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Introduction Peripheral and intraspinal schwannomas are common and clinically complex pathologies in patients with Neurofibromatosis Type 2 (NF2) and Schwannomatosis (SWNT). Functional preservation and pain relief are the major goals in treating these tumors. Methods This retrospective observational study investigates the clinical and functional outcome of 205 operated peripheral (n = 148, 72%) and intraspinal (n = 57, 28%) schwannomas in 85 patients (53 NF2, 32 SWNT) treated at our department between 2006 and 2017. Associated factors such as genetics, age, and location were evaluated. Results Persisting drug-resistant pain was the most common symptom (84%, n = 173) and indication for surgery (54%, n = 110). Improvement in pain intensity was postoperatively seen in 81%. Peripheral nerve schwannomas exhibited worse pain intensity preoperatively compared to intraspinal lesions (p = 0.017 NF2, p = 0.029 SWNT). More total resections could be achieved in 93% of SWNT vs. 82% of NF2-associated tumors, p = 0.030). NF2 patients with intraspinal lesions were more neurologically affected (p p = 0.027), and less pain (p = 0.024) in NF2-associated tumors. Mosaic NF2 patients had worse pain levels before surgery, and SWNT patients had a worse neurological function and more pain compared to non-mosaic or non-mutated cases. Conclusions Resection of peripheral and intraspinal schwannomas is an effective and low-risk treatment in both NF2 and SWNT. Patients with severe pain have a particular benefit from surgical treatment. Intraspinal lesions are associated with worse neurological function whereas peripheral lesions showed a higher pain intensity. The influence of mutations needs to be further investigated in larger cohorts.

Neurofibromatosis (NF) is an incurable genetic neurological condition. Psychosocial interventions that promote resiliency are a promising approach to address the high emotional distress and low quality of life (QoL) associated with NF. However, no studies have examined the psychosocial needs of treatment-seeking adults with NF. Our goal was to explore, using data from the largest efficacy trial of a psychosocial intervention for NF, differences in QoL, emotional distress, resiliency, and pain-related outcomes compared to other chronic medical populations and within subtypes (NF1, NF2, schwannomatosis; SCHW).Enrolled participants (N = 228) were geographically diverse adults with NF and elevated stress. We performed secondary analysis on baseline measures of QoL, emotional distress, resiliency, and pain-related outcomes. We reported descriptive statistics and normative comparisons to understand the psychosocial characteristics of the overall sample and performed between-group analyses to explore differences within NF type.Our sample endorsed worse QoL, emotional distress, resilience, and pain-related outcomes than similar chronic illness populations. Within NF types, participants with NF1 reported lower QoL and resilience compared to those with NF2. Participants with SCHW reported higher pain intensity than those with NF1. Participants with SCHW reported higher pain interference and lower physical QoL compared to those with NF1 and NF2.Our findings support the urgent need for psychosocial interventions targeting deficits in QoL, emotional distress, resilience, and pain-related outcomes in adults with NF. We recommend efforts to enhance sample diversity, prepare clinicians to provide high-levels of support, and attune skills training to each NF type.ClinicalTrials.gov NCT03406208; https://clinicaltrials.gov/ct2/show/NCT03406208 (Archived by WebCite at http://www.webcitation.org/72ZoTDQ6h ).

Neurofibromatosis type 2 (NF2) is characterized by often bilateral vestibular schwannomas (VS) that result in progressive hearing loss and compression of nearby brainstem structures causing cranial nerve palsies. Treatment of these tumors remains challenging, as both surgical removal and expectant management can result in symptom progression. Stereotactic radiosurgery (SRS) has been investigated for the management of NF2-associated VS; however, the role, promises, and pitfalls of this treatment modality remain unclear.Ovid MEDLINE, EMBASE, Web of Science, and Cochrane Reviews were searched for studies assessing SRS outcome in NF2-associated VS only. Primary endpoints included tumor control, serviceable hearing, presence of tinnitus, and cranial nerve V and VII symptoms.A total of 16 studies (589 patients harboring 750 tumors) were analyzed. Clinical tumor control was achieved in 88% of cases (95% CI 80-95%); salvage surgery was needed in 8% (95% CI 4-13%) of cases. Treatment resulted in a worsening of pre-treatment serviceable hearing (OR = 0.26, p 0.01), increased facial nerve (OR = 1.62, p 0.01) and trigeminal nerve (OR = 1.42, p = 0.07) impairment. The incidence of vestibular symptoms and hydrocephalus were not consistently reported and thus could not be assessed.The treatment of NF2-associated VS continues to pose a challenge, as current SRS regimens result in impaired hearing and worse cranial nerve comorbidities, despite achieving high tumor control. It remains unclear if these findings have to be regarded as treatment complications or, rather, continued disease progression.

