Collagen Family Genes Associated with Risk of Recurrence after Radiation Therapy for Vestibular Schwannoma and Pan-Cancer Analysis.

BACKGROUND: The safety of radiotherapy techniques in the treatment of vestibular schwannoma (VS) shows a high rate of tumor control with few side effects. Neuropeptide Y (NPY) may have a potential relevance to the recurrence of VS. Further research is still needed on the key genes that determine the sensitivity of VS to radiation therapy. MATERIALS AND METHODS: Transcriptional microarray data and clinical information data from VS patients were downloaded from GSE141801, and vascular-related genes associated with recurrence after radiation therapy for VS were obtained by combining information from MSigDB. Logistics regression was applied to construct a column line graph prediction model for recurrence status after radiation therapy. Pan-cancer analysis was also performed to investigate the cooccurrence of these genes in tumorigenesis. RESULTS: We identified eight VS recurrence-related genes from the GSE141801 dataset. All of these genes were highly expressed in the VS recurrence samples. Four collagen family genes (COL5A1, COL3A1, COL4A1, and COL15A1) were further screened, and a model was constructed to predict the risk of recurrence of VS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that these four collagen family genes play important roles in a variety of biological functions and cellular pathways. Pan-cancer analysis further revealed that the expression of these genes was significantly heterogeneous across immune phenotypes and significantly associated with immune infiltration. Finally, Neuropeptide Y (NPY) was found to be significantly and negatively correlated with the expression of COL5A1, COL3A1, and COL4A1. CONCLUSIONS: Four collagen family genes have been identified as possible predictors of recurrence after radiation therapy for VS. Pan-cancer analysis reveals potential associations between the pathogenesis of VS and other tumorigenic factors. The relevance of NPY to VS was also revealed for the first time.

Associations of Baseline Frailty Status and Age With Outcomes in Patients Undergoing Vestibular Schwannoma Resection.

Importance: Although numerous studies have evaluated the influence of advanced age on surgical outcomes following vestibular schwannoma (VS) resection, few if any large-scale investigations have assessed the comparative prognostic effects of age and frailty. As the population continues to age, it is imperative to further evaluate treatment and management strategies for older patients. Objective: To conduct a population-based evaluation of the independent associations of chronological age and frailty (physiological age) with outcomes following VS resection. Design, Setting, and Participants: In this large-scale, multicenter, cross-sectional analysis, weighted discharge data from the National Inpatient Sample were searched to identify adult patients (≥18 years old) who underwent VS resection from 2002 through 2017 using International Classification of Diseases, Ninth Revision, Clinical Modification and Tenth Revision, Clinical Modification codes. Data collection and analysis took place September to December 2020. Main Outcomes and Measures: Complex samples regression models and receiver operating characteristic curve analysis were used to evaluate the independent associations of frailty and age (along with demographic confounders) with complications and discharge disposition. Frailty was evaluated using the previously validated 11-point modified frailty index (mFI). Results: Among the 27 313 patients identified for VS resection, the mean (SEM) age was 50.4 (0.2) years, 15 031 (55.0%) were women, and 4720 (21.0%) were of non-White race/ethnicity, as determined by the National Inpatient Sample data source. Of the included patients, 15 090 (55.2%) were considered robust (mFI score = 0), 8204 (30.0%) were prefrail (mFI score = 1), 3022 (11.1%) were frail (mFI score = 2), and 996 (3.6%) were severely frail (mFI score ≥3). On univariable analysis, increasing frailty was associated with development of postoperative hemorrhagic or ischemic stroke (odds ratio [OR], 2.44 [95% CI, 2.07-2.87]; area under the curve, 0.73), while increasing age was not. Following multivariable analysis, increasing frailty and non-White race/ethnicity were independently associated with both mortality (adjusted OR [aOR], 2.32 [95% CI, 1.70-3.17], and aOR, 3.05 [95% CI, 1.02-9.12], respectively) and extended hospital stays (aOR, 1.54 [95% CI, 1.41-1.67], and aOR, 1.71 [95% CI, 1.42-2.05], respectively), while increasing age was not. Increasing frailty (aOR, 0.61 [95% CI, 0.56-0.67]), age (aOR, 0.98 [95% CI, 0.97-0.99]), and non-White race/ethnicity (aOR, 0.62 [95% CI 0.51-0.75]) were all independently associated with routine discharge. Conclusions and Relevance: In this cross-sectional study, findings suggest that frailty may be more accurate for predicting outcomes and guiding treatment decisions than advanced patient age alone following VS resection.

