A phase 1 trial of the histone deacetylase inhibitor AR-42 in patients with neurofibromatosis type 2-associated tumors and advanced solid malignancies.

PURPOSE: Given clinical activity of AR-42, an oral histone deacetylase inhibitor, in hematologic malignancies and preclinical activity in solid tumors, this phase 1 trial investigated the safety and tolerability of AR-42 in patients with advanced solid tumors, including neurofibromatosis type 2-associated meningiomas and schwannomas (NF2). The primary objective was to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives included determining pharmacokinetics and clinical activity. METHODS: This phase I trial was an open-label, single-center, dose-escalation study of single-agent AR-42 in primary central nervous system and advanced solid tumors. The study followed a 3 + 3 design with an expansion cohort at the MTD. RESULTS: Seventeen patients were enrolled with NF2 (n = 5), urothelial carcinoma (n = 3), breast cancer (n = 2), non-NF2-related meningioma (n = 2), carcinoma of unknown primary (n = 2), small cell lung cancer (n = 1), Sertoli cell carcinoma (n = 1), and uveal melanoma (n = 1). The recommended phase II dose is 60 mg three times weekly, for 3 weeks of a 28-day cycle. DLTs included grade 3 thrombocytopenia and grade 4 psychosis. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. The best response was stable disease in 53% of patients (95% CI 26.6-78.7). Median progression-free survival (PFS) was 3.6 months (95% CI 1.2-9.1). Among evaluable patients with NF2 or meningioma (n = 5), median PFS was 9.1 months (95% CI 1.9-not reached). CONCLUSION: Single-agent AR-42 is safe and well tolerated. Further studies may consider AR-42 in a larger cohort of patients with NF2 or in combination with other agents in advanced solid tumors. TRIAL REGISTRATION: NCT01129193, registered 5/24/2010.

Neurofibromatosis type 2: A nationwide population-based study focused on survival after meningioma surgery.

BACKGROUND: There is no dedicated study on outcome after meningioma surgery in neurofibromatosis type 2 (NF2) patients. METHODS: We processed the French Système National des Données de Santé (SNDS) database using an algorithm combining the type of surgical procedure and the International Classification of Diseases to retrieve cases of meningioma operated in NF2 patients between 2007 and 2017. Descriptive and survival analyses were performed. RESULTS: This nationwide study found 184 patients who were operated on for 315 meningiomas over a 10-year period. 57.6 % were female, median age at first surgery was 40 years IQR[24.8-50.2] and 10.9 % were under 18 years. Cranial convexity (23.4 %) and posterior skull base (16.8 %) were the most common locations. 89.7 % of the tumours were benign and 3.3 % malignant. 16.3 % of the patient received radiotherapy and 13.6 % stereotactic radiosurgery. Median follow-up was 6.3 years, IQR[5.3-7]. At data collection, 28 patients were dead (15.2 %) and median age at death was 41.7 years, IQR [32.7-50.4]. 5 patients died within the year of meningioma surgery. OS rates at 5 and 10 years were: 87.8 %, 95 %CI[82.6-93.3] and 73.2 %, 95 %CI[63.7-84.1] respectively. In univariable Cox regression analysis, Mortality-Related Morbidity Index (MRMI) (HR = 1.57, 95 %CI[1.3-1.9], p < 0.001) Expenditure-Related Morbidity Index (HR1.16, 95 %CI[1.09-1.24], p < 0.001), a malignant meningioma (HR=8.15, 95 %CI[2.78-23.85], p < 0.001), and a diagnosis of deafness or vestibular schwannoma (HR=2.52, 95 %CI[1.02-6.23], p = 0.0447), were associated to the outcome. In multivariable analysis, solely the MRMI and a malignant meningioma remained significant predictors of reduce OS. CONCLUSION: Using this unique database, we found that outcome of NF2 patients after meningioma surgery is impaired, especially for those with significant co-morbidities and affected by a malignant meningioma.

Clinical and molecular predictors of mortality in neurofibromatosis 2: a UK national analysis of 1192 patients.