Treatment for vestibular schwannoma (VS) in patients with neurofibromatosis type 2 (NF2) is extremely challenging due to the high risk of hearing loss. The aim of this study was to develop nomograms for the prediction of useful hearing loss in patients with NF2.The nomogram was based on a retrospective study of 111 NF2 patients who underwent resection of large VS ( 2 cm) at Beijing Tiantan Hospital between 2011 and 2018. The utility of the proposed nomogram models was evaluated by receiver operating characteristic (ROC) curve, area under ROC curve (AUC), and calibration curve. The results were validated using a prospective cohort study on 33 patients consecutively enrolled at the same institution from 2019 to 2021.On multivariate analysis of the primary cohort, large tumour size ( 3 cm) and long duration of symptoms ( 24 months) were independent risk factors for preoperative useful hearing loss (AAO-HNS Class D) (P = 0.001 and P = 0.011, respectively), while large tumour size ( 3 cm), poor hearing (Class C), and lobular growth were significantly related to postoperative useful hearing loss (P 0.001, P = 0.031 and P = 0.033, respectively). Factors derived from multivariable analysis were all assembled into the nomogram. The calibration curve for probability of hearing loss showed good agreement between predictions by nomogram models and actual observation. The ROC curves showed good predictive accuracy of the nomogram models in both cohorts (AUC: 0.708 to 0.951).The proposed nomograms resulted in accurate predictions of hearing outcomes for patients with NF2.

Neurofibromatosis type 2 (NF2), a neurogenetic condition manifest by peripheral nerve sheath tumors (PNST) throughout the neuroaxis for which there are no approved therapies. In vitro and in vivo studies presented here examine agents targeting signaling pathways, angiogenesis, and DNA repair mechanisms. In vitro dose response assays demonstrated potent activity of lapatinib and nilotinib against the mouse schwannoma SC4 (Nf2 −/−) cell line. We then examined the efficacy of everolimus, nilotinib, lapatinib, bevacizumab and radiation (RT) as mono- and combination therapies in flank and sciatic nerve in vivo NF2-PNST models. Data were analyzed using generalized linear models, two sample T-tests and paired T-tests, and linear regression models. SC4(Nf2 −/−) cells implanted in the flank or sciatic nerve showed similar rates of growth (p = 0.9748). Lapatinib, nilotinib and RT significantly reduced tumor growth rate versus controls in the in vivo flank model (p = 0.0025, 0.0062, and 0.009, respectively) whereas bevacizumab and everolimus did not. The best performers were tested in the in vivo sciatic nerve model of NF2 associated PNST, where chemoradiation outperformed nilotinib or lapatinib as single agents (nilotinib vs. nilotinib + RT, p = 0.0001; lapatinib versus lapatinib + RT, p

