Social Independence of Patients with Neurofibromatosis Type 2 in Japan: Analysis of a National Registry of Patients Receiving Medical Expense Subsidies, 2004-2013.

Although it is important for patients with neurofibromatosis type 2 (NF2) to live independently and maintain good quality of life (QOL), no study has examined the social independence status in this patient population. This study aimed to examine the state of social independence and its contributing factors in patients with NF2 using data from a national registry in Japan during the past decade. A database provided by the Ministry of Health, Labour and Welfare of Japan that contained information about all patients with newly submitted claims for medical expense subsidies for NF2 in Japan between fiscal years 2004 and 2013 was analyzed. Individuals aged 6 to 64 years were deemed eligible for the present study. Categories of "employed," "studying," and "housekeeping" were classified as "socially independent." Multivariate logistic regression analysis was performed to examine associations between demographic variables, neurological features, and social independence status. Of 334 participants, 79% were socially independent at the time of registration. Socially dependent participants had more neurological features than those who were socially independent, whereas sex, age, and family history had no significant associations with social independence status. Multivariate logistic regression analysis revealed that participants with bilateral hearing loss, unilateral hearing loss, blindness, hemiplegia, or seizures had significantly higher odd ratios for being socially dependent compared to participants without these features. Our findings, which suggest that these neurological features could restrict social independence, could contribute to the maintenance of better social functioning and QOL in patients with NF2.

Clinical and economic burden of neurofibromatosis type 2 in the United States.

OBJECTIVES: We aimed to investigate the prevalence and cost-associated risk factors for hospital stays for Neurofibromatosis Type 2 (NF2) patients in the past decade. PATIENTS AND METHODS: A multi-year cross-sectional study was performed using the National Inpatient Sample. Patients with a diagnosis code of NF2 according to the International Classification of Diseases, 9th Revision, Clinical Modification coding system were queried from 2006-2014. Sampling discharge weights were used to calculate trend estimates for national demographics, hospital characteristics, comorbidities, and surgical interventions. Regression analysis was performed to determine significant independent associations between comorbidities and admission cost. RESULTS: From 2006-2014, there were 5,078 discharges for patients diagnosed with NF2. Patient demographics, comorbidities, and procedures performed were overall consistent over time. The most common admission diagnoses were hearing loss (28.2 %), acoustic schwannoma (14.3 %), cranial meningioma (11.8 %) and epilepsy (10.8 %). The most common procedures performed were craniotomy and meningioma resection (10.2 %) and acoustic neuroma open resection (7.9 %). The median inflation-adjusted cost of admission did not change over time, with an admission cost value of $12,387 [6,042 - 26,051]. On regression analysis, obstructive hydrocephalus, craniotomy and meningioma resection, acoustic neuroma open resection, and spine tumor resection were all independent predictors of increased cost. CONCLUSION: The care for NF2 patients continues to evolve over time. We report the prevalence of patient demographics, comorbidities, and treatments in the NF2 inpatient population. Further studies are warranted to better understand the risk factors for higher costs, so that patients with NF2 may continue to receive life-long quality care in a cost-effective manner.

Auditory Brainstem Implantation for Adults With Neurofibromatosis 2 or Severe Inner Ear Abnormalities: A Health Technology Assessment.

