggest that intraoperative confocal imaging can help to distinguish normal brain from tumor and tumor margin and may have application in improving intraoperative decisions during resection of brain tumors.

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Kris A. Smith, Lynn S. Ashby, L. Fernando Gonzalez, David G. Brachman, Terry Thomas, Stephen W. Coons, Matthew Battaglia and Adrienne C. Scheck

Object

The purpose of this study was to determine whether increased local control and improved survival can be achieved in patients with glioblastoma multiformes (GBMs) who undergo aggressive resection, Gliadel wafer implantation, Gamma Knife radiosurgery (GKS), and fractionated radiotherapy (RT) as the initial treatment.

Methods

Thirty patients with radiographically suspected GBMs were screened for enrollment in a Phase I/II prospective clinical trial. Twenty-seven patients were eligible and underwent gross-total resection and Gliadel wafer implantation. Gamma Knife radiosurgery (12 Gy at 50%) was administered to the resection cavity within 2 weeks of surgery. Patients then received standard fractionated RT (total dose 60 Gy over 6 weeks). Temozolomide was prescribed for patients at the time of recurrence. Surveillance MR imaging, neurological examination, and quality-of-life evaluations were performed at 2-month intervals. To estimate the potential effects on the DNA repair mechanism, tumor tissue was analyzed with methylation-specific polymerase chain reaction analysis and immunohistochemical assays for MGMT gene promoter methylation and protein expression.

Results

The median survival for all patients was 50 weeks and the 2-year survival rate was 22%. When stratified into standard and high-risk patient groups, the median survivals were 76 and 33 weeks, respectively. Two patients remain alive at the time of this report with no clinical or radiographic evidence of disease at > 189 and 239 weeks posttreatment and excellent performance status. Local tumor control was achieved in 53% of patients, and local failure occurred in 47%. No acute early toxicity was noted; however, delayed symptomatic radionecrosis occurred in 47% of patients, which required repeated operations 9–24 months after the initial treatment. Delayed hydrocephalus requiring ventriculoperitoneal shunt placement occurred in 47% of patients. There was a significant difference in survival between patients whose tumors contained the methylated and unmethylated MGMT promoter, 103 versus 45 weeks, respectively (p = 0.0009, log-rank test).

Conclusions

The combination of aggressive resection, Gliadel wafer implantation, and GKS in addition to standard fractionated RT in selected patients resulted in increased local control and increased survival compared with a historical control group treated with surgery and involved-field RT alone. Delayed focal radionecrosis was increased to 47% in this series and was managed with steroids and repeated resection. Aggressive local tumor control with these multimodal therapies should be approached judiciously for a select group of high performance patients and the probability of developing symptomatic radionecrosis requiring surgery should be anticipated and fully disclosed to patients who undergo this treatment.

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Oral Presentations

2010 AANS Annual Meeting Philadelphia, Pennsylvania May 1–5, 2010