Vestibular Schwannoma Volume Research Articles

Concurrent fibrous dysplasia is associated with a high incidence of cystic formation in vestibular schwannomas.

Fibrous dysplasia (FD) is a rare hereditary bone disorder, typically accompanied by a seemingly-high percentage of cystic changes in central nerve system tumors. This study aimed to investigate the associations between concurrent FD lesions and the cystic formation of vestibular schwannoma (VS). Patients with VSs in our institution from January 2020 to September 2022 were retrospectively included. Based on the contrasted MRI, VSs were grouped as the cystic and solid type. Concurrent FD was diagnosed based on the radiological findings. A logistic analysis was applied to investigate the relationship between concurrent FD and cystic VSs. The effect of the interaction between gender and concurrent FD on the cystic formation of VSs was further analyzed. The current study included 1255 patients with VSs (681 females with a median age of 47 years). Of them, 142 (11.3%) were with cystic VSs. A higher percentage of cystic VSs was observed in female patients (P = 0.021), patients with concurrent FDs (P < 0.001) and those with a larger VS volume (P < 0.001). An increasing trend in percentage of cystic VSs was found among patients with from 0 to ≥ 3 FD lesions (P for trend as < 0.001). A multivariate logistic analysis identified concurrent FD (odds ratio, 6.58; 95%CI, 1.66-26.09; P = 0.007) and VS volume (odds ratio, 1.55; 95%CI, 1.66-1.70; P < 0.001) as independent risk factors related to the cystic formation. Concurrent FD is associated with a high incidence of cystic formation in VSs, which provides a new breakthrough point to investigate the underlying mechanism of cystic formation of VSs.

The Ratio of Baseline Ventricle Volume to Total Brain Volume Predicts Postoperative Ventriculo-Peritoneal Shunt Dependency after Sporadic Vestibular Schwannoma Surgery.

Background/Objectives: Obstructive hydrocephalus associated with vestibular schwannoma (VS) is the most common in giant VS. Despite tumor removal, some patients may require ongoing ventriculo-peritoneal (VP) surgery. This investigation explores the factors contributing to the requirement for VP surgery following VS surgery in instances of persistent hydrocephalus (HCP). Methods: Volumetric MRI analyses of pre- and postoperative tumor volumes, cerebellum, cerebrum, ventricle system, fourth ventricle, brainstem, and peritumoral edema were conducted using Brainlab Smartbrush and 3D Slicer. The total brain volume was defined as the sum of the cerebrum, cerebellum, and brainstem. ROC analyses were performed to identify the optimum cut-off values of the volumetric data. Results: Permanent cerebrospinal fluid (CSF) diversion after surgery was indicated in 12 patients (12/71; 16.9%). The ratio of baseline volume fraction of brain ventricles to total brain ventricle volume (VTB ratio) was found to predict postoperative VP shunt dependency. The AUC was 0.71 (95% CI: 0.51-0.91), and the optimum threshold value (</≥0.449) yielded a sensitivity and specificity of 67% and 81%, respectively. Multivariable logistic regression analyses of imaging data (pre- and postoperative VS volume, VTB ratio, and extent of resection (%) (EoR)) and patient-specific factors revealed that an increased VTB ratio (≥0.049, OR: 6.2, 95% CI: 1.0-38.0, p = 0.047) and an EoR < 96.4% (OR: 9.1, 95% CI: 1.2-69.3, p = 0.032) were independently associated with postoperative VP shunt dependency. Conclusions: Primary tumor removal remains the best treatment to reduce the risk of postoperative persistent hydrocephalus. However, patients with an increased preoperative VTB ratio are prone to needing postoperative VP shunt surgery and may benefit from perioperative EVD placement.

