The Frozen Brain State of Cryptococcus gattii: A Globe-Trotting, Tropical, Neurotropic Fungus.

Initially reported in tropical regions, Cryptococcus gattii infection is now diagnosed globally. Methods: case report; Literature review. Although initial reports described outbreaks of pulmonary and central nervous system (CNS) disease in tropical regions such as Australia and New Guinea, it is now clear that Cryptococcus gattii is a global, neurotropic pathogen. In contrast with C. neoformans, C. gattii patients are more likely to present with cryptococcomas in the brain and lungs and are often HIV negative. Imaging findings can mimick cancer leading to delays in diagnosis and definitive treatment. Some experts have speculated that the spread of C. gattii is due to climate change, newly recognized genotypes that cause disease in temperate zones (genotype VGII), international travel, and improved awareness among physicians and veterinarians. We emphasize neurocritical and neurosurgical management, because patients with CNS involvement often have high intracranial pressures (ICP). Cryptococcus gattii patients often have elevated ICP without 'red flag' radiographic signs of elevated ICP such as ventriculomegaly, cerebral edema, or effaced basal cisterns. Therefore, diagnosis of high ICP should be suspected based on clinical symptoms such as incapacitating headaches, progressive visual loss and associated papilledema, and then confirmed by measuring the opening pressure with lumbar puncture (LP). Cerebral intraparenchymal deposition of the large cryptococcal polysaccharide capsule and cryptococcal organisms causes poor brain compliance leading to a 'frozen brain state.' Mortality rates and clinical outcomes are significantly improved with early diagnosis, antifungal therapies, steroids, and aggressive management of elevated ICP including cerebrospinal fluid (CSF) diversion by serial LP's, external ventricular drains and CSF shunts. Following institution of antifungal therapy, about 10% of patients can worsen due to immune reconstitution inflammatory syndrome which responds to steroids. We recommend neurocritical and neurosurgical management of C. gattii patients with CNS involvement and elevated ICP. There is often poor correlation between elevated ICP and neuroimaging due to the frozen brain state.

Surgical management of cerebral dural arteriovenous fistulae.

Dural arteriovenous fistulae are high flow, low resistance intracranial vascular malformations defined by an aberrant connection between an artery and dural vein or sinus. Symptomatology and presentation are highly dependent on location, generally categorized as supratentorial, tentorial, or infratentorial, and consist primarily of sequelae secondary to local venous hypertension, insufficiency, and cortical venous reflux. Surgery is generally reserved for high risk or persistently symptomatic lesions that are unamenable or unresponsive to endovascular therapy. For surgical lesions, familiarity with skull base approaches, specific fistula anatomy, and technical nuances based on fistula location offer patients the best chance of a favorable outcome.

Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics.

It is not understood why healthy tissues can exhibit varying levels of sensitivity to the same toxic stimuli. Using BH3 profiling, we find that mitochondria of many adult somatic tissues, including brain, heart, and kidneys, are profoundly refractory to pro-apoptotic signaling, leading to cellular resistance to cytotoxic chemotherapies and ionizing radiation. In contrast, mitochondria from these tissues in young mice and humans are primed for apoptosis, predisposing them to undergo cell death in response to genotoxic damage. While expression of the apoptotic protein machinery is nearly absent by adulthood, in young tissues its expression is driven by c-Myc, linking developmental growth to cell death. These differences may explain why pediatric cancer patients have a higher risk of developing treatment-associated toxicities.

Fractionated radiation therapy for vestibular schwannoma.

Vestibular schwannomas are the most common tumors of the cerebellopontine angle. Multiple management paradigms exist for patients with these benign tumors, including observation, microsurgery, stereotactic radiosurgery, and fractionated radiation therapy, or some combination of these. While the proper course of management is controversial, the goals of therapy are to achieve excellent local tumor control and optimize functional outcomes with as little treatment-related morbidity as possible. Decision-making is tailored to patient-specific factors such as tumor size, clinical presentation, patient age, and goals of hearing preservation. We review the literature in order to summarize the application of fractionated radiation therapy to this tumor entity, where it is used as a primary treatment or, more commonly, as an adjunct therapy. We also provide an overview of the use of fractionated radiation therapy for the preservation of hearing and facial function, and dosing and other technical considerations, in light of the indolent natural history of vestibular schwannomas. We also discuss potential risks associated with this treatment modality, including its effects on temporal bone structures and cranial nerves among other possible complications. Lastly, we outline future directions in this rapidly evolving segment of vestibular schwannoma therapy, which has benefited from the advent of intensity-modulated radiation therapy coupled with stereotactic localization.

