Cory Adamson

Glioblastoma multiforme: a review of where we have been and where we are going

Malignant gliomas such as glioblastoma multiforme (GBM) present some of the greatest challenges in the management of cancer patients worldwide, despite notable recent achievements in oncology. Even with aggressive surgical resections using state-of-the-art preoperative and intraoperative neuroimaging, along with recent advances in radiotherapy and chemotherapy, the prognosis for GBM patients remains dismal: median survival after diagnosis is about 14 months. Established good prognostic factors are limited, but include young age, high Karnofsky Performance Status (KPS), high mini-mental status examination score, O6-methylguanine methyltransferase promoter methylation, and resection of > 98% of the tumor. Standard treatment includes resection, followed by concurrent chemotherapy and radiotherapy. GBM research is being conducted worldwide at a remarkable pace, with some of the more recent promising studies focused on identification of aberrant genetic events and signaling pathways, tumor stem cell identification and characterization, modulation of tumor immunological responses, combination therapies, and understanding of the rare long-term survivors. Past treatment strategies have failed for various reasons; however, newer strategies in trials today and on the horizon encourage optimism. To help illustrate ‘where we have been’ with this fatal disease and ‘where we are going’ with contemporary studies, we include in this review a detailed history of Phase III clinical trials for GBM, with a final emphasis on exciting new treatment strategies that offer hope for future GBM therapy.

Glioblastoma Multiforme Oncogenomics and Signaling Pathways

In the adult population, glioblastoma multiforme is one of the most common primary brain tumors encountered. Unfortunately, this highly malignant tumor represents over 50% of all types of primary central nervous system gliomas. The vast majority of GBMs develops quite rapidly without clinical, radiological, or morphologic evidence of a less malignant precursor lesion (primary or de novo GBMs), as compared to secondary GBMs that develop slowly by progression from diffuse low-grade astrocytomas. These GBM subtypes must be kept in mind because they may constitute distinct disease entities. Even though they look histologically quite similar, they likely involve different genetic alterations and signaling pathways. Decades of surgical therapy, radiotherapy, and chemotherapy have failed to drastically change survival. Clearly, we do not fully understand this tumor; however, the exciting genetic revolution in glioma research over the past decade is providing a promising outlook for exploring this tumor at the genetic level. Science has begun to elucidate the numerous genetic alterations and critical signaling pathways, and it has opened new exciting areas of research such as glioma stem cell biology and neoangiogenesis. This work has already begun to improve our understanding of GBM cell proliferation, migration, and invasion. Indeed, exciting novel targeted therapies are making their way to clinical trials based on this increased knowledge. This review provides the current understanding of GBM oncogenomics, signaling pathways, and glioma stem cell biology and discusses the potential new therapeutic targets on the horizon.

Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage–induced secondary brain injury and as potential targets for intervention

Intracerebral hemorrhage (ICH) is a subtype of stoke that may cause significant morbidity and mortality. Brain injury due to ICH initially occurs within the first few hours as a result of mass effect due to hematoma formation. However, there is increasing interest in the mechanisms of secondary brain injury as many patients continue to deteriorate clinically despite no signs of rehemorrhage or hematoma expansion. This continued insult after primary hemorrhage is believed to be mediated by the cytotoxic, excitotoxic, oxidative, and inflammatory effects of intraparenchymal blood. The main factors responsible for this injury are thrombin and erythrocyte contents such as hemoglobin. Therapies including thrombin inhibitors, N-methyl-D-aspartate antagonists, chelators to bind free iron, and antiinflammatory drugs are currently under investigation for reducing this secondary brain injury. This review will discuss the molecular mechanisms of brain injury as a result of intraparenchymal blood, potential targets for therapeutic intervention, and treatment strategies currently in development.

Vestibular schwannomas in the modern era: epidemiology, treatment trends, and disparities in management.

