Daniel T. Nagasawa

The molecular genetics and tumor pathogenesis of meningiomas and the future directions of meningioma treatments

Meningiomas are mostly benign, slow-growing tumors of the CNS that originate from arachnoidal cap cells. While monosomy 22 is the most frequent genetic abnormality found in meningiomas, a multitude of other aberrant chromosomal alterations, signaling pathways, and growth factors have been implicated in its pathogenesis. Losses on 22q12.2, a region encoding the tumor suppressor gene merlin, represent the most common genetic alterations in early meningioma formation. Malignant meningioma progression, however, is associated with more complex karyotypes and greater genetic instability. Cytogenetic studies of atypical and anaplastic meningiomas revealed gains and losses on chromosomes 9, 10, 14, and 18, with amplifications on chromosome 17. However, the specific gene targets in a majority of these chromosomal abnormalities remain elusive. Studies have also implicated a myriad of aberrant signaling pathways involved with meningioma tumorigenesis, including those involved with proliferation, angiogenesis, and autocrine loops. Understanding these disrupted pathways will aid in deciphering the relationship between various genetic changes and their downstream effects on meningioma pathogenesis. Despite advancements in our understanding of meningioma pathogenesis, the conventional treatments, including surgery, radiotherapy, and stereotactic radiosurgery, have remained largely stagnant. Surgery and radiation therapy are curative in the majority of lesions, yet treatment remains challenging for meningiomas that are recurrent, aggressive, or refractory to conventional treatments. Future therapies will include combinations of targeted molecular agents as a result of continued progress in the understanding of genetic and biological changes associated with meningiomas.

Temozolomide and Other Potential Agents for the Treatment of Glioblastoma Multiforme

This article provides historical and recent perspectives related to the use of temozolomide for the treatment of glioblastoma multiforme. Temozolomide has quickly become part of the standard of care for the modern treatment of stage IV glioblastoma multiforme since its approval in 2005. Yet despite its improvements from previous therapies, median survival remains approximately 15 months, with a 2-year survival rate of 8% to 26%. The mechanism of action of this chemotherapeutic agent, conferred advantages and limitations, treatment resistance and rescue, and potential targets of future research are discussed.

Clinical characteristics and diagnostic imaging of epidermoid tumors

Epidermoid tumors are rare, benign congenital lesions which typically present between the third and fifth decades of life. They are thought to originate from ectodermal cells misplaced during neural tube formation and separation. While epidermoids may present anywhere in the cranial vault, they are characteristically located intradurally and in a paramedian position within the cerebellopontine angle and parasellar regions. Although imaging results may vary depending upon cystic content, CT scanning generally reveals a well-circumscribed, nonenhancing, lobulated, hypodense mass. They are hypointense on T1-weighted MRI, and hyperintense on T2-weighted MRI, diffusion-weighted imaging and fluid-attenuated inversion recovery sequences. The use of appropriate neuroimaging should be utilized to differentiate epidermoids from other intracranial lesions. While gross total resection of these tumors is the definitive treatment to prevent recurrence and aseptic meningitis, a subtotal resection may be necessary to preserve neurological function.

Leptomeningeal spinal metastases from glioblastoma multiforme: treatment and management of an uncommon manifestation of disease.

Glioblastoma multiforme (GBM) is one of the most common and aggressive primary brain tumors, composing 12%-20% of all intracranial tumors in adults. Average life expectancy is merely 12-14 months following initial diagnosis. Patients with this neoplasm have one of the worst 5-year survival rates among all cancers despite aggressive multimodal treatment consisting of maximal tumor resection, radiation therapy, and adjuvant chemotherapy. With recent advancements in management strategies, there has been improvement in the overall trend in patient outcomes; however, recurrence remains nearly inevitable. While most tumors recur locally, metastases to distal locations have become more common. Specifically, the last decade has seen an increased incidence of spinal metastases, representing an emerging complication in patients with intracranial GBM. However, the literature regarding prevention strategies and the presentation of spinal metastases has remained scarce. As local control of primary lesions continues to improve, more cases of spinal metastases are likely to be seen. In this review the authors present a new case of metastatic GBM to the L-5 nerve root, and they summarize previous cases of intracranial GBM with leptomeningeal spinal metastatic disease. They also characterize key features of this disease presentation and discuss areas of future investigation necessary for enhanced prevention and treatment of this complication.

Utilizing virtual and augmented reality for educational and clinical enhancements in neurosurgery

Neurosurgery has undergone a technological revolution over the past several decades, from trephination to image-guided navigation. Advancements in virtual reality (VR) and augmented reality (AR) represent some of the newest modalities being integrated into neurosurgical practice and resident education. In this review, we present a historical perspective of the development of VR and AR technologies, analyze its current uses, and discuss its emerging applications in the field of neurosurgery.