Skull base chordomas: clinical features, prognostic factors, and therapeutics.

Chordomas of the skull base are one of the rarest intracranial malignancies that arise from ectopic remnants of embryonal notochod. The proximity of many chordomas to neurovascular structures makes gross total resection difficult, and the tendency for recurrence leads to the routine use of adjuvant postoperative radiation. Several surgical approaches are used ranging from extensive craniotomies to minimally invasive endonasal endoscopic approaches. In this review, the histopathology and epidemiology, imaging characteristics, surgical approaches, adjuvant therapies, prognostic factors, and molecular biology of chordomas are described.

Intracranial hemangiopericytoma: clinical experience and treatment considerations in a modern series of 40 adult patients.

INTRODUCTION: Intracranial hemangiopericytoma (HPC) is a malignant meningothelial tumor. Because of its rarity, few guidelines exist for optimal management. METHODS: University of California at San Francisco patients managed for intracranial HPC were compiled into a single database based on a retrospective review of patient records. Univariate and multivariate regression was performed to determine factors that independently predicted treatment outcomes. RESULTS: A total of 40 patients with intracranial HPC were treated from 1989 to 2010. Treatment and follow-up information was available for analysis on 35 patients. The median survival for all patients was 16.2 years after date of diagnosis, with 1-year, 5-year, and 10-year survival rates of 100%, 92%, and 68%, respectively. Nineteen patients (54%) had HPC recurrence. The median time until recurrence was 5 years, with 1-year, 5-year, and 10-year progression-free survival rates of 96%, 49%, and 28%, respectively. Seven patients (20%) developed extracranial metastasis. Tumor characteristics associated with earlier recurrence included size ≥6 cm (log-rank, P < .05) and nonskull base location (log-rank, P < .05). Strategies combining adjuvant radiation with tumor resection appeared to hinder tumor progression, but had no effect on overall survival or the development of metastasis. Greater extent of resection was associated with increased overall survival (log-rank, P < .05). CONCLUSIONS: Adjuvant radiation may show promise in preventing tumor progression, but recurrence remains a common treatment outcome regardless of initial strategy. When safe and feasible, gross total resection should be pursued as an initial surgical strategy to maximize overall survival. The propensity of these tumors to metastasize makes detailed staging imaging necessary.

Stereotactic radiosurgery for benign meningiomas.

Meningiomas are the second most common primary tumor of the brain. Surgical resection is the preferred treatment for easily accessible tumors that can be safely removed. However, many tumors arise deep within the skull base making complete surgical resection difficult or impossible. Stereotactic radiosurgery is a highly effective alternative to surgical resection that has been used as a primary therapy for benign meningiomas as well as an adjuvant treatment for residual or recurrent tumors. The 5-year tumor control rates for stereotactic radiosurgery are equivalent to gross-total resection with lower morbidity than surgery, especially for skull base lesions. Additionally, adjuvant treatment of subtotally resected tumors results in tumor control rates equivalent to gross-total resection. Stereotactic radiosurgery has been used extensively for the treatment of small and medium sized skull base meningiomas. This technique has also been applied to large meningiomas and superficial tumors such as convexity and parasagittal meningiomas. However, multiple studies demonstrate that tumor control is decreased for superficial lesions and with increasing tumor size. In addition, radiation toxicity increases with increasing tumor size and superficial location. Based on a thorough review of the literature, stereotactic radiosurgery should be considered the primary treatment for skull base meningiomas with high surgical risk and in cases of superficial meningiomas where surgery is contraindicated.

Management of recurrent intracranial hemangiopericytoma.