OBJECT There are a variety of treatment options for the management of vestibular schwannomas (VSs), including microsurgical resection, radiotherapy, and observation. Although the choice of treatment is dependent on various patient factors, physician bias has been shown to significantly affect treatment choice for VS. In this study the authors describe the current epidemiology of VS and treatment trends in the US in the modern era. They also illustrate patient and tumor characteristics and elucidate their effect on tumor management. METHODS Patients diagnosed with VS were identified through the Surveillance, Epidemiology, and End Results database, spanning the years 2004-2009. Age-adjusted incidence rates were calculated and adjusted using the 2000 US standard population. The chi-square and Student t-tests were used to evaluate differences between patient and tumor characteristics. Multivariate logistic regression was performed to determine the effects of various patient and tumor characteristics on the choice of tumor treatment. RESULTS A total of 6225 patients with VSs treated between 2004 and 2009 were identified. The overall incidence rate was 1.2 per 100,000 population per year. The median age of patients with VS was 55 years, with the majority of patients being Caucasian (83.16%). Of all patients, 3053 (49.04%) received surgery only, with 1466 (23.55%) receiving radiotherapy alone. Both surgery and radiation were only used in 123 patients (1.98%), with 1504 patients not undergoing any treatment (24.16%). Increasing age correlated with decreased use of surgery (OR 0.95, 95% CI 0.95-0.96; p<0.0001), whereas increasing tumor size was associated with the increased use of surgery (OR 1.04, 95% CI 1.04-1.05; p<0.0001). Older age was associated with an increased likelihood of conservative management (OR 1.04, 95% CI 1.04-1.05; p<0.0001). Racial disparities were also seen, with African American patients being significantly less likely to receive surgical treatment compared with Caucasians (OR 0.50, 95% CI 0.35-0.70; p<0.0001), despite having larger tumors at diagnosis. CONCLUSIONS The incidence of vestibular schwannomas in the US is 1.2 per 100,000 population per year. Although many studies have demonstrated improved outcomes with the use of radiotherapy for small- to medium-sized VSs, surgery is still the most commonly used treatment modality for these tumors. Racial disparities also exist in the treatment of VSs, with African American patients being half as likely to receive surgery and nearly twice as likely to have their VSs managed conservatively despite presenting with larger tumors. Further studies are needed to elucidate the reasons for treatment disparities and investigate the nationwide trend of resection for the treatment of small VSs.

Worse outcomes for patients undergoing brain tumor and cerebrovascular procedures following the ACGME resident duty-hour restrictions.

OBJECT On July 1, 2003, the Accreditation Council for Graduate Medical Education (ACGME) implemented duty-hour restrictions for resident physicians due to concerns for patient and resident safety. Though duty-hour restrictions have increased resident quality of life, studies have shown mixed results with respect to patient outcomes. In this study, the authors have evaluated the effect of duty-hour restrictions on morbidity, mortality, length of stay, and charges in patients who underwent brain tumor and cerebrovascular procedures. METHODS The Nationwide Inpatient Sample was used to evaluate the effect of duty-hour restrictions on complications, mortality, length of stay, and charges by comparing the pre-reform (2000-2002) and post-reform (2005-2008) periods. Outcomes were compared between nonteaching and teaching hospitals using a difference-in-differences (DID) method. RESULTS A total of 90,648 patients were included in the analysis. The overall complication rate was 11.7%, with the rates not significantly differing between the pre- and post-duty hour eras (p = 0.26). Examination of hospital teaching status revealed that complication rates decreased in nonteaching hospitals (12.1% vs 10.4%, p = 0.0004) and remained stable in teaching institutions (11.8% vs 11.9%, p = 0.73) in the post-reform era. Multivariate analysis demonstrated a significantly higher complication risk in teaching institutions (OR 1.33 [95% CI 1.11-1.59], p = 0.0022), with no significant change in nonteaching hospitals (OR 1.11 [95% CI 0.91-1.37], p = 0.31). A DID analysis to compare the magnitude in change between teaching and nonteaching institutions revealed that teaching hospitals had a significantly greater increase in complications during the post-reform era than nonteaching hospitals (p = 0.040). The overall mortality rate was 3.0%, with a significant decrease occurring in the post-reform era in both nonteaching (5.0% vs 3.2%, p < 0.0001) and teaching (3.2% vs 2.3%, p < 0.0001) hospitals. DID analysis to compare the changes in mortality between groups did not reveal a significant difference (p = 0.40). The mean length of stay for all patients was 8.7 days, with hospital stay decreasing from 9.2 days to 8.3 days in the post-reform era (p < 0.0001). The DID analysis revealed a greater length of stay decrease in nonteaching hospitals than teaching institutions, which approached significance (p = 0.055). Patient charges significantly increased in the post-reform era for all patients, increasing from

Glioblastoma in the elderly: the effect of aggressive and modern therapies on survival

70,900 to

Treatment recommendations for primary extradural meningiomas

96,100 (p < 0.0001). The DID analysis did not reveal a significant difference between the changes in charges between teaching and nonteaching hospitals (p = 0.17). CONCLUSIONS The implementation of duty-hour restrictions correlated with an increased risk of postoperative complications for patients undergoing brain tumor and cerebrovascular neurosurgical procedures. Duty-hour reform may therefore be associated with worse patient outcomes, contrary to its intended purpose. Due to the critical condition of many neurosurgical patients, this patient population is most sensitive and likely to be negatively affected by proposed future increased restrictions.