Gender is associated with long-term mortality after cerebellopontine angle tumor resection.

OBJECTIVE: Gender can contribute to adverse patient outcomes through social and biological factors. It is important to assess the effects of gender on long-term patient outcomes after care has already been accessed, in order to improve quality of care and mitigate healthcare disparities. PATIENTS AND METHODS: 277 consecutive patients undergoing cerebellopontine angle tumor resection over a six-year period (June 09, 2013 - April 29, 2019) at a university health system were retrospectively evaluated. Outcomes included 90-day emergency department (ED) visit, readmission, reoperation and mortality following resection. Male and female patients in the whole population were analyzed by logistic regression. Thereafter, Coarsened Exact Matching was used to match female and male on important demographic factors, including history of prior surgery, median household income, and Charlson Comorbidity Index (CCI) score, among others. Regression was carried out in the matched population, with significance set at a p-value < 0.05. RESULTS: In the matched population analysis, males were significantly more likely to experience mortality during the length of follow-up (p = 0.03) but not within 90-days of resection. There were no significant differences in 90-day mortality or reoperation during the length of follow-up in either the matched or pre-matched populations. No significant differences were found in any of the 90-day morbidity outcomes in either the matched or pre-matched populations. CONCLUSION: Gender may predict long-term outcomes in patients following CPA tumor resection. It is possible that gender also contributes to outcome disparities in other neurosurgical procedures, which future studies should evaluate.

Outcome and toxicity analysis of single dose stereotactic radiosurgery in vestibular schwannoma based on the Koos grading system.

Stereotactic radiosurgery (SRS) has evolved as widely accepted treatment option for small-sized (Koos I up to II) vestibular schwannoma (VS). For larger tumors (prevalent Koos VI), microsurgery or combined treatment strategies are mostly recommended. However, in patients not suited for microsurgery, SRS might also be an alternative to balance tumor control, hearing preservation and adverse effects. The purpose of this analysis was to evaluate the efficacy and toxicity of SRS for VS with regard to different Koos grades. All patients with untreated VS who received SRS at our center were included. Outcome analysis included tumor control, preservation of serviceable hearing based on median pure tone averages (PTA), and procedure-related adverse events rated by the Common Terminology Criteria for Adverse Events (CTCAE; v4.03) classification. In total, 258 patients (median age 58 years, range 21-84) were identified with a mean follow-up of 52 months (range 3-228 months). Mean tumor volume was 1.8 ml (range 0.1-18.5). The mean marginal dose was 12.3 Gy ± 0.6 (range 11-13.5). The cohort was divided into two groups: A (Koos grades I and II, n = 186) and B (Koos grades III and IV, n = 72). The actuarial tumor control rate was 98% after 2 years and 90% after 5 and 10 years. Koos grading did not show a significant impact on tumor control (p = 0.632) or hearing preservation (p = 0.231). After SRS, 18 patients (7%) had new transient or permanent symptoms classified by the CTCAE. The actuarial rate of CTCAE-free survival was not related to Koos grading (p = 0.093). Based on this selected population of Koos grade III and IV VS without or with only mild symptoms from brainstem compression, SRS can be recommended as the primary therapy with the advantage of low morbidity and satisfactory tumor control. The overall hearing preservation rate and toxicity of SRS was influenced by age and cannot be predicted by tumor volume or Koos grading alone.

Stereotactic radiotherapy in three weekly fractions for the management of vestibular schwannomas.

PURPOSE: This study evaluates the rates of tumor control, hearing preservation and cranial nerve toxicity with the use of CyberKnife stereotactic radiotherapy consisting of 2100 cGy to the 80% isodose line delivered in three weekly fractions to treat vestibular schwannomas. MATERIALS AND METHODS: Retrospective chart review of vestibular schwannoma patients treated with CyberKnife stereotactic radiotherapy or undergoing watchful waiting between 2006 and 2017 was performed. For inclusion, patients receiving CyberKnife stereotactic radiotherapy must have had pretreatment magnetic resonance imaging and audiography, and 2 follow-up magnetic resonance imaging and audiograms. Watchful waiting patients must have had a minimum of 2 magnetic resonance imaging and 2 audiograms. RESULTS: Forty patients met inclusion criteria. Twenty-two underwent CyberKnife stereotactic radiotherapy. Eighteen remain in watchful waiting. Crude tumor control was 86.4% at mean radiographic follow-up of 52.3 months. Kaplan-Meier progression-free survival was 76.9% at 5 years. Kaplan-Meier survival from radiographic growth was 61.5% at 5 years. Kaplan-Meier hearing preservation was 17.5% at 5 years. All patients undergoing watchful waiting presenting with serviceable hearing maintained serviceable hearing. Serviceable hearing among CyberKnife stereotactic radiotherapy patients was 42.9% prior to treatment and 14.2% through mean follow-up of 53.7 months. One patient experienced trigeminal nerve toxicity 45 months after SRT. 95.5% of CyberKnife stereotactic radiotherapy patients were complication-free. CONCLUSIONS: Our fractionation regimen provides tumor control consistent with current literature. Hearing outcomes, however, should be discussed with patients prior to CyberKnife stereotactic radiotherapy.