Intracranial hemangiopericytoma (HPC) is an aggressive meningothelial neoplasm. A particularly challenging aspect of management of patients with HPC is optimizing treatment for recurrence, progression, and extracranial metastasis. Here we describe a modern cohort of patients with recurrent HPC to better understand treatment strategies that may improve outcome. Patients managed at UCSF for recurrent intracranial HPC were compiled into a single database based on a retrospective review of patient records, including operative, radiologic, and clinic reports. Cox regression was performed to determine factors that independently predicted treatment outcomes. At UCSF, 14 patients with available treatment and follow-up data were seen for management of HPC recurrence. Eight patients underwent repeat surgical resection, of whom four received adjuvant external beam radiotherapy (EBRT), one received additional Gamma Knife radiosurgery (GKS), and one received brachytherapy. Radiosurgical intervention alone was utilized for recurrence in six patients, with four receiving GKS and two receiving CyberKnife. Nine patients suffered a second recurrence at a median time of 3.5 years following reintervention. Nine patients died following reintervention, with a median survival of 7.9 years following intervention for recurrence. In univariate analysis, factors associated with increased time to second recurrence included non-posterior fossa location (log rank, p < 0.05) and surgical resection with adjuvant EBRT (log rank, p < 0.05). The addition of adjuvant EBRT to surgical resection similarly extended overall survival compared to surgical resection alone (log rank, p < 0.05). GKS was associated with earlier second recurrence compared to surgically based strategies (log rank, p < 0.05). We conclude that when combined with surgical resection, EBRT appears promising in the extension of second recurrence-free survival and overall survival. This multimodality approach also appears to outperform GKS in extending time to second recurrence. Accordingly, when safe and feasible, surgical resection of recurrent HPC with adjuvant EBRT should be the first steps in management.

A comprehensive analysis of intracranial chordoma and survival: a systematic review.

OBJECTIVE: Despite the published information on cranial chordoma, most of the data regarding survival in these patients has come from a single institution. Here, we perform a systematic review of the literature to evaluate across multiple institutions the overall survival after treatment for intracranial chordoma. MATERIALS AND METHODS: We systematically analysed every study published in English and found a total of over 2000 patients being treated for intracranial chordoma. The overall 5-year and 10-year survivals in these patients were stratified according to the age (<5 years vs. >5 years and  <40 years vs. >40 years), treatment (surgery and radiation vs. surgery alone) and histological findings (chondroid vs. typical). Data were analysed via Pearson chi-square test and student t-test when appropriate. RESULTS: A total of 560 non-duplicated patients treated for cranial chordoma met inclusion criteria for this systematic analysis. The survival rate among these patients was 63% (299 patients) and 16% (176 patients) for 5-year and 10-year survivals, respectively. There was no difference in overall survival between the two groups when a cut-off age of 40 years was used (<40 years = 50% vs.  >40 years = 51% at 5-year survival; p = 0.1), but when 5 years was used as the cut-off age, then survival was better for patients in the group older than 5 years of age (<5 years = 14% vs.  >5 years = 66%; p = 0.001). There was no difference between 5-year survival in patients with chordoma with histological chondroid features and those with chordoma possessing typical histology (45% vs. 67%; p = 0.06). When patients who only received surgery were compared to those patients who were treated with surgical intervention in combination with adjuvant radiation treatment, no difference in survival rate was found (54% vs. 56% at 5 years; p = 0.8). CONCLUSION: The results of our systematic study provide data to predict the survival of intracranial chordoma patients across multiple institutions. Our data suggest that patients younger than 5 years of age may be associated with a worse prognosis, and adjuvant radiation therapy and histological type were not associated with the improvement of survival rates.

A critical evaluation of cystic features in primary glioblastoma as a prognostic factor for survival.