BACKGROUND: Neurofibromatosis 2 (NF2) is an autosomal-dominant tumour predisposition syndrome characterised by bilateral vestibular schwannomas, considerable morbidity and reduced life expectancy. Although genotype-phenotype correlations are well established in NF2, little is known about effects of mutation type or location within the gene on mortality. Improvements in NF2 diagnosis and management have occurred, but their effect on patient survival is unknown. METHODS: We evaluated clinical and molecular predictors of mortality in 1192 patients (771 with known causal mutations) identified through the UK National NF2 Registry. Kaplan-Meier survival and Cox regression analyses were used to evaluate predictors of mortality, with jackknife adjustment of parameter SEs to account for the strong intrafamilial phenotypic correlations that occur in NF2. RESULTS: The study included 241 deaths during 10 995 patient-years of follow-up since diagnosis. Early age at diagnosis and the presence of intracranial meningiomas were associated with increased mortality, and having a mosaic, rather than non-mosaic, NF2 mutation was associated with reduced mortality. Patients with splice-site or missense mutations had lower mortality than patients with truncating mutations (OR 0.459, 95% CI 0.213 to 0.990, and OR 0.196, 95% CI 0.213 to 0.990, respectively). Patients with splice-site mutations in exons 6-15 had lower mortality than patients with splice-site mutations in exons 1-5 (OR 0.333, 95% CI 0.129 to 0.858). The mortality of patients with NF2 diagnosed in more recent decades was lower than that of patients diagnosed earlier. CONCLUSIONS: Continuing advances in molecular diagnosis, imaging and treatment of NF2-associated tumours offer hope for even better survival in the future.

Gamma Knife radiosurgery for meningiomas in patients with neurofibromatosis Type 2.

OBJECT: Neurofibromatosis Type 2 (NF2) is a rare autosomal dominant disorder predisposing patients to meningiomatosis. The role of stereotactic radiosurgery (SRS) is poorly defined in NF2, and although the procedure has excellent control rates in the non-NF2 population, its utility has been questioned because radiation has been hypothesized to predispose patients to malignant transformation of benign tumors. To the authors' knowledge, this is the first study to examine the use of SRS specifically for meningiomas in patients with NF2. METHODS: The authors searched a tumor registry for all patients with NF2 who had undergone Gamma Knife radiosurgery (GKRS) for meningioma in the period from January 1, 1999, to September 19, 2013, at a single tertiary care cancer center. Medical records were retrospectively reviewed for patient and tumor characteristics and outcomes. RESULTS: Among the 12 patients who met the search criteria, 125 meningiomas were identified, 87 (70%) of which were symptomatic or progressive and thus treated with GKRS. The median age at the first GKRS was 31 years (interquartile range [IQR] 27-37 years). Five patients (42%) had multiple treatments with a median of 27 months (IQR 14-50 months) until the subsequent GKRS. The median follow-up in surviving patients was 43 months (IQR 34-110 months). The 5-year local tumor control and distant treatment failure rates were 92% and 77%, respectively. Toxicities occurred in 25% of the GKRS treatments, although the majority were Grade 1 or 2. At the last follow-up, 4 patients (33%) had died a neurological death at a median age of 39 years (IQR 37-46 years), and their cases accounted for 45% of all tumors, 55% of all treated tumors, and 58% of all GKRSs. Univariate analysis revealed several predictive variables for distant failure, including male sex (HR 0.28, 95% CI 0.086-0.92, p = 0.036), age at distant failure (HR 0.92, 95% CI 0.90-0.95, p < 0.0001), and prior number of GKRS treatments (HR 1.2, 95% CI 1.1-1.4, p = 0.0049). Local failure, maximum size of the treated tumor, delivered tumor margin dose, and WHO grade were not significant. On multivariate analysis, age at distant failure (HR 0.91, 95% CI 0.88-0.95, p < 0.0001) and prior number of GKRSs (HR 1.3, 95% CI 1.1-1.5, p = 0.004) remained significant. No malignant transformation events among treated tumors were observed. CONCLUSIONS: Radiosurgery represents a feasible modality with minimal toxicity for NF2-associated meningiomas. Increasing patient age was associated with a decreased rate of distant failure, whereas an increasing number of prior GKRS treatments predicted distant failure. Further studies are necessary to determine the long-term patterns of treatment failure in these patients.

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.

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.

Hypofractionated stereotactic radiation therapy in three to five fractions for vestibular schwannoma.