BACKGROUND: Neurofibromatosis 2 (NF2) is a rare genetic disorder that causes vestibular schwannomas to develop in both eighth cranial nerves. Almost all people with NF2 eventually become completely deaf as a result of progressive tumour enlargement or following surgical or radiotherapy treatment. Other rare abnormal conditions in the inner ears can also cause complete deafness. For people with either indication who are not candidates for cochlear implantation, auditory brainstem implantation is the only treatment option to restore some functional hearing. We conducted a health technology assessment of auditory brainstem implantation for adults with NF2 and severe inner ear abnormalities, which included an evaluation of effectiveness, safety, cost-effectiveness, the budget impact of publicly funding auditory brainstem implantation, and patient preferences and values. METHODS: We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) tool and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature search. We did not conduct a primary economic evaluation because the outcomes identified in our clinical evidence review were difficult to translate into measures appropriate for health economic modelling. We also analyzed the net budget impact of publicly funding auditory brainstem implantation over the next 5 years in Ontario, including the device, presurgical assessment, surgical procedure, and postsurgical rehabilitation. To contextualize the potential value of auditory brainstem implants, we spoke with six people with lived experience of NF2 and severe inner ear abnormalities. RESULTS: We included 22 publications (16 in NF2, five in severe inner ear abnormalities, and one in complications of auditory brainstem implantation) in the clinical evidence review. In adults with NF2, auditory brainstem implantation when compared with no intervention allows any degree of improvement in sound recognition (GRADE: High), allows any degree of improvement in speech perception when used in conjunction with lip-reading (GRADE: High), and provides subjective benefits of hearing (GRADE: High). It likely allows any degree of improvement in speech perception when using the implant alone (GRADE: Moderate) and may improve quality of life (GRADE: Low). In adults with severe inner ear abnormalities, auditory brainstem implantation when compared with no intervention likely allows any degree of improvement in sound recognition (GRADE: Moderate) and in any speech perception when using the implant alone (GRADE: Moderate). It may allow any degree of improvement in speech perception when used in conjunction with lip-reading (GRADE: Low), provide subjective benefits of hearing (GRADE: Low), and improve quality of life (GRADE: Low).We did not identify any economic studies on auditory brainstem implantation for adults with NF2 or adults with deafness due to severe inner ear abnormalities. We estimated that the annual net budget impact of publicly funding auditory brainstem implantation in Ontario over the next 5 years would range from about $130,000 in year 1 for two procedures to about $260,000 in year 5 for four procedures.People with whom we spoke who had received an auditory brainstem implant reported that it restored some hearing ability and improved their quality of life, though they also reported ongoing challenges in using the device or side effects from the procedure. CONCLUSIONS: When compared with no intervention, auditory brainstem implantation provides some benefit for completely deaf adults with NF2 or severe inner ear abnormalities who are not candidates for cochlear implantation. Based on evidence of moderate to high quality, auditory brainstem implants allow any degree of improvement in sound recognition and in speech perception when used in conjunction with lip-reading for people with NF2. The quality of evidence on these outcomes was low to moderate for people with severe inner ear abnormalities. These functional outcomes lead to subjective benefits of hearing which are consistently reported in the literature and in interviews with patients. We were unable to determine the cost-effectiveness of this treatment. We estimate that publicly funding auditory brainstem implantation in Ontario would result in additional costs of about $130,000 to $260,000 annually over the next 5 years.

Preclinical assessment of MEK1/2 inhibitors for neurofibromatosis type 2-associated schwannomas reveals differences in efficacy and drug resistance development.

BACKGROUND: Neurofibromatosis type 2 (NF2) is a genetic tumor-predisposition disorder caused by NF2/merlin tumor suppressor gene inactivation. The hallmark of NF2 is formation of bilateral vestibular schwannomas (VS). Because merlin modulates activity of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, we investigated repurposing drugs targeting MEK1 and/or MEK2 as a treatment for NF2-associated schwannomas. METHODS: Mouse and human merlin-deficient Schwann cell lines (MD-MSC/HSC) were screened against 6 MEK1/2 inhibitors. Efficacious drugs were tested in orthotopic allograft and NF2 transgenic mouse models. Pathway and proteome analyses were conducted. Drug efficacy was examined in primary human VS cells with NF2 mutations and correlated with DNA methylation patterns. RESULTS: Trametinib, PD0325901, and cobimetinib were most effective in reducing MD-MSC/HSC viability. Each decreased phosphorylated pERK1/2 and cyclin D1, increased p27, and induced caspase-3 cleavage in MD-MSCs. Proteomic analysis confirmed cell cycle arrest and activation of pro-apoptotic pathways in trametinib-treated MD-MSCs. The 3 inhibitors slowed allograft growth; however, decreased pERK1/2, cyclin D1, and Ki-67 levels were observed only in PD0325901 and cobimetinib-treated grafts. Tumor burden and average tumor size were reduced in trametinib-treated NF2 transgenic mice; however, tumors did not exhibit reduced pERK1/2 levels. Trametinib and PD0325901 modestly reduced viability of several primary human VS cell cultures with NF2 mutations. DNA methylation analysis of PD0325901-resistant versus -susceptible VS identified genes that could contribute to drug resistance. CONCLUSION: MEK inhibitors exhibited differences in antitumor efficacy resistance in schwannoma models with possible emergence of trametinib resistance. The results support further investigation of MEK inhibitors in combination with other targeted drugs for NF2 schwannomas.

Low-dose T1W DCE-MRI for early time points perfusion measurement in patients with intracranial tumors: A pilot study applying the microsphere model to measure absolute cerebral blood flow.