Complications associated with the treatment for spinal ependymomas

Spinal cord ependymomas are rare neoplasms, comprising approximately 5% of all CNS tumors and 15% of all spinal cord tumors. Although surgery was once reserved for diagnosis alone, the evolution of surgical practices has elevated resection to the treatment of choice for these lesions. While technological advances continue to improve the capacity for gross-total resections and thus decrease the risk of recurrence, ependymoma spinal surgery still contains a variety of potential complications. The presence of neurological deficits and deterioration are not uncommonly associated with spinal cord ependymoma surgery, including sensory loss, dorsal column dysfunction, dysesthetic syndrome, and bowel and bladder dysfunction, particularly in the immediate postoperative period. Surgical treatment may also lead to wound complications and CSF leaks, with increased risk when radiotherapy has been involved. Radiation therapy may also predispose patients to radiation myelopathy and ultimately result in neurological damage. Additionally, resections of spinal ependymomas have been associated with postoperative spinal instability and deformities, particularly in the pediatric population. Despite the advances in microsurgical techniques and intraoperative cord monitoring modalities, there remain a number of serious complications related to the treatment of spinal ependymoma tumors. Identification and acknowledgment of these potential problems may assist in their prevention, early detection, and increased quality of life for patients afflicted with this disease.

Prognostic factors for post-operative seizure outcomes after cavernous malformation treatment

Although patients with cerebral cavernous malformations may remain asymptomatic, they often present with neurological symptoms of headache, hemorrhage and, most commonly, seizure. A review of articles published between 1985 and 2009 was performed to elucidate the prognostic factors which may predict post-operative seizure control. The following characteristics were found to consistently correlate with a more favorable post-operative seizure-free outcome: (i) extent of resection of the cavernous malformation and its surrounding hemosiderin rim; (ii) single or sporadic seizures compared to chronic epilepsy; (iii) illness duration less than 1 or 2 years; and (iv) size of cavernous malformation less than 1.5 cm. Radiosurgery may achieve post-operative seizure-free rates ranging from 25% to 64.3%, and may be an alternative to surgical resection for deep or eloquent cavernous malformations, or those in patients with co-morbidities. There was no clear association between post-operative seizures and either lesion location, age, or gender. Prognostic features of cavernous malformations should be utilized for both guidance of lesion treatment, and prediction of post-operative seizure outcomes.

The role of regulatory T-cells in glioma immunology.

Despite recent advances in treatment, the prognosis for glioblastoma multiforme (GBM) remains poor. The lack of response to treatment in GBM patients may be attributed to the immunosuppressed microenvironment that is characteristic of invasive glioma. Regulatory T-cells (Tregs) are immunosuppressive T-cells that normally prevent autoimmunity when the human immune response is evoked; however, there have been strong correlations between glioma-induced immunosuppression and Tregs. In fact, induction of Treg activity has been correlated with glioma development in both murine models and patients. While the exact mechanisms by which regulatory T-cells function require further elucidation, various cytokines such as interleukin-10 (IL-10) and transforming growth factor-β (TFG-β) have been implicated in these processes and are currently under investigation. In addition, hypoxia is characteristic of tumor development and is also correlated with downstream induction of Tregs. Due to the poor prognosis associated with immunosuppression in glioma patients, Tregs remain a promising area for immunotherapeutic research.

Intraoperative neuromonitoring techniques in the surgical management of acoustic neuromas

Unfavorable outcomes such as facial paralysis and deafness were once unfortunate probable complications following resection of acoustic neuromas. However, the implementation of intraoperative neuromonitoring during acoustic neuroma surgery has demonstrated placing more emphasis on quality of life and preserving neurological function. A modern review demonstrates a great degree of recent success in this regard. In facial nerve monitoring, the use of modern electromyography along with improvements in microneurosurgery has significantly improved preservation. Recent studies have evaluated the use of video monitoring as an adjunctive tool to further improve outcomes for patients undergoing surgery. Vestibulocochlear nerve monitoring has also been extensively studied, with the most popular techniques including brainstem auditory evoked potential monitoring, electrocochleography, and direct compound nerve action potential monitoring. Among them, direct recording remains the most promising and preferred monitoring method for functional acoustic preservation. However, when compared with postoperative facial nerve function, the hearing preservation is only maintained at a lower rate. Here, the authors analyze the major intraoperative neuromonitoring techniques available for acoustic neuroma resection.

Chromosomal alterations, prognostic factors, and targeted molecular therapies for malignant meningiomas

Meningiomas are the second most common intracranial neoplasm in adults and originate from arachnoidal cap cells. Malignant meningiomas are resistant to conventional treatments such as surgery, chemotherapy, and radiotherapy. Unlike benign meningiomas, atypical and anaplastic tumors generally display more complex karyotypes associated with aggressive behavior. While these chromosomal anomalies are associated with greater malignancy in meningiomas, the specific genes involved remain unknown. Malignant meningiomas are characterized by increased tumor aggressiveness, rapid recurrence, local invasion, atypical histological appearance, and a high mitotic index. Potential prognostic factors include extent of resection, treatment with radiotherapy or stereotactic radiosurgery, Ki-67/MIB-1 labeling index, p53 overexpression, percentage of tumor cells in the S-phase, telomerase activity, and numerous genetic expression profiles. A greater understanding of prognostic factors and molecular markers involved in critical signaling pathways may aid in the identification of novel therapeutic targets. As such, further studies are needed to establish reliable prognostic factors and develop more effective treatments for malignant meningiomas.