NFS-11. PHASE II STUDY OF AXITINIB IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2-RELATED SCHWANNOMATOSIS AND PROGRESSIVE VESTIBULAR SCHWANNOMAS

Abstract BACKGROUND Axitinib is an oral multi-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and c-KIT. These represent a clinically and/or preclinically validated molecular targets in vestibular schwannoma (VS). METHODS Eligible participants were age &amp;gt;5 years with a clinical diagnosis of neurofibromatosis type 2-related schwannomatosis (NF2-SWN) and at least one volumetrically measurable, progressive VS. Axitinib was given continuously in 28-day cycles for up to of 12 cycles. Primary endpoint was objective volumetric response rate to axitinib, hearing response was a secondary endpoint, along with validated quality of life assessments (NFTI-QOL). RESULTS Twelve participants were enrolled and eight completed 12 cycles, including two pediatric patients. Two patients were non-evaluable due to coming off study prior to the first scheduled response evaluation: one withdrew from the study for personal reasons and one for non-compliance. Due to slowing accrual, the study closed prior to meeting planned enrollment of 17 evaluable patients. Ten patients were evaluable for the primary endpoint, defined as ≥20% decrease in VS volume, with two volumetric responses observed; both were reached after three cycles and sustained during treatment. Best volumetric response was −53.9% after nine cycles. Hearing response was evaluable in nine participants, with three hearing responses observed, one of which was sustained during treatment. All participants experienced drug-related toxicities, the most common were diarrhea, hematuria and skin toxicity, not exceeding grade 2, as well as hypertension, not exceeding grade 3. NFTI-QOL scores remained stable or improved during treatment in all participants. CONCLUSIONS Axitinib therapy targeting VEGFR, PDGFR and c-KIT is feasible in this population and associated with volumetric and hearing responses in a subset of patients. The convenience of oral administration appears to be offset, however, by increased toxicity and lower response rates compared to VEGF-A targeted therapy with bevacizumab.

Development of Predictive Models for the Response of Vestibular Schwannoma Treated with Cyberknife®: A Feasibility Study Based on Radiomics and Machine Learning.

to predict vestibular schwannoma (VS) response to radiosurgery by applying machine learning (ML) algorithms on radiomic features extracted from pre-treatment magnetic resonance (MR) images. patients with VS treated with radiosurgery in two Centers from 2004 to 2016 were retrospectively evaluated. Brain T1-weighted contrast-enhanced MR images were acquired before and at 24 and 36 months after treatment. Clinical and treatment data were collected contextually. Treatment responses were assessed considering the VS volume variation based on pre- and post-radiosurgery MR images at both time points. Tumors were semi-automatically segmented and radiomic features were extracted. Four ML algorithms (Random Forest, Support Vector Machine, Neural Network, and extreme Gradient Boosting) were trained and tested for treatment response (i.e., increased or non-increased tumor volume) using nested cross-validation. For training, feature selection was performed using the Least Absolute Shrinkage and Selection Operator, and the selected features were used as input to separately build the four ML classification algorithms. To overcome class imbalance during training, Synthetic Minority Oversampling Technique was used. Finally, trained models were tested on the corresponding held out set of patients to evaluate balanced accuracy, sensitivity, and specificity. 108 patients treated with Cyberknife® were retrieved; an increased tumor volume was observed at 24 months in 12 patients, and at 36 months in another group of 12 patients. The Neural Network was the best predictive algorithm for response at 24 (balanced accuracy 73% ± 18%, specificity 85% ± 12%, sensitivity 60% ± 42%) and 36 months (balanced accuracy 65% ± 12%, specificity 83% ± 9%, sensitivity 47% ± 27%). radiomics may predict VS response to radiosurgery avoiding long-term follow-up as well as unnecessary treatment.

Joint Vestibular Schwannoma Enlargement Prediction and Segmentation Using a Deep Multi-task Model.