OBJECTIVE: To retrospectively examine the outcomes of hypofractionated stereotactic radiation therapy in three to five fractions for vestibular schwannomas. METHODS: Twenty-five patients with 26 vestibular schwannomas were treated with hypofractionated stereotactic radiation therapy using a CyberKnife. The vestibular schwannomas of 5 patients were associated with type II neurofibromatosis. The median follow-up time was 80 months (range: 6-167); the median planning target volume was 2.6 cm(3) (0.3-15.4); and the median prescribed dose (≥D90) was 21 Gy in three fractions (18-25 Gy in three to five fractions). Progression was defined as ≥2 mm 3-dimensional post-treatment tumor enlargement excluding transient expansion. Progression or any death was counted as an event in progression-free survival rates, whereas only progression was counted in progression-free rates. RESULTS: The 7-year progression-free survival and progression-free rates were 78 and 95%, respectively. Late adverse events (≥3 months) with grades based on Common Terminology Criteria for Adverse Events, v4.03 were observed in 6 patients: Grade 3 hydrocephalus in one patient, Grade 2 facial nerve disorders in two and Grade 1-2 tinnitus in three. In total, 12 out of 25 patients maintained pure tone averages ≤50 dB before hypofractionated stereotactic radiation therapy, and 6 of these 12 patients (50%) maintained pure tone averages at this level at the final audiometric follow-up after hypofractionated stereotactic radiation therapy. However, gradient deterioration of pure tone average was observed in 11 of these 12 patients. The mean pure tone averages before hypofractionated stereotactic radiation therapy and at the final follow-up for the aforementioned 12 patients were 29.8 and 57.1 dB, respectively. CONCLUSIONS: Treating vestibular schwannomas with hypofractionated stereotactic radiation therapy in three to five fractions may prevent tumor progression with tolerable toxicity. However, gradient deterioration of pure tone average was observed.

Surgery for neurofibromatosis 2.

PURPOSE OF REVIEW: This study reviews the latest literature relating to the surgical treatment of otologic manifestations in patients with neurofibromatosis 2 (NF2). The emphasis is on vestibular and other schwannomas. We review surgical approaches, including hearing preservation and nonhearing preservation surgery, as well as outcomes, including hearing and facial nerve function. RECENT FINDINGS: Vestibular schwannomas in NF2 are difficult to manage because they are bilateral and may be aggressive. Depending on hearing status, tumor size and the presence or absence of compressive symptoms, these tumors can be managed by observation, radiotherapy or surgery. The goal is to maximize the years of useful hearing. Surgery may attempt to preserve hearing or aim for complete tumor resection and preservation of facial nerve function. SUMMARY: The natural history of vestibular schwannomas and other tumors in patients with NF2 is difficult to predict. The decision between observation and either medical or surgical intervention, as well as the choice of surgical procedure, depend on patient factors and preferences and on the experience of the treating center.

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.

Management of skull based meningiomas in the elderly patient.

BACKGROUND: The demographic evolution of Western society together with availability of modern imaging techniques leads to an increasing diagnosis of meningioma patients over 70 years of age. This raises the question of appropriate management of this histologically benign tumour in a geriatric population. DESIGN: Forty-three patients aged over 70 years were analyzed and matched in a retrospective study with a younger group of 89 patients according to tumour size, histology, symptoms, recurrence and presence of neurofibromatosis II. RESULTS: Changes in postoperative Karnofsky scores were not statistically different between the two age groups. Neurological outcome was worse among the younger group (12% vs. 7% deterioration). Regarding surgical complications we noted only a statistically significant higher infection rate in the geriatric age group. There was no peri-operative mortality. CONCLUSIONS: Age alone is not a criterion to deny a priori skull base surgery, since well selected geriatric patients may benefit from a meningioma operation that may enhance future quality of life.

Neurofibromatosis types 1 and 2.

BACKGROUND: Neurofibromatosis types 1 and 2 (NF1 and NF2) are autosomal dominant neurocutaneous disorders with some similarities and many differences. They are frequently discussed together and often confused for one another by clinicians. Both disorders have widely variable presentations and degrees of severity. A thorough understanding of these complex disorders is essential for proper medical management, anticipatory care, and patient education. REVIEW SUMMARY: In this article, the clinical features, genetics, pathogenesis, and management of neurofibromatosis types 1 and 2 are reviewed and compared. CONCLUSIONS: NF1 and NF2 are complex genetic disorders with numerous manifestations and wide phenotypic variability. The complex nature of these disorders requires coordinated multidisciplinary care.