Adjunctive Gamma Knife Surgery or Wait and Scan Policy After Optimal Resection of Large Vestibular Schwannomas: Clinical and Radiologic Outcomes.

OBJECTIVES: Patients with large vestibular schwannomas (VSs) will require surgical treatment owing to the potential consequences of long tract and cranial nerve compression. We assessed the long-term clinical and radiologic outcomes of patients harboring large VSs treated with a facial nerve (FN)-sparing technique. METHODS: We performed a single-center retrospective cohort study of 169 consecutive large VSs treated surgically from January 2003 to May 2015. The postoperative volume of the tumor residue was assessed using thin-slice magnetic resonance imaging 6 months after surgery. Postoperatively, the patients were allocated to a wait and rescan (W&reS) or an upfront gamma knife surgery (GKS) policy. RESULTS: At the last follow-up examination, FN function was good (House-Brackmann grade I or II) in 84% of the patients. Of the 169 patients, 11% had undergone gross total resection, 59% near total, 21% subtotal, and 9% partial resection. In the 143 patients without gross total resection, the overall median tumor residue volume was 0.39 cm3. Of these 143 patients, 66 had been allocated to the W&reS policy and 77 to upfront GKS. Overall tumor control was achieved in 83% of cases, with a mean follow-up of 62 months. Of the 27 growing residues, 17 required salvage treatment (11% failure rate). The 1-, 5-, and 7-year progression-free survival rate was 95%, 82%, and 76% in the W&reS group and 99%, 81%, and 78% in the GKS group, respectively (P = 0.57). CONCLUSIONS: Functional nerve-sparing resection provides satisfactory FN preservation. The low probability of long-term regrowth of small remnants is an argument for a W&reS protocol. GKS is a legitimate option for salvage treatment.

Natural History of Sporadic Vestibular Schwannoma: A Volumetric Study of Tumor Growth.

Objective (1) Assess 3-dimensional volumetric growth of untreated sporadic vestibular schwannomas (VSs) in a large cohort of patients treated with conservative observation. (2) Compare volumetric and conventional linear diameter measurements for detecting tumor growth. Study Design Case series with chart review. Setting Tertiary skull base referral center. Subjects and Methods Patients with sporadic VS who elected initial conservative treatment with at least 2 serial magnetic resonance imaging (MRI) scans were included. Tumor volume was determined with 3-dimensional segmentation of MRI sequences. The volumetric threshold for tumor growth was an increase ≥20% from baseline tumor volume. Tumor size based on linear diameter was assessed with the 1995 American Academy of Otolaryngology-Head and Neck Surgery Foundation guidelines for VS outcome reporting, with growth defined as an increase ≥2 mm. Results A total of 361 patients were included with a median radiologic follow-up of 4.1 years (interquartile range [IQR], 2.5-6.8). At diagnosis, 232 VSs (64%) were purely intracanalicular, and 129 (36%) extended into the cerebellopontine angle. The median baseline tumor volume was 0.161 cm3 (IQR, 0.054-0.418). Overall, 69% of tumors demonstrated volumetric growth at a median of 1.1 years (IQR, 0.6-2.1) after initial MRI. In contrast, based on linear measurement assessment, 48% of tumors demonstrated growth at a median of 1.8 years (IQR, 0.8-3.1) from first MRI scan. Disequilibrium, facial hypoesthesia, aural fullness, initial tumor size, and nonincidental diagnosis were associated with tumor growth. Conclusion Three-dimensional volumetric assessment of VS provides a more sensitive measure of tumor growth when compared with linear diameter assessment. Through volumetric analysis, the current study revealed that a significant proportion of VSs demonstrate growth during observation.

Dosimetric Analysis of Neural and Vascular Structures in Skull Base Tumors Treated with Stereotactic Radiosurgery.

