Glioblastoma (GBM) is the most common type of malignant primary brain tumor in adults. It is a uniformly fatal disease (median overall survival 16 months) even with aggressive resection and an adjuvant temozolomide-based chemoradiation regimen. Age remains an independent risk factor for a poor prognosis. Several factors contribute to the dismal outcomes in the elderly population with GBM, including poor baseline health status, differences in underlying genomic alterations, and variability in the surgical and medical management of this subpopulation. The latter arises from a lack of adequate representation of elderly patients in clinical trials, resulting in limited data on the response of this subpopulation to standard treatment. Results from retrospective and some prospective studies have indicated that resection of only contrast-enhancing lesions and administration of hypofractionated radiotherapy in combination with temozolomide are effective strategies for optimizing survival while maintaining baseline quality of life in elderly GBM patients; however, survival remains dismal relative to that in a younger cohort. Here, the authors present historical context for the current strategies used for the multimodal management (surgical and medical) of elderly patients with GBM. Furthermore, they provide insights into elderly GBM patient–specific genomic signatures such as isocitrate dehydrogenase 1/2 (IDH1/2) wildtype status, telomerase reverse transcriptase promoter (TERTp) mutations, and somatic copy number alterations including CDK4/MDM2 coamplification, which are becoming better understood and could be utilized in a clinical trial design and patient stratification to guide the development of more effective adjuvant therapies specifically for elderly GBM patients.
Chibawanye I. Ene, Patrick J. Cimino, Howard A. Fine, and Eric C. Holland
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.
Anne-Marie Bleau, Brian M. Howard, Lauren A. Taylor, Demirkan Gursel, Jeffrey P. Greenfield, H. Y. Lim Tung, Eric C. Holland, and John A. Boockvar
Brain tumor stem cells (TSCs) hypothetically drive the malignant phenotype of glioblastoma multiforme (GBM), and evidence suggests that a better understanding of these TSCs will have profound implications for treating gliomas. When grown in vitro, putative TSCs grow as a solid sphere, making their subsequent characterization, particularly the cells within the center of the sphere, difficult. Therefore, the purpose of this study was to develop a new method to better understand the proteomic profile of the entire population of cells within a sphere.
Tumor specimens from patients with confirmed GBM and glioma models in mice were mechanically and enzymatically dissociated and grown in traditional stem cell medium to generate neurospheres. The neurospheres were then embedded in freezing medium, cryosectioned, and analyzed with immunofluorescence.
By sectioning neurospheres as thinly as 5 μm, the authors overcame many of the problems associated with immunolabeling whole neurospheres, such as antibody penetration into the core of the sphere and intense background fluorescence that obscures the specificity of immunoreactivity. Moreover, the small quantity of material required and the speed with which this cryosectioning and immunolabeling technique can be performed make it an attractive tool for the rapid assessment of TSC character.
This study is the first to show that cryosectioning of neurospheres derived from glioma models in mice and GBM in humans is a feasible method of better defining the stem cell profile of a glioma.
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
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.
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.
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.
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.
Proceedings from the National Institutes of Health workshop
Elizabeth B. Claus, May Abdel-Wahab, Peter C. Burger, Herbert H. Engelhard, David W. Ellison, Nicholas Gaiano, David H. Gutmann, Daniel A. Heck Jr., Eric C. Holland, George I. Jallo, Carol Kruchko, Larry E. Kun, Bernard L. Maria, Zoran Rumboldt, Daniela Seminara, Giovanna M. Spinella, Linda Stophel, Robert Wechsler-Reya, Margaret Wrensch, and Richard J. Gilbertson
The relative rarity of spinal cord tumors has hampered the study of these uncommon nervous system malignancies. Consequently, the understanding of the fundamental biology and optimal treatment of spinal cord tumors is limited, and these cancers continue to inflict considerable morbidity and mortality in children and adults. As a first step to improving the outcome of patients affected with spinal cord tumors, the National Institutes of Health Office of Rare Diseases Research in cooperation with the National Cancer Institute and the National Institute of Neurological Disorders and Stroke convened a workshop to discuss the current status of research and clinical management of these tumors. The overall goal of this meeting was to initiate a process that would eventually translate fundamental basic science research into improved clinical care for this group of patients. Investigational priorities for each of these areas were established, and the opportunities for future multidisciplinary research collaborations were identified.