Neurofibromatosis type 2 (NF2) patients uniformly develop multiple schwannomas. The tumor-microenvironment (TME) is associated with hypoxia and consists of immunosuppressive cells, including regulatory T cells (Tregs) and tumor-associated macrophages (TAMs). The hypoxic TME of NF2 schwannomas remains unclear. In addition, no comparative study has investigated immunosuppressive cells in NF2 and sporadic schwannomas. In 22 NF2 and 21 sporadic schwannomas, we analyzed the immunohistochemistry for Ki-67, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2, platelet derived growth factor receptor-beta (PDGFR-β), programmed cell death-1 (PD-1)/ programmed cell death ligand-1 (PD-L1), Foxp3, CD163, CD3, and CD8 to assess the immunosuppressive TME. Most vessels in sporadic schwannomas exhibited slight or negative VEGFR1 and 2 expressions with pericytes coverage. In contrast, large vessels in NF2 schwannomas exhibited strong VEGFR1 and 2 expressions without pericytes. The number of CD3+, CD8+, and CD163+ cells was significantly higher in NF2 schwannomas than in sporadic ones. The expression of PD-L1 and nestin positive cell ratio was higher in NF2 schwannomas than that in sporadic ones. The number of CD163+ cells, nestin positive cell ratio, and HIF-1α expression were significantly associated with shorter progression-free survival in NF2 schwannomas. This study presents the clinicopathological features of the differences in immunosuppressive cells and the expression of immune checkpoint molecules between NF2 and sporadic schwannomas. Hypoxic TME was first detected in NF2-schwannomas, which was associated with the tumor progression.

Patients with NF2 who are deaf or have significant hearing loss face numerous and unique challenges which lead to poor quality of life, and thus may benefit from resiliency programs. We performed secondary data analyses on a single blind, randomized controlled trial of an 8 week mind–body resiliency program (the Relaxation Response and Resiliency program for Deaf NF2; d3RP-NF2) versus a health education control (Health Enhancement Program for Deaf NF2;dHEP-NF2) which showed improvement in quality of life (Funes in JAMA 2019, https://doi.org/10.1007/s11060-019-03182-3). Here we report on improvements in resiliency factors (i.e. optimism, gratitude, perceived social support, mindfulness, and perceived coping abilities) assessed at baseline, post-test and 6-month follow-up. Both programs were delivered via Skype using Communication Access Real-Time Translation. Patients who were randomized to the d3RP-NF2 program exhibited significant improvements from baseline to post-program in gratitude (Mdifference = 4.04, 95% CI 1.58–6.50; p = 0.002), perceived social support (Mdifference = 16.36, 95% CI 9.20–23.51; p

Individual evidence suggests that the anti-angiogenic agent bevacizumab may control vestibular schwannoma (VS) growth and promote hearing preservation in patients with neurofibromatosis type 2 (NF2). However, such metadata has yet to be consolidated, as well as its side-effect profile yet to be fully understood. Our aim was to pool systematically-identified metadata in the literature and substantiate the clinical efficacy and safety of bevacizumab with respect to radiographic tumor response, hearing, and treatment outcomes. Searches of seven electronic databases from inception to March 2019 were conducted following PRISMA guidelines. Articles were screened against pre-specified criteria. The incidence of outcomes was then extracted and pooled by random-effects meta-analysis of proportions. Eight articles reporting 161 NF2 patients with 196 assessable VS met satisfied all criteria. Radiographic response to bevacizumab was partial regression in 41% (95% CI 31–51%), no change in 47% (95% CI 39–55%), and tumor progression in 7% (95% CI 1–15%). In patients with assessable audiometric data, bevacizumab treatment resulted in hearing improvement in 20% (95% CI 9–33%), stability in 69% (95% CI 51–85%) and additional loss in 6% (95% CI 1–15%) Serious bevacizumab toxicity was observed in 17% (95% CI 10–26%). Subsequent surgical intervention was required in 11% (95% CI 2–20%). Bevacizumab may arrest both tumor progression and hearing loss in select NF2 patients presenting with VS lesions. However, a considerable proportion of patients are anticipated to experience serious adverse events; correspondingly, judicious use of bevacizumab for symptomatic management of VS in NF2 is recommended.