To develop a deep-learning-based multi-task (DMT) model for joint tumor enlargement prediction (TEP) and automatic tumor segmentation (TS) for vestibular schwannoma (VS) patients using their initial diagnostic contrast-enhanced T1-weighted (ceT1) magnetic resonance images (MRIs). Initial ceT1 MRIs for VS patients meeting the inclusion/exclusion criteria of this study were retrospectively collected. VSs on the initial MRIs and their first follow-up scans were manually contoured. Tumor volume and enlargement ratio were measured based on expert contours. A DMT model was constructed for jointly TS and TEP. The manually segmented VS volume on the initial scan and the tumor enlargement label (≥20% volumetric growth) were used as the ground truth for training and evaluating the TS and TEP modules, respectively. We performed 5-fold cross-validation with the eligible patients (n=103). Median segmentation dice coefficient, prediction sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUC) were measured and achieved the following values: 84.20%, 0.68, 0.78, 0.72, and 0.77, respectively. The segmentation result is significantly better than the separate TS network (dice coefficient of 83.13%, p=0.03) and marginally lower than the state-of-the-art segmentation model nnU-Net (dice coefficient of 86.45%, p=0.16). The TEP performance is significantly better than the single-task prediction model (AUC=0.60, p=0.01) and marginally better than a radiomics-based prediction model (AUC=0.70, p=0.17). The proposed DMT model is of higher learning efficiency and achieves promising performance on TEP and TS. The proposed technology has the potential to improve VS patient management. NA Laryngoscope, 133:2754-2760, 2023.

Vestibular Schwannoma Volume and Tumor Growth Correlates with Macrophage Marker Expression.

Simple SummaryThe variable growth behavior of vestibular schwannomas (VS) makes therapy decisions very difficult. These benign tumors, which originate from the eighth cranial nerve, partly show a very slow growth rate over many years. Nevertheless, VS can lead to severe symptoms such as hearing loss and dizziness within a short time due to their increase in size. Despite numerous preliminary studies, no apparent influencing factor on size progression could be found so far. In our study, we consider the influence of growth factors and macrophage markers on the volume and growth rate of VS. While growth factors show no effect on tumor growth, higher expression of macrophage markers indicates an infiltration of macrophages. They may thus enhance the growth of VS and therefore represent a potential therapeutic target.Vestibular schwannoma is the most common benign tumor of the cerebellopontine angle and originates from Schwann cells surrounding the vestibulocochlear nerve. Since the size of the VS varies widely, affected patients suffer from symptoms of varying severity. It is often difficult to determine the optimal time for therapy, due to the unpredictability of the growth rate. Despite many investigations on influencing factors, no mechanism responsible for the increase in the growth rate of certain VS has been identified so far. Therefore, the present study investigates the influence of the seven markers: Ki-67, cyclooxygenase 2 (COX2), vascular endothelial growth factor (VEGF), macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), CD163, and CD68 on tumor progression and tumor size in a cohort of 173 VS. The markers were determined by quantitative PCR and correlated with tumor volume and VS growth rate. The analysis showed a significantly negative correlation of the Ki-67, COX2, and VEGF on tumor volume. Moreover, with a higher volume of VS, the expression of the macrophage markers CD68, CD163, and GM-CSF increased significantly. Our results suggest that the increase in VS size is not primarily due to Schwann cell growth but to an infiltration of macrophages. This may have an impact on non-invasive therapy to preserve the hearing function of affected patients.

Immunophenotype of Vestibular Schwannomas.

Vestibular schwannomas exhibit a uniquely variable natural history of growth, stability, or even spontaneous regression. We hypothesized that a transitory population of immune cells, or immunomodulation of tumors cells, may influence the growth pattern of schwannomas. We therefore sought to characterize the impact of the immune microenvironment on schwannoma behavior. Forty-eight vestibular schwannomas with preoperative magnetic resonance imaging and 11 with serial imaging were evaluated for presence of immune infiltrates (including the pan-leukocyte marker Cluster of Differentiation (CD)45, CD4 and CD8 T-cell, and CD68 and CD163 macrophages) as well as expression of immunomodulatory regulators (Programmed Death Ligand 1 (PD-L1), Programmed Death Ligand 2 (PD-L2), LAG-3, TIM-3, V-domain Ig Suppressor of T cell Activation). Maximal diameter, volume, and recurrence were annotated. Vestibular schwannomas were characterized by diverse signatures of tumor infiltrating leukocytes and immunomodulatory markers. The median tumor volume was 4.7 cm (Interquartile Range (IQR) 1.0-13.0) and maximum diameter was 2.3 cm (IQR 1.5-3.2). Among tumors with serial imaging, the median volumetric growth was 0.04 cm/mo (IQR 0.01-0.18). Tumor volume and maximum diameter demonstrated strong concordance (R = 0.90; p < 0.001). Vestibular schwannoma volume was positively associated with CD4, CD68, and CD163, but not CD8, immune infiltration (all p < 0.05). Tumor growth was positively associated with CD163 and PD-L1 (both p < 0.05). Further, CD163 modified this effect: the relationship between PD-L1 and growth strengthened with increasing CD163 infiltration (R = 0.81, p = 0.007). No other immune cell types modified this relationship. These associations were inconsistently observed for maximum diameter and linear growth. Vestibular schwannomas demonstrate variable expression of immune regulatory markers as well as immune infiltrates. Tumor size is associated with immune infiltrates and tumor growth is associated with PD-L1, especially in the presence of M2-subtype macrophages. Volumetric measures may associate with the biological signature more accurately than linear parameters. Future exploration of the role of immune modulation in select schwannomas will further enhance our understanding of the biology of these tumors and suggest potential therapeutic avenues for control of tumor growth.