Objective To examine the relationship between the prescribed target dose and the dose to healthy neurovascular structures in patients with vestibular schwannomas treated with stereotactic radiosurgery (SRS). Study Design Case series with chart review. Setting SRS center from 2011 to 2013. Subjects Twenty patients with vestibular schwannomas treated at the center from 2011 to 2013. Methods Twenty patients with vestibular schwannomas were included. The average radiation dose delivered to healthy neurovascular structures (eg, carotid artery, basilar artery, facial nerve, trigeminal nerve, and cochlea) was analyzed. Results Twenty patients with vestibular schwannomas who were treated with fused computed tomography/magnetic resonance imaging-guided SRS were included in the study. The prescribed dose ranged from 10.58 to 17.40 Gy over 1 to 3 hypofractions to cover 95% of the target tumor volume. The mean dose to the carotid artery was 5.66 Gy (95% confidence interval [CI], 4.53-6.80 Gy), anterior inferior cerebellar artery was 8.70 Gy (95% CI, 4.54-12.86 Gy), intratemporal facial nerve was 3.76 Gy (95% CI, 3.04-4.08 Gy), trigeminal nerve was 5.21 Gy (95% CI, 3.31-7.11 Gy), and the cochlea was 8.70 Gy (95% CI, 7.81-9.59 Gy). Conclusions SRS for certain vestibular schwannomas can expose the anterior inferior cerebellar artery (AICA) and carotid artery to radiation doses that can potentially initiate atherosclerotic processes. The higher doses to the AICA and carotid artery correlated with increasing tumor volume. The dose delivered to other structures such as the cochlea and intratemporal facial nerve appears to be lower and much less likely to cause immediate complications when shielded.

Operative Mortality Rates of Acoustic Neuroma Surgery: A National Cancer Database Analysis.

INTRODUCTION: Optimal acoustic neuroma (AN) management involves choosing between three treatment modalities: microsurgical excision, radiation, or observation with serial imaging. The reported in-hospital mortality rate of surgery for AN in the United States is 0.5%. However, there has yet to be a nationwide examination of the AN surgery mortality rate encompassing the period beyond initial hospital discharge. METHODS: The National Cancer Data Base (NCDB) from 2004 to 2013 identified AN patients receiving surgery. Multivariate logistic regression assessed 30-day operative mortality, adjusting for several variables including patient age, race, sex, income, geographic region, primary payer for care, tumor size, and medical comorbidities. RESULTS: Ten thousand one hundred thirty six patients received surgery as solitary treatment for AN. Mortality at 30 days postoperatively occurred in 49 patients (0.5%); only a Charlson/Deyo score of 2 (odds ratio [OR] = 6.6;95% confidence interval [CI] = 2.6-16.6; p = 0.002) was predictive of increased mortality. No other patient demographic including African-American race, minimum age of 65 or government insurance was predictive of 30-day operative mortality. CONCLUSIONS: The 30-day mortality rate following surgery for AN is 1 of 200 (0.5%), equivalent to the established in-hospital operative mortality rate, and 2.5 times higher than the cumulative assessment from single-center studies. No patient demographic other than increasing medical comorbidities reached significance in predicting 30-day operative mortality. The nearly identical rates of 30-day and in-hospital mortality from separate nationwide analyses indicate that nearly all of the operative mortality occurs before initial postoperative discharge from the hospital. This mortality rate provides a framework for comparing the true risks and benefits of surgery versus radiation or observation for AN.

Fractionated vs. single-fraction stereotactic radiotherapy in patients with vestibular schwannoma : Hearing preservation and patients' self-reported outcome based on an established questionnaire.

BACKGROUND: Stereotactic radiotherapy (RT) has been established as a valid treatment alternative in patients with vestibular schwannoma (VS). There is ongoing controversy regarding the optimal fractionation. Hearing preservation may be the primary goal for patients with VS, followed by maintenance of quality of life (QoL). METHODS: From 2002 to 2015, 184 patients with VS were treated with radiosurgery (RS) or fractionated stereotactic radiotherapy (FSRT). A survey on current symptoms and QoL was conducted between February and June 2016. RESULTS: Median follow-up after RT was 7.5 years (range 0-14.4 years). Mean overall survival (OS) after RT was 31.1 years, with 94 and 87% survival at 5 and 10 years, respectively [corrected]. Mean progression-free survival (PFS) was 13.3 years, with 5­ and 10-year PFS of 92%. Hearing could be preserved in RS patients for a median of 36.3 months (range 2.3-13.7 years). Hearing worsened in 17 (30%) cases. Median hearing preservation for FSRT was 48.7 months (range 0.0-13.8 years); 29 (23%) showed hearing deterioration. The difference in hearing preservation was not significant between RS and FSRT (p = 0.3). A total of 123/162 patients participated in the patient survey (return rate 76%). The results correlate well with the information documented in the patient files for tinnitus and facial and trigeminal nerve toxicity. Significant differences appeared regarding hearing impairment, gait uncertainty, and imbalance. CONCLUSION: These data confirm that RS and FSRT are comparable in terms of local control for VS. RS should be reserved for smaller lesions, while FSRT can be offered independently of tumor size. Patient self-reported outcome during follow-up is of high value. The established questionnaire could be validated in the independent cohort.