Age at symptom onset and long-term survival in patients with neurofibromatosis Type 2.

OBJECT: Neurofibromatosis Type 2 (NF2) is an intractable disorder predisposing to multiple, recurrent tumors of the central nervous system (CNS). To clarify the survival rate and characteristics that predict poor survival, we retrospectively reviewed clinical data in cases of NF2. METHODS: From among 283 patients with neurofibromatosis who had been registered in a nationwide study in Japan between 1986 and 1987, 74 patients with bilateral vestibular schwannomas were analyzed. The mean duration of follow up after diagnosis was 121 months (range 2-287 months). Results of a Kaplan-Meier product-limit analysis indicated that overall 5-, 10-, and 20-year patient survival rates following diagnosis of NF2 were 85, 67, and 38%, respectively. Early onset of the initial symptom significantly compromised survival; 5-, 10-, and 20-year survival rates in patients with symptom onset at an age younger than 25 years were 80, 60, and 28%, respectively, whereas in patients with symptom onset at an age of 25 years or older the rates were 100, 87, and 62%, respectively. Patients with small vestibular schwannomas at diagnosis (< 2 cm in diameter) had better rates of survival. Other variables such as sex, additional tumors in the CNS, or dermal abnormalities did not significantly affect survival. CONCLUSIONS: This first report of long-term follow-up results concerning the survival of patients with NF2 indicates an adverse effect of early symptom onset.

Predictors of the risk of mortality in neurofibromatosis 2.

To evaluate clinical and molecular predictors of the risk of mortality in people with neurofibromatosis 2 (NF2), we analyzed the mortality experience of 368 patients from 261 families in the United Kingdom NF2 registry, using the Cox proportional-hazards model and the jackknife method. Age at diagnosis, intracranial meningiomas, and type of treatment center were informative predictors of the risk of mortality. In Cox models, the relative risk of mortality increased 1.13-fold per year decrease in age at diagnosis (95% confidence interval [CI] 1.08-1.18) and was 2.51-fold greater in people with meningiomas compared with those without meningiomas (95% CI 1.38-4.57). The relative risk of mortality in patients treated at specialty centers was 0.34 compared with those treated at nonspecialty centers (95% CI 0.12-0.98). In a separate model, the relative risk of mortality in people with constitutional NF2 missense mutations was very low compared with those with other types of mutations (nonsense or frameshift mutations, splice-site mutations, and large deletions), but the CI could not be well quantified because there was only one death among people with missense mutations. We conclude that age at diagnosis, the strongest single predictor of the risk of mortality, is a useful index for patient counseling and clinical management (as are intracranial meningiomas). To ensure optimal care, we recommend that people with NF2 be referred to specialty treatment centers.

[Vestibular schwannoma. A new interpretation of tumor growth]. / Vestibularisschwannomer. En ny fortolkning af vaekstresultater.

INTRODUCTION: The goal of the present paper was to investigate the growth of vestibular schwannoma (VS). MATERIAL AND METHOD: A series of 123 patients with 127 tumours were allocated to the wait and scan group in the period 1973 to 1999. The material was updated three times medio 1993, medio 1996 and medio 1999. Via the Danish national register, data on whether the included patients were alive or dead were collected medio 1999. Three sets of growth results were obtained. RESULTS: The results medio 1993 revealed: tumour growth in 94 tumours (74%), no growth in 23 tumors (18%) and negative growth in 10 tumors (8%). Medio 1996 the results changed to: tumour growth in 104 tumors (82%), no growth in 15 tumours (12%) and negative growth in eight tumours (6%). The growth figures changed again in medio 1999 to: tumour growth in 108 tumours (85%), no growth in 11 tumours (9%) and negative growth in eight tumours (6%). However, the results may also be interpreted in another way: 52 patients (42%) are alive, tumour growth did not demand any intervention, 23 patients (19%) died due to non-tumour related causes and 35 patients (28%) were previously treated and alive by the termination of the third observation period. CONCLUSION: It is concluded that tumour growth is time dependent, surgery at diagnosis is the ultimate solution, however the current study provides a number of arguments in favour of the wait and scan policy.