The Association of Vestibular Schwannoma Volume With Facial Nerve Outcomes After Surgical Resection.

To explore the relationship between tumor size and facial nerve outcomes following vestibular schwannoma (VS) resection. Single institutional retrospective chart review of all adult patients with untreated sporadic VS who underwent surgical resection from 2008 to 2018 with preoperative magnetic resonance imaging (MRI) and 1 year of follow-up. The primary outcome measure was facial nerve outcome as assessed by the House-Brackmann facial nerve grading system. One hundred sixty-seven patients, 54.5% female, with a median age of 49 years (20-76 years), were identified who underwent VS resection. Surgical resection was performed by translabyrinthine (76.7%), middle cranial fossa (14.4%), retrosigmoid (7.2%), and transpromontorial (1.8%) approaches. The median tumor diameter and volume were 25.3 mm (range: 4.1-47.1 mm) and 3.17 cm3 (range: 0.01-30.6 cm3 ), respectively. The median follow-up was 24.2 months (range: 12-114.2 months). Gross total resection was performed in 79% of cases, with residual tumor identified on MRI in 17% of cases. For patients with tumors <3 cm3 , 92.7% had grade 1 or 2 facial function after at least 1 year follow-up, compared to 81.2% for those with tumors >3 cm3 (univariate logistic regression OR = 2.9, P = .03). Tumor volume >3 cm3 was predictive of facial weakness on multivariate regression analysis (OR = 7.4, P = .02) when controlling for surgical approach, internal auditory canal extension, anterior extension, age, gender, and extent of resection. Tumor volume >3 cm3 is associated with worse facial nerve outcomes 12 months following surgical resection. IV Laryngoscope, 131:E1328-E1334, 2021.

MRI Monitoring of Residual Vestibular Schwannomas: Modeling and Predictors of Growth.

The aim was to model residual Vestibular Schwannoma (VS) over time to identify prognostic factors of postsurgical growth. Multicenter retrospective study. Tertiary referral centers. A group of 135 patients who underwent incomplete resection for VS between January 2010 and December 2018. On magnetic resonance imaging (MRI) examinations at baseline (1 year after surgery), patients included were divided into two groups: near-total resection (NTR, <25 mm × 2 mm) and subtotal resection (STR, greater volume). Monitoring of residual VS volume. 3D volumetric segmentation of residual tumors was performed on every MRI examination at baseline and during follow-up to model volume changes over time using the Lambda-Mu-Sigma method. The study followed-up 127 patients (median age: 56 yr) over a median follow-up of 39 months. Most VS residues (76.7%; 89/116) showed no growth at 5 years. Only 27 (23.3%) residues showed signs of regrowth (increase in volume >0.05 cm). The extent of resection is a predictor of tumor growth (odds ratio [OR] = 4.85; for STR over NTR; p = 0.003), but the growth rate was significantly different between STR and NTR residues (p < 0.001). At first, over 2 years after surgery, STR residues decreased (-1.0% volume per year), whereas NTR ones grew (+8% per year). Then, both residues showed sign of regrowth. Postoperative recommendations should now include the natural history of VS residue after resection: even though the growth rate differs between STR and NTR residues, most VS residues showed no growth.

Association between patient-reported outcomes and objective disease indices in people with NF2.