Development of an evidence-based decision pathway for vestibular schwannoma treatment options.

OBJECTIVE: To integrate multiple sources of clinical information with patient feedback to build evidence-based decision support model to facilitate treatment selection for patients suffering from vestibular schwannomas (VS). METHODS: This was a mixed methods study utilizing focus group and survey methodology to solicit feedback on factors important for making treatment decisions among patients. Two 90-minute focus groups were conducted by an experienced facilitator. Previously diagnosed VS patients were recruited by clinical investigators at the University of Pittsburgh Medical Center (UPMC). Classical content analysis was used for focus group data analysis. Providers were recruited from practices within the UPMC system and were surveyed using Delphi methods. This information can provide a basis for multi-criteria decision analysis (MCDA) framework to develop a treatment decision support system for patients with VS. RESULTS: Eight themes were derived from these data (focus group + surveys): doctor/health care system, side effects, effectiveness of treatment, anxiety, mortality, family/other people, quality of life, and post-operative symptoms. These data, as well as feedback from physicians were utilized in building a multi-criteria decision model. DISCUSSION: The study illustrated steps involved in the development of a decision support model that integrates evidence-based data and patient values to select treatment alternatives. CONCLUSIONS: Studies focusing on the actual development of the decision support technology for this group of patients are needed, as decisions are highly multifactorial. Such tools have the potential to improve decision making for complex medical problems with alternate treatment pathways.

Vestibular schwannomas treated with Cyberknife®: clinical outcomes.

PURPOSE: Fractionated stereotactic radiotherapy (FSR) is a recognized treatment for vestibular schwannomas (VS). This study's aim is to present clinical outcomes and local control (LC) results for patients with VS treated with FSR using the Cyberknife® (CK) in 2 French cancer centers. METHODS: Patients treated with FSR for VS between 2007 and 2012 were retrospectively analyzed. Local control was determined using follow-up MRI. The hearing preservation (HP) rate was determined by analyzing pretreatment and posttreatment audiograms. RESULTS: Forty patients were treated for VS with the CK in both centers. The mean maximal VS dimension was 18.3 mm (range 3-30). The median follow-up was 36 months and the LC was 97% at 3 years of follow-up and 89% after 5 years. The HP rate was 83% and no facial nerve impairment was reported. CONCLUSIONS: Our results in terms of LC and HP rate are congruent with similar studies that use the CK to treat VS. It appears that the CK is safe and efficient in VS management even for large lesions. Further studies with larger cohorts are warranted.

Fatal Superior Sagittal Sinus and Torcular Thrombosis After Vestibular Schwannoma Surgery: Report of a Rare Complication and Review of the Literature.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) is a rare condition with the potential to cause severe morbidity and mortality. CVST can also occur after vestibular schwannoma (VS) surgery with the thrombosis of transverse and sigmoid sinus. However, there is not a single report of superior sagittal sinus (SSS) thrombosis after VS surgery reported in the literature. CASE DESCRIPTION: A 45-year-old woman presented to our center with large left-sided solid cystic VS. On admission she was dehydrated, and after clinical stabilization, she underwent gross total excision of tumor through left retromastoid suboccipital craniotomy after cerebrospinal fluid drainage through an external ventricular drain. Surgery was uneventful, but postoperatively she had an episode of seizure. Immediate postoperative computed tomography (CT) brain scan was normal with good operative cavity. However, 24 hours later, she developed left-sided motor deficit, and a repeat CT scan showed right frontal parenchymal hemorrhage with intraventricular extension. On further evaluation, magnetic resonance venography showed entire SSS thrombosis, with patent bilateral transverse and sigmoid sinuses. She was not started on the anticoagulants in view of intracranial hemorrhage. Subsequently, she underwent right-sided decompressive craniectomy because there was progressive deterioration in her Glasgow Coma Scale, and she succumbed despite all efforts. Retrospectively, dehydration and intracranial hypotension could be likened to her sinus thrombosis. CONCLUSIONS: This case underscores the significance of adequate optimization of the patients prior to surgery, besides adequate operative skills to avoid this rare but serious complication of SSS and torcular thrombosis after VS surgery.