BACKGROUND: Previous studies have measured cerebral blood flow (CBF) with DSC-MRI using an "early time points" (ET) method based on microsphere theory. PURPOSE: To develop and assess a new ET method for absolute CBF estimation using low-dose high-temporal (LDHT) T1W-DCE-MRI. STUDY TYPE: Retrospective cohort study. SUBJECTS: Seven patients with sporadic vestibular schwannoma (VS) who underwent test-retest imaging; one patient with glioblastoma multiforme (GBM) imaged pretreatment; and 12 neurofibromatosis type 2 (NF2) patients undergoing bevacizumab treatment, imaged pre- and 90 days posttreatment. FIELD STRENGTH/SEQUENCE: LDHT-DCE-MRI was performed at 1.5 and 3.0T, using 3D spoiled gradient echo with phase cycling. DSC-MRI performed in one patient, using 3D echo-shifted multi-shot echo-planar imaging (PRESTO) at 3T. ASSESSMENT: Through Monte Carlo simulations, CBF estimation using three newly developed average contrast agent concentration (AC) -based methods (ACrPK, ACrMG, ACcomb), was compared against conventional maximum gradient (MG) approaches, at varying Rician noise levels. Reproducibility and applicability of the ACcomb method was assessed in our sporadic-VS/GBM/NF2 patient cohort, respectively. STATISTICAL TESTS: Reproducibility was measured using test-retest coefficient of variation (CoV). Pre- and posttreatment CBF values were compared using paired t-test with Bonferroni correction. RESULTS: Monte Carlo stimulations demonstrated that AC-based methods, particularly ACcomb, offered superior accuracy to conventional MG approaches. Overall test-retest CoV using the ACcomb method was 5.76 in normal-appearing white matter (NAWM). The new ACcomb method produced gray matter/white matter CBF estimates in the NF2 patient cohort of 55.9 ± 13.9/25.8 ± 3.5 on day 0; compared with 155.6 ± 17.2/128.4 ± 29.1 for the classical MG method. There was a moderate (10% using ACcomb and ACrPK) increase in CBF of NAWM 90 days post therapy (P = 0.03 and 0.005). DATA CONCLUSION: Our new AC-based method of CBF estimation offers excellent reproducibility, and displays more accuracy in both Monte Carlo analysis and clinical data application, than conventional MG-based approaches. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. MAGN. RESON. IMAGING 2018;48:543-557.

Health literacy assessment in adults with neurofibromatosis: electronic and short-form measurement using FCCHL and Health LiTT.

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.

Ultrasound assessment of peripheral nerve pathology in neurofibromatosis type 1 and 2.

OBJECTIVE: The neurofibromatoses (NF) type 1 and 2 are hereditary tumor predisposition syndromes caused by germline mutations in the NF1 and NF2 tumor suppressor genes. In NF1 and 2, peripheral nerve tumors occur regularly. For further characterizing nerve ultrasound was performed in patients with NF1 and 2. METHODS: Patients with established diagnosis of NF1 (n=27) and NF2 (n=10) were included. Ultrasound of peripheral nerves and cervical roots was performed during routine follow-up visits. Healthy volunteers were studied for comparison. RESULTS: In patients with NF1, median cross-sectional area (CSA) of most nerves was significantly increased compared to controls and to NF2 due to generalized plexiform tumors, which arose out of multiple fascicles in 23 of 27 patients (85%). These were often accompanied by cutaneous or subcutaneous neurofibromas. In NF2, the overall aspect of peripheral nerves consisted of localized schwannomas (80%) and, apart from that, normal nerve segments. CONCLUSION: Nerve ultrasound is able to visualize different nerve pathologies in NF1 and NF2. It is a precise and inexpensive screening method for peripheral nerve manifestation in neurofibromatosis and should be considered as the first choice screening imaging modality for all peripheral nerves within reach of non-invasive ultrasound techniques. SIGNIFICANCE: Ultrasound patterns of peripheral nerve pathologies are described for the first time in a large cohort of patients with NF1 and NF2. It is a suitable screening tool and enables targeted MRI analysis.

Mechanism-based modeling of the clinical effects of bevacizumab and everolimus on vestibular schwannomas of patients with neurofibromatosis type 2.