OBJECT: The presence of cystic features in glioblastoma (GBM) has been described as a favorable prognostic factor. The aim of this study was to determine the survival outcome in patients undergoing surgery for newly diagnosed primary GBM with a large cystic component as compared with a large cohort of patients with noncystic GBM, while controlling for well-characterized prognostic factors. METHODS: A retrospective review of 354 consecutive patients treated with resection of primary GBM was performed using medical records and imaging information obtained at the University of California, San Francisco from 2005 to 2009. Within this cohort, 37 patients with large cysts (≥ 50% of tumor) were identified. Clinical presentations and surgical outcomes were statistically compared between the cystic and noncystic patients. RESULTS: There were no statistically significant differences in clinical presentation between groups, including differences in age, sex, presenting symptoms, tumor location, or preoperative functional status, with the exception of tumor size, which was marginally larger in the cystic group. Surgical outcomes, including extent of resection and postoperative functional status, were equivalent. The median actuarial survival for the patients with cystic GBM was 17.0 months (95% CI 12.6-21.3 months), and the median survival for patients with noncystic GBM was 15.9 months (95% CI 14.6-17.2 months). There was no significant between-groups difference in survival (p = 0.99, log-rank test). A Cox multivariate regression model was constructed, which identified only age and extent of resection as independent predictors of survival. The presence of a cyst was not a statistically significant prognostic factor. CONCLUSIONS: This study, comprising the largest series of cases of primary cystic GBM reported in the literature to date, demonstrates that the presence of a large cyst in patients with GBM does not significantly affect overall survival as compared with survival in patients without a cyst. Preoperative discussions with patients with GBM should focus on validated prognostic factors. The presence of cystic features does not confer a survival advantage.

Implications of cystic features in vestibular schwannomas of patients undergoing microsurgical resection.

BACKGROUND: Cystic vestibular schwannomas (VSs) are described as being more aggressive than solid tumors. OBJECTIVE: We examined 468 VS patients to evaluate whether the presence of cystic components in VSs may be an important feature for predicting postoperative outcome. METHODS: We selected all VS patients from a prospectively collected database (1984-2009) who underwent microsurgical resection for VS. Hearing data were analyzed using American Association of Otolaryngology-Head and Neck Surgery. Facial nerve dysfunction was analyzed using the House-Brackmann scale. We used univariate comparisons to determine the clinical impact of cystic changes on preoperative and postsurgical hearing and facial nerve preservation. RESULTS: We identified 58 patients (11%) with cystic changes and 410 patients with solid VSs. In this analysis, cystic VS patients tended to have larger tumors (78% of patients with >2.0 cm extrameatal extension) compared with the solid VS group, which consisted of many smaller and medium-sized tumors (P < .0001). Univariate analyses found that tumors with cystic changes did not lead to worse rates of preoperative hearing loss (χ(2), P = not significant) compared with solid VSs. Cystic changes conferred worse postoperative hearing in patients with medium-sized tumors (P = .035). Cystic changes also did not significantly affect facial nerve outcomes (χ(2), P = not significant). CONCLUSION: Cystic tumors tend to be larger than noncystic tumors and affect outcomes by reducing the rate at which hearing preservation is attempted and by worsening hearing outcome in medium-sized tumors. Further, peripheral cysts cause lower rates of hearing preservation compared with centrally located cysts.

The next step: innovative molecular targeted therapies for treatment of intracranial chordoma patients.

BACKGROUND: Chordomas are rare, locally aggressive malignancies that often exhibit an insidious natural history and are difficult to eradicate. Surgery and radiotherapy are the treatment mainstays of chordoma, but the chance of local recurrence remains high. Patients who relapse or cannot undergo a complete en bloc resection generally have a poor prognosis. New agents for postoperative adjuvant treatment of chordomas are needed. OBJECTIVE: To highlight potential clinical trials that could evolve from new insights into the molecular biology of chordoma. METHODS: We performed a review of recent studies published in the literature that have begun to characterize the molecular features of chordoma, and with this knowledge, several targets for potential clinical therapies have been determined. RESULTS: Several receptor tyrosine kinases and their downstream signaling cascades show dysregulation in chordoma and represent attractive targets for future therapeutic interventions. The pathways shown to be of particular importance in chordoma involve the platelet-derived growth factor receptor, epidermal growth factor receptor, hepatocyte growth factor receptor, and common downstream cascade of phosphoinositide 3-kinases, Akt, and mammalian target of rapamycin. CONCLUSION: Recent findings characterizing the molecular biology of chordoma have illuminated multiple possible targets for future clinical trials. The availability of inhibitors against these aberrant pathways makes clinical trials with chordoma both feasible and immediately realizable. Additionally, we emphasize the rationale for combination therapy when implementing molecular therapy in chordoma and other cancers.

Surgical resection and adjuvant radiotherapy for a large pineal hemangiopericytoma.