Surgery for sporadic vestibular schwannoma. Part I: General outcome and risk of tumor recurrence.

BACKGROUND: Vestibular schwannomas are slow growing, benign tumors. There are three possible management options: surgery, radiation treatment or active surveillance. The aim of this study was to assess the general outcome and risk of tumor recurrence. MATERIALS AND METHODS: The study included 220 consecutive patients (134 women, 86 men; the age ranged from 18 to 74) operated with the retrosigmoid transmeatal approach. The largest extrameatal diameter of the tumor ranged from 8 to 72mm (mean 30mm). According to the Samii grading scale, the tumors were classified as follows: T2-12 (6%), T3-51 (23%) and T4-157 (71%). Gross total resection was performed in 217 patients and neartotal in 3. RESULTS: Two hundred and eighteen (99.1%) patients were discharged home in a satisfactory neurological condition (GR or MD in GOS). One (0.5%) patient died due to brainstem infarction. One (0.5%) patient had unchanged severe cerebellar syndrome in comparison to the preoperative period (SD in GOS). In long-term follow-up, one patient went blind within a few months after surgery. Including the results of further neurosurgical procedures for CSF leak, shunt implantation, tumor regrowth and facial nerve reanimation, 98.6% of the patients were fully independent but with different neurological deficits. Tumor recurrence was observed in 5 (2.3%) patients during the follow-up period (mean term: 6.4 years). The average time to recurrence diagnosis was 8.8 years. All those patients were operated on again without any adjuvant therapy and there was no further re-growth at mean follow-up of 5.2 years. CONCLUSIONS: Complete removal of VS is usually curative and poses very low risks of severe disability (if audio-facial sequels are not included), mortality and long-term recurrence. For recurrent tumors, carefully tailored revision surgery without irradiation offers a high efficacy with low risk of complications.

Long-term follow-up studies of Gamma Knife surgery for patients with neurofibromatosis Type 2.

OBJECT: The aim of this study was to evaluate long-term clinical outcomes after Gamma Knife surgery (GKS) for patients with neurofibromatosis Type 2 (NF2) and the role of GKS in the management of NF2. METHODS: From December 1994 through December 2008, a total of 46 patients (21 male, 25 female) with NF2 underwent GKS and follow-up evaluation for at least 5 years at the Gamma Knife Center of the Beijing Neurosurgical Institute. GKS was performed using the Leksell Gamma Knife Models B and C. The mean age of the patients was 30 years (range 13-59 years). A family history of NF2 was found for 9 (20%) patients. The NF2 phenotype was thought to be Wishart for 20 (44%) and Feiling-Gardner for 26 (56%) patients. Among these 46 patients, GKS was performed to treat 195 tumors (73 vestibular schwannomas and 122 other tumors including other schwannomas and meningiomas). For vestibular schwannomas, the mean volume was 5.1 cm(3) (median 3.6 cm(3), range 0.3-27.3 cm(3)), the mean margin dose was 12.9 Gy (range 10-14 Gy), and the mean maximum dose was 27.3 Gy (range 16.2-40 Gy). For other tumors, the mean volume was 1.7 cm(3) (range 0.3-5.5 cm(3)), the mean margin dose was 13.3 Gy (range 11-14 Gy), and the mean maximum dose was 26.0 Gy (range 18.0-30.4 Gy). The median duration of follow-up was 109 months (range 8-195 months). RESULTS: For the 73 vestibular schwannomas that underwent GKS, the latest follow-up MR images demonstrated regression of 30 (41%) tumors, stable size for 31 (43%) tumors, and enlargement of 12 (16%) tumors. The total rate of tumor control for bilateral vestibular schwannomas in patients with NF2 was 84%. Of the 122 other types of tumors that underwent GKS, 103 (85%) showed no tumor enlargement. The rate of serviceable hearing preservation after GKS was 31.9% (15/47). The actuarial rates for hearing preservation at 3 years, 5 years, 10 years, and 15 years were 98%, 93%, 44%, and 17%, respectively. Of the 46 patients, 22 (48%) became completely bilaterally deaf, 17 (37%) retained unilateral serviceable hearing, and 7 (15%) retained bilateral serviceable hearing. The mean history of the disease course was 12 years (range 5-38 years). CONCLUSIONS: GKS was confirmed to provide long-term local tumor control for small- to medium-sized vestibular schwannomas and other types of tumors, although vestibular schwannomas in patients with NF2 responded less well than did unilateral sporadic vestibular schwannomas. Phenotype is the most strongly predictive factor of final outcome after GKS for patients with NF2. The risk for loss of hearing is high, whereas the risk for other cranial nerve complications is low.