The association between patient-reported outcomes and currently used clinical trial endpoints, including total vestibular schwannoma (VS) volume and word recognition score (WRS) in neurofibromatosis type 2 (NF2), is not known. A prospective observational study enrolling adult patients with NF2 was conducted at a single specialty center. Measures included: NF2 impact on quality of life (NFTI-QOL), short form (SF)-36; total VS volume, WRS; provider- and patient-reported disease severity (ProvSev, PatSev) measured with an institutionally derived multi-item (e.g., symptom burden, age-of-onset, and fatality-risk) and single-item Likert (mild, moderate, severe) scale. Fifty-one patients were enrolled between June 2014 and August 2017. Mean age was 42.1 ± 18.2 years and 37.3% patients were male. Mean WRS was 74.4 ± 37.3%; mean total VS volume was 4.2 ± 5.2 cc. Additional lesions were common including meningioma (79.2%) and spinal ependymoma (39.6%). Mean NFTI-QOL score was 7.6 ± 4.9 and correlated with responses on the SF-36. NFTI-QOL also correlated well with PatSev (r = 0.63, p < 0.001) and both multi- and single-item ProvSev (r = 0.62, p < 0.001; r = 0.52, p < 0.001, respectively). A weak correlation was observed between NFTI-QOL and WRS (r = -0.34, p = 0.0156). There was no correlation with VS volume (r = 0.23, p = 0.15). The NFTI-QOL correlated well with multiple measures of disease severity but not commonly accepted endpoints for NF2 clinical trials including total VS volume in this US cohort of patients with NF2. This suggests that the NFTI-QOL captures components of the patient experience not sufficiently represented by objective measures of disease and underscores the important and complementary role of patient-focused measures in therapeutic outcome assessment in people with NF2.

Relationship of a “Fundal Fluid Cap” and Vestibular Schwannoma Volume: Analysis of Preoperative Radiographic Findings and Outcomes

To evaluate the relationship between radiographic fundal fluid cap in the lateral internal auditory canal, preoperative clinical characteristics, and postoperative outcomes in patients with vestibular schwannoma who underwent microsurgical excision. Retrospective chart review. Academic tertiary referral center. Thirty-six consecutive patients (mean age 49.4 yr [range 29-74]) who underwent microsurgical vestibular schwannoma excision. Microsurgical excision. Linear fundal fluid size and tumor size calculated using volumetric analysis were measured on preoperative magnetic resonance imaging, and correlated to hearing status and postoperative facial nerve function. Mean fundal fluid size was 2.18 mm (range 0-7.32). Mean tumor volume was 5.58 cm (range, 0.210-40.3 cm). Short- and long-term postoperative House-Brackmann scores were 2.4 and 1.4, respectively. Fundal fluid size was associated with tumor volume (rs = 0.488, p = 0.003) but not preoperative hearing status (p = 0.333). The presence of fundal fluid and larger tumor volumes were statistically associated with poorer short-term and long-term postoperative facial nerve function (p < 0.05). Radiographic fundal fluid size is correlated to tumor volume.

Long-Term Effects of Bevacizumab on Vestibular Schwannoma Volume in Neurofibromatosis Type 2 Patients.

Introduction Bevacizumab offers a medical treatment that may slow the growth of vestibular schwannomas (VS) and possibly preserve hearing in patients with neurofibromatosis type 2 (NF2). This study aims to investigate the effect of long-term bevacizumab treatment on VS progression. Methods Demographic, clinical, audiometric, and radiographic data were collected from the medical records of NF2 patients treated with bevacizumab at a tertiary medical center. Results Eleven tumors from seven NF2 patients treated with bevacizumab were analyzed. The median age was 17 years (range: 12-47 years). Median bevacizumab treatment time was 33 months (range: 12-74 months). Of five patients with serviceable hearing pretreatment, one (20%) maintained serviceable hearing during bevacizumab therapy. Significantly slower growth rates for both tumor diameters and tumor volumes were identified during active bevacizumab treatment. Median tumor diameters and volumes during active bevacizumab treatment were 0 cm/year (range: -0.13-0.17 cm/year) and 0.1 cm 3 /year (range: -0.92-0.41), compared with 0.37 cm/year (range: 0-1.5 cm/year, p = 0.0011) and 1.38 cm 3 /year (range: 0.013-3.74), respectively, without bevacizumab treatment ( p = 0.0263). Reduced tumor progression was noted with bevacizumab treatment utilizing both linear greatest diameter (hazard ratio 0.16, p = 0.006) and segmentation volumes (hazard ratio 0.15, p = 0.023). Complications of bevacizumab treatment included fatigue (43%), nausea/vomiting (43%), hypertension (43%), epistaxis (29%), and proteinuria (29%). One subject had a cerebrovascular accident detected on screening magnetic resonance imaging without symptoms or neurological sequelae. Discussion Bevacizumab may reduce tumor growth rate and the risk of progression based on both volumetric and linear measurements.

