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Christian A. Helland, Morten Lund-Johansen and Knut Wester

Object

The aim of this study was to examine the distribution of intracranial arachnoid cysts in a large and unselected patient population with special emphasis on sidedness and sex distribution.

Methods

In total, 299 patients with 305 arachnoid cysts were studied. These patients were consecutively referred to our department during a 20-year period from a well-defined geographical area with a stable population.

Results

There was a strong predilection (198 patients [66.2%]) for intracranial arachnoid cysts in the temporal fossa. Forty-two patients had cysts overlying the frontal convexity, 36 had cysts in the posterior fossa, and 23 patients had cysts in other, different locations. Of 269 cysts with clearly unilateral distribution, 163 were located on the left side and 106 on the right side. This difference resulted from the marked preponderance of temporal fossa cysts on the left side (left-to-right ratio 2.5:1; p < 0.0001 [adjusted < 0.0005]). For cysts in the cerebellopontine angle (CPA), there was preponderance on the right side (p = 0.001 [adjusted = 0.005]). Significantly more males than females had cysts in the temporal fossa (p = 0.002 [adjusted = 0.004]), whereas in the CPA a significant female preponderance was found (p = 0.016 [adjusted = 0.032]). For all other cyst locations, there was no difference between the 2 sexes.

Conclusions

Arachnoid cysts have a strong predilection for the temporal fossa. There is a sex dependency for some intracranial locations of arachnoid cysts, with temporal cysts occurring more frequently in men, and CPA cysts found more frequently in women. Furthermore, there is a strong location-related sidedness for arachnoid cysts, independent of patient sex. These findings and reports from the literature suggest a possible genetic component in the development of some arachnoid cysts.

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Jobin Kotakkathu Varughese, Cathrine Nansdal Breivik, Tore Wentzel-Larsen and Morten Lund-Johansen

Object

Small vestibular schwannomas (VSs) are often conservatively managed and treated only upon growth. Growth is usually reported in mm/year, but describing the growth of a 3D structure by a single diameter has been questioned. As a result, VS growth dynamics should be further investigated. In addition, baseline clinical parameters that could predict growth would be helpful. In this prospective study the authors aimed to describe growth dynamics in a cohort of conservatively managed VSs. They also compared different growth models and evaluated the ability of baseline parameters to predict future growth.

Methods

Between 2000 and 2006, 178 consecutive patients with unilateral de novo small-sized VSs identified among the Norwegian population of 4.8 million persons were referred to a tertiary care center and were included in a study protocol of conservative management. Tumor size was defined by MR imaging–based volume estimates and was recorded along with clinical data at regular visits. Mixed-effects models were used to analyze the relationships between observations. Three growth models were compared using statistical diagnostic tests: a mm/year–based model, a cm3/year–based model, and a volume doubling time (VDT)-based model. A receiver operating characteristic curve analysis was used to determine a cutoff for the VDT-based model for distinguishing growing and nongrowing tumors.

Results

A mean growth rate corresponding to a VDT of 4.40 years (95% CI 3.49–5.95) was found. Other growth models in this study revealed mean growth rates of 0.66 mm/year (95% CI 0.47–0.86) and 0.19 cm3/year (95% CI 0.12–0.26). Volume doubling time was found to be the most realistic growth model. All baseline variables had p values > 0.09 for predicting growth.

Conclusions

Based on the actual measurements, VDT was the most correct way to describe VS growth. The authors found that a cutoff of 5.22 years provided the best value to distinguish growing from nongrowing tumors. None of the investigated baseline predictors were usable as predictors of growth.

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Douglas Kondziolka

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Svein J. T. Nygaard, Hans K. R. Haugland, Ole Didrik Laerum, Morten Lund-Johansen, Rolf Bjerkvig and Ole-Björn Tysnes

Object. The goal of this study was to evaluate whether there is any relationship between survival of patients with brain tumor and tumor proliferation or tumor invasion in vitro.

Methods. Samples of freshly resected brain tumors from 14 patients with glioblastoma multiforme (GBM) were directly grown as three-dimensional multicellular spheroids. The tumor spheroids were cocultured with fetal rat brain cell aggregates (BCAs), used to represent an organotypical normal brain tissue model. Before the coculture, the tumor spheroids and the BCAs were stained with two different carbocyanine dyes, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI) and 3,3′-dioctadecycloxacarbocyanine perchlorate (DiO), respectively. During the coculture, confocal laser scanning microscopy allowed a sequential analysis of tumor cell invasion by visualizing dynamic aspects of the invasive process. Single cocultures were examined at three different time points (24, 48, and 96 hours). During the observation period there was a change in the structural morphology of the cocultures, with a progressive decrease in BCA volume. Furthermore, the scanning confocal micrographs revealed a bidirectional movement of tumor cells and normal cells into brain and tumor tissue, respectively. It is also shown that there is a considerable variation in the rate of BCA destruction in cocultures of glioma spheroids generated directly from biopsy specimens. This variation is seen both between spheroids generated from the same biopsy as well as between spheroids that are grown from different biopsy specimens.