Hemangiopericytoma of the pineal region is exceedingly rare. We describe a patient with a large pineal region hemangiopericytoma who underwent a third ventriculostomy followed by a gross total resection by a unilateral interhemispheric approach with adjuvant radiotherapy. The patient remains recurrence free 4 years after treatment.

Pediatric intracranial aneurysms.

Intracranial pediatric aneurysms arising in children are rare. The treatment of these lesions requires both an understanding of their unique features as well as surgical, interventional, and pediatric critical care expertise offered through a multidisciplinary setting. The patient population, clinical presentation, complications, and trends in treatments are discussed in this article.

Cranial chondrosarcoma and recurrence.

The literature regarding recurrences in patients with cranial chondrosarcoma is limited to small series performed at single institutions, raising the question if these data precisely reflect the true recurrence of this tumor for guiding the clinician in the management of these patients. An extensive systematic review of the English literature was performed. The patients were stratified according to treatment modality, treatment history, histological subtype, and histological grade, and the recurrence rates were analyzed. A total of 560 patients treated for cranial chondrosarcoma were included. Five-year recurrence rate among all patients was 22% with median follow-up of 60 months and median disease-free interval of 16 months. Tumor recurrence was more common in patients who only received surgery or had mesenchymal subtype tumors. Our systematic review closely reflects the actuarial recurrence rate and provides predictive factors in the recurrence of cranial chondrosarcoma.

Monitoring immune responses after glioma vaccine immunotherapy.

Immunotherapy provides the ideal candidate of therapeutic attack against malignant gliomas because it allows for targeting of cancer cells without the potential for nonspecific toxicity. This is important when glial tumor cells spread far through normal brain tissue. Current vaccine therapies are in clinical trials and are showing beneficial responses. Given that the inflammatory response may make serial radiographic imaging more difficult to interpret, newer methodologies of immunomonitoring must be developed to assess the biologic efficacy of these immunotherapies. This article reviews methods of monitoring the immune system after vaccination against malignant gliomas. Improvements in immunomonitoring should lead to an increase in the efficiency of identifying viable avenues of therapeutic research, and assess the efficacy of those currently employed.

Adjuvant radiation therapy and chondroid chordoma subtype are associated with a lower tumor recurrence rate of cranial chordoma.

Cranial chordomas are rare tumors that have been difficult to study given their low prevalence. Individual case series with decades of data collection provide some insight into the pathobiology of this tumor and its responses to treatment. This meta-analysis is an attempt to aggregate the sum experiences and present a comprehensive review of their findings. We performed a comprehensive review of studies published in English language literature and found a total of over 2,000 patients treated for cranial chordoma. Patient information was then extracted from each paper and aggregated into a comprehensive database. The tumor recurrences in these patients were then stratified according to age (<21 vs. >21 years), histological findings (chondroid vs. typical) and treatment (surgery and radiation vs. surgery only). Data was analyzed via Pearson chi-square and t-test. A total of 464 non-duplicated patients from 121 articles treated for cranial chordoma met the inclusion criteria. The recurrence rate among all patients was 68% (314 patients) with an average disease-free interval of 45 months (median, 23 months). The mean follow-up time was 39 months (median, 27 months). The patients in younger group, patients with chordoma with chondroid histologic type, and patients who received surgery and adjuvant radiotherapy had significantly lower recurrence rate than their respective counterparts. The results of our systematic analysis provide useful data for practitioners in objectively summarizing the tumor recurrence in patients with cranial chordomas. Our data suggests that younger patients with chondroid type cranial chordoma treated with both surgery and radiation may have improved rates of tumor recurrence in the treatment of these tumors.

A systematic review of intracranial chondrosarcoma and survival.

Most data regarding survival in patients with chondrosarcoma are limited to case studies and small series performed at single institutions. A systematic review was performed to study the relationship between potential prognostic factors and survival. The survival rates were analyzed according to modality of treatment, treatment history, histological subtype, and histological grade. A total of 560 patients with intracranial chondrosarcoma were analyzed. Median follow-up time was 60 months. The 5-year mortality among all patients was 11.5% with median survival of 24 months. Mortality at 5 years was significantly greater for patients with tumors of higher grade, or of the mesenchymal subtype, or who had received surgical resection alone. The results of our systematic review provide useful data in predicting survival among intracranial chondrosarcoma patients.