A comprehensive analysis of 41 patients with rosette-forming glioneuronal tumors of the fourth ventricle

OBJECTIVE The prognosis of elderly patients with glioblastoma (GBM) is universally poor. Currently, few studies have examined postoperative outcomes and the effects of various modern therapies such as bevacizumab on survival in this patient population. In this study, the authors evaluated the effects of various factors on overall survival in a cohort of elderly patients with newly diagnosed GBM. METHODS A retrospective review was performed of elderly patients (≥ 65 years old) with newly diagnosed GBM treated between 2004 and 2010. Various characteristics were evaluated in univariate and multivariate stepwise models to examine their effects on complication risk and overall survival. RESULTS A total of 120 patients were included in the study. The median age was 71 years, and sex was distributed evenly. Patients had a median Karnofsky Performance Scale (KPS) score of 80 and a median of 2 neurological symptoms on presentation. The majority (53.3%) of the patients did not have any comorbidities. Tumors most frequently (43.3%) involved the temporal lobe, followed by the parietal (35.8%), frontal (32.5%), and occipital (15.8%) regions. The majority (57.5%) of the tumors involved eloquent structures. The median tumor size was 4.3 cm. Every patient underwent resection, and 63.3% underwent gross-total resection (GTR). The vast majority (97.3%) of the patients received the postoperative standard of care consisting of radiotherapy with concurrent temozolomide. The majority (59.3%) of patients received additional agents, most commonly consisting of bevacizumab (38.9%). The median survival for all patients was 12.0 months; 26.7% of patients experienced long-term (≥ 2-year) survival. The extent of resection was seen to significantly affect overall survival; patients who underwent GTR had a median survival of 14.1 months, whereas those who underwent subtotal resection had a survival of 9.6 months (p = 0.038). Examination of chemotherapeutic effects revealed that the use of bevacizumab compared with no bevacizumab (20.1 vs 7.9 months, respectively; p < 0.0001) and irinotecan compared with no irinotecan (18.0 vs 9.7 months, respectively; p = 0.027) significantly improved survival. Multivariate stepwise analysis revealed that older age (hazard ratio [HR] 1.06 [95% CI1.02-1.10]; p = 0.0077), a higher KPS score (HR 0.97 [95% CI 0.95-0.99]; p = 0.0082), and the use of bevacizumab (HR 0.51 [95% CI 0.31-0.83]; p = 0.0067) to be significantly associated with survival. CONCLUSION This study has demonstrated that GTR confers a modest survival benefit on elderly patients with GBM, suggesting that safe maximal resection is warranted. In addition, bevacizumab significantly increased the overall survival of these elderly patients with GBM; older age and preoperative KPS score also were significant prognostic factors. Although elderly patients with GBM have a poor prognosis, they may experience enhanced survival after the administration of the standard of care and the use of additional chemotherapeutics such as bevacizumab.

Low-grade astrocytomas: the prognostic value of fibrillary, gemistocytic, and protoplasmic tumor histology

Primary extradural meningiomas (PEMs) represent about 2% of all meningiomas and are often encountered by non‐neurosurgeons. These lesions typically present as enlarging, painless, benign masses that can be surgically cured. Imaging is critical for defining involvement of adjacent structures; however, diagnosis depends on classic histologic patterns. Treatment for benign PEMs (WHO I) consists of resection with wide margins, whereas adjuvant therapy after resection of atypical (WHO II) or malignant (WHO III) PEMs should be considered. By using the collective experience from our comprehensive cancer center, including neuro‐oncologists, neuroradiologists, and neurosurgeons, in addition to a complete literature review, the authors have established treatment guidelines not previously reported. This manuscript describes key features of these challenging tumors to aid in diagnosis, presents the largest published review of all reported PEMs (n = 163), and provides salient treatment guidelines to surgeons unfamiliar with these challenging tumors. Cancer 2011.

Outcome and prognostic factors in adult cerebellar glioblastoma

The rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle is a recently described, rare, and distinct tumor of the glioneuronal family. The presentation, natural history, and treatment response of these tumors has been unclear as there are no significant series of a sizeable population with long-term follow-up. We report a comprehensive analysis of 41 patients with RGNT to provide the most current understanding of this rare tumor. Treatment of these patients has consisted of resection via the transvermian and telovelar approaches, with one patient requiring radiotherapy due to tumor recurrence. Various unique imaging characteristics may allow for the preoperative identification of these tumors. Resection via the telovelar approach should be considered for symptomatic tumors and those that pose a risk of obstructive hydrocephalus. Due to their benign nature and low propensity for recurrence, subtotal resection may be appropriate for those that are adherent to the brainstem. Radiotherapy may be considered for patients with tumor recurrence.