Microsurgery for vestibular schwannoma after Gamma Knife surgery: challenges and treatment strategies.

OBJECT: Resection of vestibular schwannoma (VS) after Gamma Knife surgery (GKS) is infrequently performed. The goals of this study were to analyze and discuss the neurological outcomes and technical challenges of VS resection and to explore strategies for treating tumors that progress after GKS. METHODS: In total, 708 patients with VS underwent GKS between 1993 and 2012 at Taipei Veterans General Hospital. The post-GKS clinical courses, neurological presentations, and radiological changes in these patients were analyzed. Six hundred patients with imaging follow-up of at least 1 year after GKS treatment were included in this study. RESULTS: Thirteen patients (2.2%) underwent microsurgery on average 36.8 months (range 3-107 months) after GKS. The indications for the surgery included symptomatic adverse radiation effects (in 4 patients), tumor progression (in 6), and cyst development (in 3). No morbidity or death as a result of the surgery was observed. At the last follow-up evaluation, all patients, except 1 patient with a malignant tumor, had stable or near-normal facial function. CONCLUSIONS: For the few VS cases that require resection after radiosurgery, maximal tumor resection can be achieved with modern skull-based techniques and refined neuromonitoring without affecting facial nerve function.

Linear accelerator stereotactic radiosurgery for vestibular schwannomas: a UK series.

AIMS: To evaluate non-auditory toxicity and local control after linear accelerator stereotactic radiosurgery (SRS) for the treatment of vestibular schwannomas. MATERIALS AND METHODS: The institutional policy was to use SRS for radiologically progressing vestibular schwannomas. Case notes and plans were retrospectively reviewed for all patients undergoing SRS for vestibular schwannomas between September 2002 and June 2012. All patients were surgically immobilised using a BrainLab stereotactic head frame. The treatment plan was generated using BrainLab software (BrainScan 5.03). The aim was to deliver 12 Gy to the surface of the target with no margin. Patients with a minimum of 12 months of follow-up were included for toxicity and local control assessment. Radiological progression was defined as growth on imaging beyond 2 years of follow-up. Overall local control was defined in line with other series as absence of surgical salvage. RESULTS: Ninety-nine patients were identified. Two patients were lost to follow-up. After a median follow-up interval of 2.4 years, the actuarial radiological progression-free survival at 3 years was 100% and overall local control was also 100%. However, two patients progressed radiologically at 3.3 and 4.5 years, respectively. Twenty-one of 97 (22%) evaluable patients suffered trigeminal toxicity and this was persistent in 8/97 (8%). Two of 97 (2%) suffered long-term facial nerve toxicity (one with associated radiological progression causing hemi-facial spasm alone). One of 97 (1%) required intervention for obstructive hydrocephalus. No statistically significant dosimetric relationship could be shown to cause trigeminal or facial nerve toxicity. However, 7/8 patients with persistent trigeminal nerve toxicity had tumours in contact with the trigeminal nerve. CONCLUSIONS: SRS delivering 12 Gy using a linear accelerator leads to high local control rates, but only prospective evaluation will fully establish short-term toxicity. In this study, persistent trigeminal toxicity occurred almost exclusively in patients whose tumour was in contact with the trigeminal nerve.

Stereotactic radiosurgery for neurofibromatosis 2-associated vestibular schwannomas: toward dose optimization for tumor control and functional outcomes.