To test the feasibility, acceptability, and preliminary efficacy of a mind–body program for patients with neurofibromatosis 2 (NF2) who are deaf or have significant hearing loss (d3RP-NF2) against an attention placebo control (dHEP-NF2) in a single-blind randomized control trial. Both were delivered using Communication Access Real-Time Translation and live group videoconferencing. Forty-five adults with NF2 were randomized. Co-primary outcomes were physical quality of life (QoL) and psychological QoL and secondary outcomes were social QoL and environmental QoL, all measured with the World Health Organization Quality of Life Abbreviated Instrument (WHOQOL-BREF). Assessments were conducted at baseline, post-treatment, and six-month follow-up. Forty-one participants (91%) completed the intervention, and 29 (64%) completed the six-month follow up. Participants in the d3RP-NF2 showed significantly greater improvements from baseline to post-treatment on physical QoL (14.79, 95% CI 5.41–24.18; p ≤ 0.001), psychological QoL (18.77, 95% CI 7.09–30.44, p ≤ 0.001), and environmental QoL (13.25, 95% CI 1.10–25.39, p = 0.03) compared to the dHEP-NF2. Social QoL also significantly increased in the d3RP-NF2 (16.32, 95% CI 6.66–25.97, p = 0.001), but improvement was not beyond the dHEP-NF2. Gains in QoL were clinically meaningful and maintained at the 6-month follow-up for d3RP-NF2 participants across all QoL domains. There were more treatment responders in the d3RP-NF2 compared to the dHEP-NF2. The d3RP-NF2 was well accepted, highly feasible, and resulted in sustained improvements in QoL in patients with NF2 who are deaf or have significant hearing loss.

The patient reported outcomes measurement information system (PROMIS) provides clinicians and researchers access to reliable, validated measures of physical, mental, and social well-being. The use of PROMIS can facilitate comparisons among clinical subpopulations and with the U.S. general population. We report on the first study using PROMIS measures in patients with neurofibromatosis (NF). Eighty-six adult patients (mean age = 44; 55% female; 87% white; 50% NF1, 41% NF2 and 9% schwannomatosis) completed a battery of PROMIS computerized adaptive tests (CATs). Across all PROMIS instruments, mean scores for each CAT were between 48.97 and 52.60, which is within ±0.5 SD of the U.S. general population norms. However, scores were distributed across a broad range for each PROMIS measure (±3 SDs). Clinically meaningful scores (defined >1 SD impairment) were observed in 20% (pain interference), 17% (pain behavior), 16% (physical function), 16% (anxiety), 16% (depression), 15% (satisfaction with social roles), 13% (fatigue), 6% (anger), and 5% (satisfaction with discretionary social activities) of the sample. All PROMIS measures were highly interrelated in bivariate analysis (P ≤ .001). There were no differences in PROMIS scores by disease type (NF1, NF2 and schwannomatosis), or self reported learning disabilities, or compared with the US population. Scores suggest a broad continuum of symptoms and functioning in patients with NF that is not affected by NF type, as well as interrelation among the physical and psychosocial domains as measured by PROMIS. PROMIS measures may be useful in clinical practice to monitor changes in symptoms and functioning over time, as well as in clinical trials to determine patient reported changes during drug and psychosocial clinical trials.

Surgical treatment of vestibular schwannoma (VS) in patients with neurofibromatosis type 2 (NF2) along with functional preservation of cranial nerves is challenging. The aim of this study was to analyze the outcomes of hearing and facial nerve function in patients with NF2 who underwent large-size VS (> 2 cm) surgery. From 2006 to 2016, one hundred and forty NF2 patients were included with 149 large-size VS resections using retrosigmoid approach. Hearing function was classified according to the American Academy of Otolaryngology–Head and Neck Surgery (AAO–HNS) criteria. Preoperative and one-year postoperative facial nerve function were both assessed using the House–Brackmann (H–B) grading scale. A multivariate logistic regression was performed to identify preoperative predictors for facial function outcomes. No operative death we noted. Total tumor removal was achieved in 82.6% of the operated VSs. The anatomical integrity of the facial nerve was preserved in 67.8% of surgeries. Good facial nerve function (H–B Grades I–III) was maintained in 49.6% of patients at 12 months after surgery. Tumor size larger than 3 cm and preoperative facial weakness related with worse outcome of facial nerve function (P