PURPOSE: To describe the natural growth of vestibular schwannoma in patients with neurofibromatosis type 2 and to predict tumor volume evolution in patients treated with bevacizumab and everolimus. METHODS: Clinical data, including longitudinal tumor volumes in patients treated by bevacizumab (n = 13), everolimus (n = 7) or both (n = 2), were analyzed by means of mathematical modeling techniques. Together with clinical data, data from the literature were also integrated to account for drugs mechanisms of action. RESULTS: We developed a model of vestibular schwannoma growth that takes into account the effect of vascular endothelial growth factors and mammalian target of rapamycin complex 1 on tumor growth. Behaviors, such as tumor growth rebound following everolimus treatment stops, was correctly described with the model. Preliminary results indicate that the model can be used to predict, based on early tumor volume dynamic, tumor response to variation in treatment dose and regimen. CONCLUSION: The developed model successfully describes tumor volume growth before and during bevacizumab and/or everolimus treatment. It might constitute a rational tool to predict patients' response to these drugs, thus potentially improving management of this disease.

Bevacizumab (BZM) en Neurofibromatosis tipo 2 (NF2) / Bevacizumab (BZM) in Neurofibromatosis type 2 (NF2)

INTRODUCCIÓN Y CONTEXTO: Un paciente presentó en el Ministerio de Salud de la Nación (MSN) un pedido de autorización para el uso del Bevacizumab (BZM) por su caso de Neurofibromatosis tipo 2. El MSN pide opinión a la ANMAT. (Expediente MSN 1-2002-30984-15-5, Nota ANMAT: 197/2016) En el expediente consta que el paciente padece una neurofibromatosis tipo 2. (NF2) según criterios internacionales de diagnóstico de la enfermedad. (Manchester y NNFF - National Neurofibromatosis Foundation). Presenta varios informes de TAC y RMI de cerebro desde diciembre 2012 hasta julio 2015. Los informes no encuentran progresión de las lesiones durante ese tiempo de aproximadamente 30 meses. Si bien hay un certificado de hipoacusia bilateral neuroperceptiva progresiva, no hay en el expediente, un estudio completo de audiometría y logoaudiometría para evaluar la evolución funcional, ni el grado de la misma. Este parámetro resulta de extrema importancia como punto de partida, para saber si el paciente tiene o no capacidad de mejora en el reconocimiento de la palabra, dado que es una de las variables que determinan el uso y la exposición al BZM. Además, falta un Consentimiento Informado completo, firmado por el paciente, aceptando el uso de la droga. Sin embargo, expresa conocer los beneficios dudosos según cada caso y los efectos adversos del BZM que se detallan en el expediente y coinciden con el prospecto y la Disposición ANMAT. En este contexto, la Administración de ANMAT solicitó un informe ultrarrápido de ETS para saber si había evidencia suficiente para dar opinión sobre el uso de BZM fuera de ficha técnica del producto en la NF2. La NF2 es una enfermedad compleja que se caracteriza por el desarrollo de múltiples neuromas / schwannomas, especialmente schwannomas vestibulares, así como otros tipos de tumores benignos en otros nervios craneales, espinales o periféricos. También meningiomas y ependimomas espinales y gliomas del SNC. La carga tumoral finalmente termina siendo importante. Debido a su naturaleza multisistémica, la gestión de la NF2 requiere un enfoque multidisciplinario. La NF2 es causada por mutaciones en el gen supresor NF2 en el cromosoma 22q12, que codifica para una proteína llamada "merlin" o "schwannomin" y otras mutaciones que la hacen más compleja y heteromorfa cuando se expresa antes de la pubertad. Esta alteración produce desinhibición y crecimiento de neuromas. Basados en los datos de estudios in vitro y en animales en la vía Merlin, se permitieron estrategias de tratamiento dirigidas biológicamente (empleando lapatinib, erlotinib, everolimus, picropodofilina, OSU.03012, imatinib, sorafenib y bevacizumab), destinadas a la detención o regresión del tumor y la mejoría funcional. Una de las recomendaciones más importantes se refiere a que dada la rareza de su presentación, se deben centralizar y estandarizar la evaluación de los pacientes y cooperar para llevar adelante y acelerar estudios experimentales, fase 0 y fase 2, seleccionando con precisión que pacientes incorporar primero según evolución y condición física, realizándolos sin placebo y sin azar. TECNOLOGÍA: El BZM es un anticuerpo monoclonal humanizado IgG1 dirigido contra el factor de crecimiento vascular endotelial (VEGF) y es utilizado como droga antiangiogénica aprobada por la ANMAT cuyas características