Vestibular schwannomas: Accuracy of tumor volume estimated by ice cream cone formula using thin-sliced MR images.

PurposeWe estimated the volume of vestibular schwannomas by an ice cream cone formula using thin-sliced magnetic resonance images (MRI) and compared the estimation accuracy among different estimating formulas and between different models.MethodsThe study was approved by a local institutional review board. A total of 100 patients with vestibular schwannomas examined by MRI between January 2011 and November 2015 were enrolled retrospectively. Informed consent was waived. Volumes of vestibular schwannomas were estimated by cuboidal, ellipsoidal, and spherical formulas based on a one-component model, and cuboidal, ellipsoidal, Linskey’s, and ice cream cone formulas based on a two-component model. The estimated volumes were compared to the volumes measured by planimetry. Intraobserver reproducibility and interobserver agreement was tested. Estimation error, including absolute percentage error (APE) and percentage error (PE), was calculated. Statistical analysis included intraclass correlation coefficient (ICC), linear regression analysis, one-way analysis of variance, and paired t-tests with P < 0.05 considered statistically significant.ResultsOverall tumor size was 4.80 ± 6.8 mL (mean ±standard deviation). All ICCs were no less than 0.992, suggestive of high intraobserver reproducibility and high interobserver agreement. Cuboidal formulas significantly overestimated the tumor volume by a factor of 1.9 to 2.4 (P ≤ 0.001). The one-component ellipsoidal and spherical formulas overestimated the tumor volume with an APE of 20.3% and 29.2%, respectively. The two-component ice cream cone method, and ellipsoidal and Linskey’s formulas significantly reduced the APE to 11.0%, 10.1%, and 12.5%, respectively (all P < 0.001).ConclusionThe ice cream cone method and other two-component formulas including the ellipsoidal and Linskey’s formulas allow for estimation of vestibular schwannoma volume more accurately than all one-component formulas.

Long-Term Effects of Bevacizumab on Vestibular Schwannoma Volume in Neurofibromatosis Type 2 Patients: The UT Southwestern Experience

Long-Term Effects of Bevacizumab on Vestibular Schwannoma Volume in Neurofibromatosis Type 2 Patients: The UT Southwestern Experience

Correlation Between Aspirin Intake and Reduced Growth of Human Vestibular Schwannoma

To determine whether people with sporadic vestibular schwannoma (VS) who take aspirin for unrelated medical reasons exhibit less tumor growth than nonaspirin users. We previously demonstrated the efficacy of salicylates in inhibiting VS growth in vitro, corroborating the results of our retrospective clinical study, which found halted VS growth (based on linear tumor measurements) in aspirin users. The current study evaluates this association using more accurate tumor volumetric measurements, and quantifies the degree of frequency-specific, VS-induced hearing loss. Retrospective analysis. Tertiary care hospital. Diagnosed with VS between 1980 and 2012, followed by serial magnetic resonance imaging for at least 1 year. Patient history of aspirin intake; change in VS volume over time of observation; frequency-specific, VS-induced audiometric threshold shifts. Of the 347 patients followed by serial magnetic resonance imaging scans, 86 had sequential scans available for 3D-segmented volumetric analysis for up to 11 years of follow-up (median 53 mo). Twenty-five (29%) had documented history of aspirin intake; 8 (32%) of these demonstrated VS growth. Of the 61 (71%) nonusers, 36 (59%) demonstrated growth. A significant inverse association was found among aspirin users and VS growth: odds ratio 0.32, 95% confidence interval 0.11 to 0.91. VS-induced audiometric thresholds shifts were larger above than below 2000 Hz. Our volumetric analysis of VS growth reaffirms the results of our linear analysis and suggests that aspirin may inhibit VS growth. The audiometric findings are consistent with the previously reported VS-induced predominantly high-frequency sensorineural hearing loss.