INTRODUCTION: Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) or its ligand (PD-L1) have been shown to be effective in treating patients with a variety of cancers. Biomarker studies have found positive associations between clinical response rates and PD-L1 expression on tumor cells, as well as the presence of tumor infiltrating lymphocytes (TILs). It is currently unknown whether tumors associated with neurofibromatosis types 1 and 2 (NF1 and NF2) express PD-L1. METHODS: We performed immunohistochemistry for PD-L1 (clones SP142 and E1L3N), CD3, CD20, CD8, and CD68 in NF1-related tumors (10 dermal and 6 plexiform neurofibromas) and NF2-related tumors (10 meningiomas and 10 schwannomas) using archival formalin-fixed paraffin-embedded tissues. Expression of PD-L1 was considered positive in cases with >5% membranous staining of tumor cells, in accordance with previously published biomarker studies. RESULTS: PD-L1 expression in tumor cells (using the SP142 and E1L3N clones, respectively) was assessed as positive in plexiform neurofibromas (6/6 and 5/6) dermal neurofibromas (8/10 and 6/10), schwannomas (7/10 and 10/10), and meningiomas (4/10 and 2/10). Sparse to moderate presence of CD68, CD3, or CD8 positive TILs was found in 36 (100%) of tumor specimens. CONCLUSIONS: Our findings indicate that adaptive resistance to cell-mediated immunity may play a major role in the tumor immune microenvironment of NF1 and NF2-associated tumors. Expression of PD-L1 on tumor cells and the presence of TILs suggest that these tumors might be responsive to immunotherapy with immune checkpoint inhibitors, which should be explored in clinical trials for NF patients.

Determining health literacy level is an important prerequisite for effective patient education. We assessed multiple dimensions of health literacy and sociodemographic predictors of health literacy in patients with neurofibromatosis. In 86 individuals with a confirmed diagnosis of neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), or schwannomatosis, we assessed health literacy status using two HL tools-the adapted functional, communicative, and critical health literacy scale (adapted FCCHL) and health literacy assessment using talking touchscreen technology (Health LiTT). Factor analyses of the adapted FCCHL in NF patients showed factor structure and psychometric properties similar to pilot work in other patient populations. As a group, patients with NF had moderate scores on the Health LiTT and moderate to high scores on the adapted FCCHL, with the highest score on the functional health literacy subscale. Patients with NF1, those with lower education and those with learning disabilities had lower scores on Health LiTT; in multivariate analysis, learning disability and education remained significant predictors of HealthLiTT scores. Only lower education was associated with lower adapted FCCHL scores. Results suggest utilizing health literacy tools in NF patients is feasible and could provide physicians with valuable information to tailor health communication to subpopulations with lower health literacy levels.

NF1, NF2, and Schwannomatosis are incurable tumor suppressor syndromes associated with poor quality of life. The aim of this study was to determine the feasibility, acceptability, and preliminary efficacy of an NF adapted, 8-week group mind body skills based intervention, the relaxation response resiliency program (3RP) aimed at improving resiliency and increasing satisfaction with life. Patients seen at MGH’s Neurofibromatosis Clinic were offered participation if they described difficulties coping to a treating physician. Participants completed measures of life satisfaction, resiliency, stress, mood, lifestyle, pain, post-traumatic growth and mindfulness at baseline and after completing the 3RP program. The intervention had relative feasible enrollment rate (48 % rate, 32 out of 67 of patients signing the informed consent form). However, out of the 32 patients who signed the informed consent, only 20 started the study (62.5 %) and only 16 completed it (50 %), suggesting problems with feasibility. The main reason cited for non-participation was burden of travel to the clinic. The intervention was highly acceptable, as evidenced by an 80 % completion rate (16/20). Paired t tests showed significant improvement in resiliency, satisfaction with life, depression, stress, anxiety, mindfulness and post traumatic growth, with effect sizes ranging from 0.73–1.33. There was a trend for significance for improvement in somatization and sleepiness (p = 0.06), with effect sizes of 0.54–0.92 respectively. Statistically nonsignificant improvement was observed in all other measures, with effect sizes small to medium. In sum, the 3RP was found to be relatively feasible, highly acceptable and preliminary efficacious in decreasing symptom burden in this population, supporting the need of a randomized controlled trial.