e indicaciones figuran en su prospecto. OBJETIVO: Eficacia, seguridad y efectividad del BZM para el tratamiento de la NF2. RESUMEN DE LOS RESULTADOS DE LOS ESTUDIOS SELECCIONADOS: Existe un estudio Fase II ya concluido que incluyó a 14 pacientes, cuyos resultados no están disponibles aún. La evidencia disponible, es de baja calidad y pocos casos. No solamente porque la enfermedad es muy poco frecuente, sino porque los criterios para incluir pacientes en BZM también restringen aún más la población a tratar. Del análisis surge que los tratamientos recomendados pueden durar a lo sumo un año. El NHS/Oxford recomienda seis meses. La frecuencia de aplicación del BZM es cada dos o tres semanas. La dosis de la sesión varía entre 5 y 10 mg/kg, administrado en un ámbito adecuado y con un tiempo de duración de la infusión muy controlado. Es muy importante evaluar la respuesta volumétrica de los schawnnomas medidos y seguidos, dado que un criterio muy claro es que se detenga o disminuya su crecimiento más de un 20% de la medida inicial. La medición con criterios otológicos válidos y reproducibles de la interpretación de la palabra en el estudio de audición constituyen criterios estrictos de seguimiento y tardan habitualmente en mejorar desde 3 a 6 meses luego del inicio del tratamiento. Se insiste en que para usar el BZM, no debe haber dudas de que la radiocirugía o la microcirugía no puedan mejorar la oferta de beneficio para el paciente o por lo menos que haya mucho riesgo de defecto residual postcirugía, como suele ocurrir. No se conoce cuánto tiempo dura el efecto antiangiogénico e inhibidor del crecimiento de los neuromas y es, sin lugar a dudas un tratamiento adyuvante y paliativo que retrasa sobre todo la sordera definitiva o la compresión de lugares clave dentro del SNC y sus consecuencias. Según un estudio de 31 pacientes retrospectivo, el tamaño de los tumores medidos permaneció estable en la mitad de los pacientes a tres años. A pesar de ser una débil evidencia, es la única que hay disponible. El efecto antiangiogénico y antiedema del BZM, son postulados como explicación para la mejoría de la capacidad funcional, la atrofia muscular y hasta como radiosensibilizador para el uso de radioterapia a menores dosis. Una revisión narrativa publicada en 2011, intenta sistematizar el uso de las distintas terapéuticas, concluyendo que la radiocirugía parecería mantener el control del tumor durante una cantidad creciente de años de seguimiento. La radioterapia fraccionada, con especial atención a la limitación de la dosis de radiación coclear, parece ofrecer los mejores resultados funcionales para el nervio auditivo. El tratamiento microquirúrgico sigue siendo la mejor terapia citorreductora y aunque no puede lograr los resultados sobre el nervio facial y auditivo de la radiocirugía, sigue siendo el tratamiento de elección para las lesiones grandes que causan efecto de masa y la hidrocefalia obstructiva. El BZM resulta una promesa sustancial para el tratamiento de lesiones progresivas en neurofibromatosis tipo 2. CONCLUSIONES: No hay estudios científicos de calidad que sustenten el tratamiento de NF2 con BZM. No hay estudios científicos de calidad que sustenten la contraindicación del tratamiento de NF2 con BZM. La evidencia disponible sugiere beneficio pero pone en duda su utilidad si se toma en cuenta que los efectos adversos son frecuentes y manejables pero a veces, mortales. Por el propio mecanismo de acción puede saberse cuando comienza el tratamiento pero por ahora no se sabe cuándo termina. El NHS solo lo autoriza por seis meses. Hay una recomendación muy fuerte de que los pacientes elegibles deben cumplir dos condiciones: que los tumores que dan mayor compromiso o síntomas sean de crecimiento volumétrico medido y significativo en el último año de evolución y que el paciente tenga chances de mejorar su audición y entendimiento de la palabra. Por este mismo motivo se recomienda ser cuidadoso en el uso y seguimiento para evitar daños sin mejoría significativa en capacidad funcional, calidad de vida o crecimiento tumoral. Hasta disponer de nueva evidencia, es razonable el uso fuera de ficha técnica de BZM para el NF2 en las condiciones muy controladas antedichas, siempre que se cumplan los criterios de cuidados extremos para la exposición a la droga y cumpliendo con la firma de un consentimiento informado muy completo y la responsabilidad de médico tratante y paciente y familia. Debe tenerse en cuenta que ANMAT según ha expresado en comunicaciones públicas de posición, "enfoque ANMAT", NO autoriza NI prohíbe el uso "off label" de los medicamentos en plaza; siendo esta facultad, de exclusiva responsabilidad del médico tratante.