BACKGROUND: Management of neurofibromatosis type 2 (NF2)-associated vestibular schwannomas (VSs) remains controversial. Stereotactic radiosurgery (SRS) with conventional dosing is less effective for NF2-related VS compared with sporadic lesions. OBJECTIVE: To evaluate optimal SRS dose parameters for NF2-related VS and to report long-term outcomes. METHODS: A prospective database was reviewed and outcome measures, including radiographic progression, American Academy of Otolaryngology-Head and Neck Surgery hearing class, and facial nerve function, were analyzed. Progression-free survival was estimated with Kaplan-Meier methods. Associations between tumor progression and radiosurgical treatment parameters, tumor volume, and patient age were explored with the use of Cox proportional hazards regression. RESULTS: Between 1990 and 2010, 26 patients with 32 NF2-related VSs underwent SRS. Median marginal dose and tumor volume were 14 Gy and 2.7 cm, respectively. Twenty-seven tumors (84%) showed no growth (median follow-up, 7.6 years). Kaplan-Meier estimates for 5- and 10-year progression-free survival were 85% and 80%, respectively. Cox proportional hazards demonstrated a significant inverse association between higher marginal doses and tumor progression (hazard ratio, 0.49; 95% confidence interval, 0.17-0.92; P = .02). Audiometric data were available in 30 ears, with 12 having class A/B hearing before SRS. Only 3 maintained serviceable hearing at the last follow-up. Four underwent cochlear implantation. Initially, 3 achieved open-set speech recognition, although only 1 experienced long-term benefit. Facial nerve function remained stable in 50% of cases. CONCLUSION: Higher marginal doses than commonly prescribed for sporadic VS were associated with improved tumor control in patients with NF2. Hearing outcomes were poor even when contemporary reduced marginal doses were used. However, SRS allows an anatomically preserved cochlear nerve and may permit hearing rehabilitation with cochlear implantation. Further consideration should be given to optimum dosing to achieve long-term control while maximizing functional outcomes. ABBREVIATIONS: HB, House-BrackmannNF2, neurofibromatosis type 2SRS, stereotactic radiosurgeryVS, vestibular schwannoma.

Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas.

BACKGROUND: Activation of the mammalian target of rapamycin (mTOR) signaling pathway is thought to be a key driver of tumor growth in Merlin (NF2)-deficient tumors. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with antitumor activity in a variety of cancers. METHODS: We conducted a single-institution, prospective, 2-stage, open-label phase II study to estimate the response rate to everolimus in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Ten eligible patients were enrolled, including 2 pediatric patients. Everolimus was administered at a daily dose of 10 mg (adults) or 5 mg/m(2)/day (children <18 y) orally in continuous 28-day courses, for up to 12 courses. Response was assessed every 3 months with MRI, using 3-dimensional volumetric tumor analysis, and audiograms. Nine patients were evaluable for the primary response, defined as ≥15% decrease in VS volume. Hearing response was evaluable as a secondary endpoint in 8 patients. RESULTS: None of the 9 patients with evaluable disease experienced a clinical or MRI response. No objective imaging or hearing responses were observed in stage 1 of the trial, and the study was closed according to predefined stopping rules. CONCLUSION: Everolimus is ineffective for the treatment of progressive VS in NF2 patients. We are currently conducting a pharmacokinetic/pharmacodynamic ("phase 0") study of everolimus in presurgical VS patients to elucidate the biological basis for apparent treatment resistance to mTORC1 inhibition in these tumors.

Single institution experience treating 104 vestibular schwannomas with fractionated stereotactic radiation therapy or stereotactic radiosurgery.

UNLABELLED: The pupose of this study is to assess the long-term outcome and toxicity of fractionated stereotactic radiation therapy (FSRT) and stereotactic radiosurgery (SRS) for 100 vestibular schwannomas treated at a single institution. From 1993 to 2007, 104 patients underwent were treated with radiation therapy for vestibular schwannoma. Forty-eight patients received SRS, with a median prescription dose of 12.5 Gy for SRS (range 9.7-16 Gy). For FSRT, two different fraction schedules were employed: a conventional schedule (ConFSRT) of 1.8 Gy per fraction (Gy/F) for 25 or 28 fractions to a total dose of 45 or 50.4 Gy (n = 19); and a once weekly hypofractionated course (HypoFSRT) consisting of 4 Gy/F for 5 fractions to a total dose of 20 Gy (n = 37). Patients treated with FSRT had better baseline hearing, facial, and trigeminal nerve function, and were more likely to have a diagnosis of NF2. The 5-year progression free rate (PFR) was 97.0 after SRS, 90.5% after HypoFSRT, and 100.0% after ConFSRT (p = NS). Univariate analysis demonstrated that NF2 and larger tumor size (greater than the median) correlated with poorer local control, but prior surgical resection did not. Serviceable hearing was preserved in 60.0% of SRS patients, 63.2% of HypoFSRT patients, and 44.4% of ConFSRT patients (p = 0.6). Similarly, there were no significant differences in 5-year rates of trigeminal toxicity facial nerve toxicity, vestibular dysfunction, or tinnitus. CONCLUSIONS: Equivalent 5-year PFR and toxicity rates are shown for patients with vestibular schwanoma selected for SRS, HypoFSRT, and ConFSRT after multidisciplinary evaluation. Factors correlating with tumor progression included NF2 and larger tumor size.