The aim of this study was to review the literature on quality of life among adult patients with neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis, and to identify the specific aspects of quality of life that were studied and reported in this population. We also set out to report predictors of quality of life. Published research reports were included if they described quality of life in this population and met methodological quality according to a list of predefined criteria. Eight studies (7 in NF1, 1 in NF2, 0 in schwannomatosis), conducted between 2001 and 2013, met inclusion criteria. The methodological quality of the eight studies was mostly high according to ratings by predefined criteria. Most studies reported that patients with NF experience decreased quality of life when compared to the general population. Visibility and disease severity were strong predictors of skin-specific quality of life in NF1 patients. However, the majority of findings regarding predictors of quality of life were weak or inconclusive. Given the decreased quality of life in NF patients, it is important to examine more comprehensively the psychosocial factors in this population, especially in patients with NF2 and schwannomatosis. Mind body interventions that address these domains may provide comprehensive and efficacious long term treatment.

Bevacizumab is considered an established part of the treatment strategies available for schwannomas in patients with Neurofibromatosis type 2 (NF2). In the UK, it is available through NHS National Specialized Commissioning to NF2 patients with a rapidly growing target schwannoma. Regrowth of the tumour on suspension of treatment is often observed resulting in prolonged periods of exposure to bevacizumab to control the disease. Hypertension and proteinuria are common events with bevacizumab use and there are concerns with regards to the long-term risks of prolonged treatment. Dosing, demographic and adverse event (CTCAE 4.03) data from the UK NF2 bevacizumab cohort are reviewed with particular consideration of renal and cardiovascular complications. Eighty patients (48 male:32 female), median age 24.5 years (range 11-66 years), were followed for a median of 32.7 months (range 12.0-60.2 months). The most common adverse events were fatigue, hypertension and infection. A total of 19/80 patients (24 %) had either a grade 2 or grade 3 hypertension event and 14/80 patients (17.5 %) had proteinuria. Of 36 patients followed for 36 months, 78 % were free from hypertension and 86 % were free of proteinuria. Logistic regression modeling identified age and induction dosing regime to be independent predictors of development of hypertension with dose of 7.5 mg/kg 3 weekly and age30years having higher rates of hypertension. Proteinuria persisted in one of three patients after cessation of bevacizumab. One patient developed congestive heart failure and the details of this case are described. Further work is needed to determine optimal dosing regimes to limit toxicity without impacting on efficacy.

Brain-invasive growth of a subset of meningiomas is associated with less favorable prognosis. The molecular mechanisms causing invasiveness are only partially understood, however, the expression of matrix metalloproteinases (MMPs) has been identified as a contributing factor. We have previously found that loss of density enhanced phosphatase-1 (DEP-1, also designated PTPRJ), a transmembrane protein-tyrosine phosphatase, promotes meningioma cell motility and invasive growth in an orthotopic xenotransplantation model. We have now analyzed potential alterations of the expression of genes involved in motility control, caused by DEP-1 loss in meningioma cell lines. DEP-1 depleted cells exhibited increased expression of mRNA encoding MMP-9, and the growth factors EGF and FGF-2. The increase of MMP-9 expression in DEP-1 depleted cells was also readily detectable at the protein level by zymography. MMP-9 upregulation was sensitive to chemical inhibitors of growth factor signal transduction. Conversely, MMP-9 mRNA levels could be stimulated with growth factors (e.g. EGF) and inflammatory cytokines (e.g. TNFα). Increase of MMP-9 expression by DEP-1 depletion, or growth factor/cytokine stimulation qualitatively correlated with increased invasiveness in vitro scored as transmigration through matrigel-coated membranes. The studies suggest induction of MMP-9 expression promoted by DEP-1 deficiency, or potentially by growth factors and inflammatory cytokines, as a mechanism contributing to meningioma brain invasiveness.