Health-related Quality of Life of Individuals With Neurofibromatosis Type 2: Results From the NF2 Natural History Study.

To explore health-related quality of life (HRQoL) reported by individuals with neurofibromatosis type 2 (NF2) and to assess for correlations between HRQoL and objective measures of disease manifestations. Prospective observational study. Seven international NF2 centers. Eighty-one individuals with NF2, 73 adults (>18 years) and 8 children/adolescents (10-17 years). Quality of life was measured by Short Form-36 (SF-36) norm-based scores. Objective clinical measures were hearing (categorized by word-recognition scores), facial function (categorized by the House-Brackmann scale) and the volume of subjects' larger vestibular schwannoma (VS). At baseline, adults showed significant deficits in all but two subscales of the SF-36 compared with age- and gender-adjusted United States population norms. In linear regression models including age, gender, inheritance status, hearing, facial weakness and VS volume, demographic and functional measures showed no relationship to any SF-36 subscale. Larger baseline VS volume was significantly related to reduced physical role performance, reduced mental health, and increased pain (p < 0.05). In bivariate analysis, previous VS surgery was not significantly associated with baseline HRQoL; receipt of VS surgery or tumor growth during the observation period was not significantly associated with changes in HRQoL. NF2 patients report reduced HRQoL in physical, social, and mental domains, but this was not significantly related to objective measures of hearing or facial functioning. Larger baseline VS volume negatively impacted patient-reported HRQoL whereas VS surgery or tumor growth did not. Future studies should explore the relationship between tumor volume and HRQoL and psychosocial factors that may moderate this relationship.

QOL-23ASSOCIATION BETWEEN QUALITY OF LIFE AND VESTIBULAR SCHWANNOMA VOLUME, WORD RECOGNITION SCORES, AND PATIENT- AND PHYSICIAN-REPORTED DISEASE SEVERITY IN A US POPULATION OF NF2 PATIENTS

BACKGROUND: Neurofibromatosis type 2 (NF2) is associated with histologically benign but morbid tumors. Patient-reported outcomes (PROs) are important measures of patient function for this neuro-oncologic syndrome which impacts quality of life (QOL) due to multiple chronic tumors. Hence, NF2 serves as a model for developing PROs in neuro-oncology trials. The NFTI-QOL is a validated disease-specific QOL-instrument developed in the United Kingdom which has not been compared against historical clinical trial endpoints in NF2 including total vestibular schwannoma (VS) volume and best word recognition score (WRS). METHODS: An IRB-approved prospective observational study was conducted enrolling adult NF2 patients at Johns Hopkins. Measures included: NFTI-QOL, SF-36; total volume of bilateral VS, best WRS, provider- and patient-reported disease severity (ProvSev, PatSev) by institutionally-derived multi-item (e.g. symptom burden, age-of-onset, fatality-risk) and single-item Likert (mild, moderate, severe) scales. RESULTS: Twenty patients were enrolled; mean age at testing 46 + 21 years and age at diagnosis 32 + 18 years; 35% male. Prior treatment included surgery (50%), radiotherapy (25%), and systemic therapy (40%). Mean best WRS was 71.8 + 37% (n = 20). Two patients had no functional hearing and 10 had unilateral hearing. Mean total VS volume was 5.8 + 7.4 cc (n = 15). Additional lesions included meningioma (75%) and ependymoma (20%). Mean NFTI-QOL score was 8.5 + 5.1 and correlated well with all physical dimensions of the SF-36 (all p < 0.002). NFTI-QOL correlated well with PatSev (r = 0.60, 95%CI 0.21-0.82, p < 0.005) and multi-item ProvSev (r = 0.66, 0.31-0.85, p = 0.002) but not single-item ProvSev (r = 0.33, -0.13-0.68, p = 0.15). A trend toward positive correlation was observed between PatSev and multi-item ProvSev (r = 0.41, -0.04-0.72, p = 0.07). NFTI-QOL scores did not correlate with VS volume (r = 0.10, -0.44-0.58, p = 0.73), or best WRS (r = -0.40, -0.71-0.05, p-0.08). CONCLUSION: NFTI-QOL scores did not correlate with hearing function or tumor volume, but did correlate with patient and provider-reported disease severity underscoring the importance of patient-focused measures in therapeutic outcome assessment in NF2.