Cell proliferation measured by Ki-67 immunohistochemical analysis of biopsy samples obtained in the same patients revealed a correlation between tumor cell proliferation and tissue destruction of the BCAs, as determined by a reduction in BCA volume (p = 0.0338). No correlation was found when survival was related to the same parameters (p > 0.05).

Conclusions. The present work provides a model for quick and efficient assessment of dynamic interactions between tumor and normal brain tissue shortly after surgery.

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Aril Løge Håvik, Ove Bruland, Erling Myrseth, Hrvoje Miletic, Mads Aarhus, Per-Morten Knappskog and Morten Lund-Johansen

OBJECTIVE

Vestibular schwannoma (VS) is a benign tumor with associated morbidities and reduced quality of life. Except for mutations in NF2, the genetic landscape of VS remains to be elucidated. Little is known about the effect of Gamma Knife radiosurgery (GKRS) on the VS genome. The aim of this study was to characterize mutations occurring in this tumor to identify new genes and signaling pathways important for the development of VS. In addition, the authors sought to evaluate whether GKRS resulted in an increase in the number of mutations.

METHODS

Forty-six sporadic VSs, including 8 GKRS-treated tumors and corresponding blood samples, were subjected to whole-exome sequencing and tumor-specific DNA variants were called. Pathway analysis was performed using the Ingenuity Pathway Analysis software. In addition, multiplex ligation-dependent probe amplification was performed to characterize copy number variations in the NF2 gene, and microsatellite instability testing was done to investigate for DNA replication error.

RESULTS

With the exception of a single sample with an aggressive phenotype that harbored a large number of mutations, most samples showed a relatively low number of mutations. A median of 14 tumor-specific mutations in each sample were identified. The GKRS-treated tumors harbored no more mutations than the rest of the group. A clustering of mutations in the cancer-related axonal guidance pathway was identified (25 patients), as well as mutations in the CDC27 (5 patients) and USP8 (3 patients) genes. Thirty-five tumors harbored mutations in NF2 and 16 tumors had 2 mutational hits. The samples without detectable NF2 mutations harbored mutations in genes that could be linked to NF2 or to NF2-related functions. None of the tumors showed microsatellite instability.

CONCLUSIONS

The genetic landscape of VS seems to be quite heterogeneous; however, most samples had mutations in NF2 or in genes that could be linked to NF2. The results of this study do not link GKRS to an increased number of mutations.

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Øystein Vesterli Tveiten, Matthew L. Carlson, Frederik Goplen, Erling Myrseth, Colin L. W. Driscoll, Rupavathana Mahesparan, Michael J. Link and Morten Lund-Johansen

OBJECTIVE

Patient-reported outcomes are increasingly used in studies of vestibular schwannoma (VS); however, few studies have examined self-evaluated facial nerve function and its relation to physician-reported outcomes. The primary objective of this study was to compare patient self-evaluations of facial disability with physician-evaluated facial nerve status and with self-evaluations of a healthy control group. The second objective was to provide insight into the controversial subject of the optimal initial management of small- and medium-sized VSs; consequently, the authors compared patient-reported facial nerve disability following treatment via observation (OBS), Gamma Knife surgery (GKS), or microsurgery (MS). Lastly, the authors sought to identify risk factors for facial nerve dysfunction following treatment for small- and medium-sized VSs.

METHODS

All patients with a VS 3 cm or smaller that was singly treated with OBS, GKS, or MS at either of 2 independent treatment centers between 1998 and 2008 were retrospectively identified. Longitudinal facial nerve measures and clinical data, including facial nerve evaluation according to the House-Brackmann (HB) grading system, were extracted from existing VS databases. Supplementing the objective data were Facial Disability Index (FDI) scores, which were obtained via survey of patients a mean of 7.7 years after initial treatment.

RESULTS

The response rate among the 682 eligible patients was 79%; thus, data from a total of 539 patients were analyzed. One hundred forty-eight patients had been managed by OBS, 247 with GKS, and 144 with MS. Patients who underwent microsurgery had larger tumors and were younger than those who underwent OBS or GKS. Overall, facial nerve outcomes were satisfactory following treatment, with more than 90% of patients having HB Grade I function at the last clinical follow-up. Treatment was the major risk factor for facial nerve dysfunction. Almost one-fifth of the patients treated with MS had an objective decline in facial nerve function, whereas only 2% in the GKS group and 0% in the OBS cohort had a decline. The physical subscale of the FDI in the VS patients was highly associated with HB grade; however, the social/well-being subscale of the FDI was not. Thus, any social disability caused by facial palsy was not detectable by use of this questionnaire.