To analyze the effect of Gamma Knife radiosurgery (GKS) on tumor control and hearing preservation rates in patients with vestibular schwannomas (VS) in a setting of neurofibromatosis type 2 (NF 2), a retrospective study was carried out at a tertiary-level referral Gamma Knife unit. Dose plans, pre- and postoperative radiology, and follow-up clinical records of patients with NF 2 who had undergone GKS for VS using a Leksell Gamma Knife (Elekta Instruments AB, Stockholm, Sweden) model B unit from 1997 to 2008 were reviewed. Thirty patients with 54 VS underwent GKS. The average age of the cohort was 29 years (range 10–56 years). Twenty-four patients had bilateral VS. The commonest clinical presentation was hearing loss and tinnitus. Primary GKS was given to 36 tumors, while 18 tumors received it as an adjunct to surgery. Average tumor size was 3.7 cc (range 0.1–13.3 cc). A median 12 Gy prescription dose (range 10–15 Gy) was administered at the 50% isodose (range 42–50%) to cover on average 91.5% of the tumor. Eighteen patients were available for clinical, 14 patients for radiological, and 5 patients (with useful hearing) for audiometric follow-up at an average of 26.6 months. The tumor control rate was 87.5% in this series (33.3% tumor regression), while hearing preservation was noted in 66.7% of cases. One patient developed worsening of facial function. GKS for VS provides satisfactory tumor control and hearing preservation in patients with NF 2. Long-term follow-up will determine future recommendations.

Neurofibromatosis type 2 (NF2) is a tumor suppressor gene syndrome characterized by multiple schwannomas, especially vestibular schwannomas (VS), and meningiomas. Anticancer drug trials are now being explored, but there are no standardized endpoints in NF2. We review the challenges of NF2 clinical trials and suggest possible response criteria for use in initial phase II studies. We suggest two main response criteria in such trials. Objective radiographic response is defined as a durable 20% or greater reduction in VS volume based on post-contrast T1-weighted MRI images collected with 3 mm or finer cuts through the internal auditory canal. Hearing response is defined as a statistically significant improvement in word recognition scores using 50-word recorded lists in audiology. A possible composite endpoint incorporating both radiographic response and hearing response is outlined. We emphasize pitfalls in response assessment and suggest guidelines to minimize misinterpretations of response. We also identify research goals in NF2 to facilitate future trial conduct, such as identifying the expectations for time to tumor progression and time to measurable hearing loss in untreated NF2-related VS, and the relation of both endpoints to patient prognostic factors (such as age, baseline tumor volume, and measures of disease severity). These data would facilitate future use of endpoints based on stability of tumor size and hearing, which might be more appropriate for testing certain drugs. We encourage adoption of standardized endpoints early in the development of phase II trials for this population to facilitate comparison of results across trials of different agents.

To develop a reproducible in vivo model for the growth of human acoustic neuromas and neurofibromas, we implanted tumor specimens (6 acoustic neuromas; 4 neurofibromas; 3 schwannomas arising in skin and soft tissues) from 13 different patients into the subrenal capsules of 67 nude mice and sciatic nerves of 64 nude mide. The animals were anesthetized and the tumors were microscopically implanted. Serial tumor volumes were determined at intervals up to 2 months by reopening the incision and directly measuring the tumor size with a micrometer. The percentages of acoustic neuromas that survived or grew were 57.1% in the subrenal capsule and 88.9% in the sciatic nerves; the percentages of neurofibromas that survived and grew were 50% in the subrenal capsule and 70% in the sciatic nerves; and the percentages of schwannomas that survived and grew were 57.1% in the subrenal capsule and 94.1% in the sciatic nerve. Tumors in the sciatic nerve also survived and grew for a longer period than those in the subrenal capsules. Tumor enlargement and stability correlated with neovascularity. At 1 or 2 months after engraftment, the tumors showed histologic appearances similar to the original tumors and immunohistochemical analysis of cryostat sections demonstrated staining of the tumors, but not the host mouse tissues for human beta 2-microglobulin, a species-specific marker. Furthermore, analysis of genomic DNA from implanted tumors revealed its human origin. We conclude that human acoustic neuromas, neurofibromas and schwannomas are readily grown in two sites in nude mice and that they retain their morphologic features and genomic identities. These tumors grow better and more consistently in the sciatic nerve than in the subrenal capsule. These are useful model systems for studying tumor growth and cellular modulation.