Vascular biomarkers derived from dynamic contrast-enhanced MRI predict response of vestibular schwannoma to antiangiogenic therapy in type 2 neurofibromatosis.

BackgroundAntiangiogenic therapy of vestibular schwannoma (VS) in type 2 neurofibromatosis can produce tumor shrinkage with response rates of 40%–60%. This study examines the predictive value of parameter-derived MRI in this setting.MethodsTwelve patients with 20 VSs were recruited. Each had at least one rapidly growing tumor. Patients were treated with bevacizumab, 5 mg/kg every 2 weeks. Patients with stable or reduced VS volume were maintained at 2.5–5 mg every 4 weeks after 6 months. Those who failed treatment had their bevacizumab discontinued. Dynamic contrast-enhanced (DCE) MRI performed prior to treatment using a high temporal resolution technique, and data were analyzed to allow measurement of contrast transfer coefficient (Ktrans), vascular fraction (vp), extravascular-extracellular fraction (ve). Relaxation rate (R1N) was measured using a variable flip angle technique. Apparent diffusional coefficient (ADC) was calculated from diffusion-weighted imaging. The predictive power of microvascular parameters and ADC were examined using logistic regression modeling.ResultsResponding tumors were larger (P < .001), had lower R1N (P < .001), and higher Ktrans (P < .05) and ADC (P < .01). They showed increases in R1N (P < .01) and reduction of Ktrans (P < .01) and ADC (P < .01). Modeling to predict response demonstrated significant independent predictive power for R1N (Β = − 0.327, P < .001), and Ktrans (Β = 0.156, P < .05). Modeling to predict percentage change in tumor volume at 90 days identified baseline tumor volume (Β = 5.503, P < .05), R1N (Β = − 5.844, P < .05), and Ktrans (Β = 5.622, P < .05) as independent significant predictors.ConclusionsIn patients with type 2 neurofibromatosis, biomarkers from DCE-MRI are predictive of VS volume response to inhibition of vascular endothelial growth factor inhibition.

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

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. 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. 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. 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.

Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas

This single-institution phase II study was performed to estimate the response rate to lapatinib in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Twenty-one eligible patients were enrolled. Brain and spine MRIs, including 3-dimensional volumetric tumor analysis, and audiograms were performed once at baseline and again every 12 weeks. The primary response end point was evaluable in 17 patients and defined as ≥15% decrease in VS volume. Hearing was evaluable as a secondary end point in 13 patients, with responses defined as an improvement in the pure tone average of at least 10 dB or a statistically significant increase in word recognition scores. Four of 17 evaluable patients experienced an objective volumetric response (23.5%; 95% confidence interval [CI], 10%-47%), with median time to response of 4.5 months (range, 3-12). In responders, reduction in VS volumes ranged from -15.7% to -23.9%. Four of 13 patients evaluable for hearing met hearing criteria for response (30.8%; 95% CI, 13%-58%). One sustained response exceeded 9 months in duration. Median time to overall progression (ie, volumetric progression or hearing loss) was 14 months. The estimated overall progression-free survival and volumetric progression-free survival at 12 months were 64.2% (95% CI, 36.9%-82.1%) and 70.6% (95% CI, 43.1%-86.6%), respectively. Toxicity was generally minor, and no permanent dose modifications were required. Lapatinib carries minor toxicity and has objective activity in NF2 patients with progressive VS, including volumetric and hearing responses. Future studies could explore combination therapy with other molecular targeted agents such as bevacizumab.