CONCLUSIONS

The majority of patients with small- and medium-sized VSs attain excellent long-term facial nerve function and low facial nerve disability regardless of treatment modality. Tumor size and microsurgical treatment are risk factors for facial nerve dysfunction and self-reported disability. The FDI questionnaire is sensitive to the physical but not the social impairment associated with facial dysfunction.

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Matthew L. Carlson, Øystein Vesterli Tveiten, Colin L. Driscoll, Christopher J. Boes, Molly J. Sullan, Frederik K. Goplen, Morten Lund-Johansen and Michael J. Link

OBJECT

The primary goals of this study were: 1) to examine the influence of disease and treatment on headache in patients with sporadic vestibular schwannoma (VS); and 2) to identify clinical predictors of long-term headache disability.

METHODS

This was a cross-sectional observational study with international multicenter enrollment. Patients included those with primary sporadic < 3-cm VS and a separate group of general population control subjects without tumors. Interventions included a postal survey incorporating the Headache Disability Inventory (HDI), the Hospital Anxiety and Depression Scale, and a VS symptom questionnaire. The main outcome measures were univariate and multivariable associations with HDI total score.

RESULTS

The overall survey response rate was 79%. Data from 538 patients with VS were analyzed. The mean age at time of survey was 64 years, 56% of patients were female, and the average duration between treatment and survey was 7.7 years. Twenty-seven percent of patients received microsurgery, 46% stereotactic radiosurgery, and 28% observation. Patients with VS who were managed with observation were more than twice as likely to have severe headache disability compared with 103 control subjects without VS. When accounting for baseline differences, there was no statistically significant difference in HDI outcome between treatment modalities at time of survey. Similarly, among the microsurgery cohort, the long-term risk of severe headache disability was not different between surgical approaches. Multivariable regression demonstrated that younger age, greater anxiety and depression, and a preexisting diagnosis of headache were the primary predictors of severe long-term headache disability, while tumor size and treatment modality had little influence.

CONCLUSIONS

At a mean of almost 8 years following treatment, approximately half of patients with VS experience headaches of varying frequency and severity. Patient-driven factors including age, sex, mental health, and preexisting headache syndrome are the strongest predictors of long-term severe headache disability. Tumor size and treatment modality have less impact. These data may assist with patient counseling regarding long-term expectations following diagnosis and treatment.

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Matthew L. Carlson, Oystein Vesterli Tveiten, Colin L. Driscoll, Frederik K. Goplen, Brian A. Neff, Bruce E. Pollock, Nicole M. Tombers, Marina L. Castner, Monica K. Finnkirk, Erling Myrseth, Paal-Henning Pedersen, Morten Lund-Johansen and Michael J. Link

OBJECT

The optimal treatment for sporadic vestibular schwannoma (VS) is highly controversial. To date, the majority of studies comparing treatment modalities have focused on a narrow scope of technical outcomes including facial function, hearing status, and tumor control. Very few publications have investigated health-related quality of life (HRQOL) differences between individual treatment groups, and none have used a disease-specific HRQOL instrument.

METHODS

All patients with sporadic small- to medium-sized VSs who underwent primary microsurgery, stereotactic radiosurgery (SRS), or observation between 1998 and 2008 were identified. Subjects were surveyed via postal questionnaire using the 36-Item Short Form Health Survey (SF-36), the 10-item Patient-Reported Outcomes Measurement Information System short form (PROMIS-10), the Glasgow Benefit Inventory (GBI), and the Penn Acoustic Neuroma Quality-of-Life (PANQOL) scale. Additionally, a pool of general population adults was surveyed, providing a nontumor control group for comparison.

RESULTS

A total of 642 respondents were analyzed. The overall response rate for patients with VS was 79%, and the mean time interval between treatment and survey was 7.7 years. Using multivariate regression, there were no statistically significant differences between management groups with respect to the PROMIS-10 physical or mental health dimensions, the SF-36 Physical or Mental Component Summary scores, or the PANQOL general, anxiety, hearing, or energy subdomains. Patients who underwent SRS or observation reported a better total PANQOL score and higher PANQOL facial, balance, and pain subdomain scores than the microsurgical cohort (p < 0.02). The differences in scores between the nontumor control group and patients with VS were greater than differences observed between individual treatment groups for the majority of measures.

CONCLUSIONS

The differences in HRQOL outcomes following SRS, observation, and microsurgery for VS are small. Notably, the diagnosis of VS rather than treatment strategy most significantly impacts quality of life. Understanding that a large number of VSs do not grow following discovery, and that intervention does not confer a long-term HRQOL advantage, small- and medium-sized VS should be initially observed, while intervention should be reserved for patients with unequivocal tumor growth or intractable symptoms that are amenable to treatment. Future studies assessing HRQOL in VS patients should prioritize use of validated disease-specific measures, such as the PANQOL, given the significant limitations of generic instruments in distinguishing between treatment groups and tumor versus nontumor subjects.