The neuroimaging and clinical spectrum of neurofibromatosis 2.

Neurofibromatosis 2 (NF2) is an autosomal dominant disease predisposing to multiple tumors of the central and peripheral nervous system. Bilateral vestibular schwannomas are the hallmark of the disease. To define the clinical spectrum of the disease, we performed gadolinium-enhanced magnetic resonance imaging of the brain and spine as well as neurological, dermatological, and ocular examinations in 48 patients with NF2 diagnosed with the National Institutes of Health diagnostic criteria. Patients were ascertained from patient workshops and publications and from referral as a result of vestibular schwannoma surgery. Vestibular schwannomas were found in 46 patients (96%, 43 bilateral and 3 unilateral), spinal tumors were found in 43 (90%), posterior subcapsular cataracts were found in 30 (63%), meningiomas were found in 28 (58%), and trigeminal schwannomas were found in 14 (29%). The presenting symptoms included hearing loss or tinnitus in 15 patients (31%), multiple or nonspecific symptoms in 15 (31%), skin tumors in 12 (25%), and ocular symptoms in 6 (13%). When the complete spine was imaged, spinal tumors were more common in patients with NF2 than has previously been reported. This is a noteworthy finding, because spinal tumors are a major cause of NF2 morbidity and mortality.

Staged removal of acoustic tumors: techniques and lessons learned from a series of 83 patients.

The removal of large acoustic tumors is associated with increased mortality and cranial nerve injury. One method for treating these difficult lesions is staged resection. Between 1972 and 1992, more than 600 acoustic tumors were resected at our institution. Of these, 83 were removed in stages. This represents the largest series of staged acoustic tumor resections reported to date. A review of available films and patient records was performed for all acoustic tumors resected in stages between 1972 and early 1993 to analyze demographic information, tumor size, operative technique, outcome, and complications. The information was collected on standardized data sheets and entered into a computer database. Virtually all tumors were large, with the average size being 4 cm in greatest diameter. The average patient age was 41 years, and there was a slight preponderance of female patients. Ten patients had neurofibromatosis Type 2. The suboccipital approach was used in most patients. Anatomic preservation of the VIIth cranial nerve was achieved in > 72% of patients, with an average House-Brackmann score of Grade 3 at the longest follow-up (mean, 43 mo). Facial reanimation was performed in 19 of 23 patients with transected VIIth cranial nerves. Complications included cerebrospinal fluid fistulas in 11 patients, with 8 of 11 fistulas resolving after lumbar drainage. Six patients had meningitis (bacterial in three and aseptic in three). Two patients developed wound infections, and 10 patients developed exposure keratitis. There were two documented recurrences. There were no operative deaths. In most series, the incidence of cranial nerve deficits as well as morbidity and mortality is directly related to tumor size. Our operative strategy involved debulking the lateral aspect of large tumors during Stage I. Second stage removal is performed after the remaining tumor is shown to decompress out of the pons on computed tomographic or magnetic resonance images. During the second procedure, the residual tumor is less vascular and no longer densely adherent to the brain stem. Although staged removal is not without risk, there seems to be no apparent increase in morbidity when these results are compared with the results of series from the literature. Although there remain no absolute indications for staged resection of acoustic tumors, we think that it may represent the safest option for these difficult lesions.

A genetic study of type 2 neurofibromatosis in the United Kingdom. II. Guidelines for genetic counselling.

The major defining features, age at onset of symptoms, and survival in 150 patients with type 2 neurofibromatosis (NF2) have been studied. The mean age at onset was 21.57 years (n = 110) and no cases presented after 55 years of age. Patients presented with symptoms attributable to vestibular schwannomas (acoustic neuroma), cranial meningiomas, and spinal tumours. In 97 cases studied personally by the authors, skin and eye examination were found to be useful to detect early signs of the condition. Examination of the skin is likely to assist in early diagnosis in at least 10% of cases and examination of the eye for a lens opacity or cataract in at least as many again. There are marked interfamilial differences in disease severity and tumour susceptibility. Vestibular schwannomas are not fully penetrant, but the condition is usually expressed in another way. Alteration to the current diagnostic criteria is advocated to cover the lack of provision for new mutations. A screening protocol is proposed and the effect of disease heterogeneity on management is discussed.