A Systematic Assessment of Accuracy in Detecting Somatic Mosaic Variants by Deep Amplicon Sequencing: Application to NF2 Gene.

The accurate detection of low-allelic variants is still challenging, particularly for the identification of somatic mosaicism, where matched control sample is not available. High throughput sequencing, by the simultaneous and independent analysis of thousands of different DNA fragments, might overcome many of the limits of traditional methods, greatly increasing the sensitivity. However, it is necessary to take into account the high number of false positives that may arise due to the lack of matched control samples. Here, we applied deep amplicon sequencing to the analysis of samples with known genotype and variant allele fraction (VAF) followed by a tailored statistical analysis. This method allowed to define a minimum value of VAF for detecting mosaic variants with high accuracy. Then, we exploited the estimated VAF to select candidate alterations in NF2 gene in 34 samples with unknown genotype (30 blood and 4 tumor DNAs), demonstrating the suitability of our method. The strategy we propose optimizes the use of deep amplicon sequencing for the identification of low abundance variants. Moreover, our method can be applied to different high throughput sequencing approaches to estimate the background noise and define the accuracy of the experimental design.

Quality of Life (QoL) Assessment in Patients with Neurofibromatosis Type 2 (NF2).

OBJECTIVE: The aim of this study was to develop a multidimensional metric for assessing quality of life (QoL) in patients with neurofibromatosis type 2 (NF2). STUDY DESIGN: Electronically distributed questionnaire. SETTING: University tertiary care hospital, NF2 support groups. SUBJECTS AND METHODS: Structured interviews with NF2 providers and patients identified relevant domains. Items in each domain were extracted from validated QoL modules, then combined with items unique to NF2 and pretested on NF2 providers and patients. The final 61-item questionnaire was administered electronically to patients with NF2 (N = 118). The form assessed overall QoL and 11 additional domains, including hearing, balance, facial function, vision, oral intake, future uncertainty, psychosocial, cognition, sexual activity, pain, and vocal communication. Responses were compared with reference values for the general population, patients with head and neck cancer, and patients with brain cancer. RESULTS: Overall, QoL in patients with NF2 was lower than that of the general population (P < .01) and similar to that of patients with cancer. Patients with more facial weakness, hearing loss, and imbalance reported significantly lower QoL. However, domains most predictive of overall QoL were psychosocial, future uncertainty, and pain. Compared with patients with head and neck and brain cancer, patients with NF2 demonstrated significantly higher levels of psychosocial stressors, including disease-related anxiety, personal and financial stress, and lack of social support (P < .01). CONCLUSION: Psychosocial stress and pain significantly affect QoL in NF2, indicating that mental health, pain management, and financial counseling could have an important impact on QoL in this population.

Semi-quantitative parameter analysis of DCE-MRI revisited: monte-carlo simulation, clinical comparisons, and clinical validation of measurement errors in patients with type 2 neurofibromatosis.

PURPOSE: To compare semi-quantitative (SQ) and pharmacokinetic (PK) parameters for analysis of dynamic contrast enhanced MR data (DCE-MRI) and investigate error-propagation in SQ parameters. METHODS: Clinical data was collected from five patients with type 2-neurofibromatosis (NF2) receiving anti-angiogenic therapy for rapidly growing vestibular schwannoma (VS). There were 7 VS and 5 meningiomas. Patients were scanned prior to therapy and at days 3 and 90 of treatment. Data was collected using a dual injection technique to permit direct comparison of SQ and PK parameters. Monte Carlo modeling was performed to assess potential measurement errors in SQ parameters in persistent, washout, and weakly enhancing tissues. The simulation predictions for five semi-quantitative parameters were tested using the clinical DCE-MRI data. RESULTS: In VS, SQ parameters and Ktrans showed close correlation and demonstrated similar therapy induced reductions. In meningioma, only the denoised Signal Enhancement Ratio (Rse1/se2(DN)) showed a significant therapy induced reduction (p<0.05). Simulation demonstrated: 1) Precision of SQ metrics normalized to the pre-contrast-baseline values (MSErel and ∑MSErel) is improved by use of an averaged value from multiple baseline scans; 2) signal enhancement ratio Rmse1/mse2 shows considerable susceptibility to noise; 3) removal of outlier values to produce a new parameter, Rmse1/mse2(DN), improves precision and sensitivity to therapy induced changes. Direct comparison of in-vivo analysis with Monte Carlo simulation supported the simulation predicted error distributions of semi-quantitative metrics. CONCLUSION: PK and SQ parameters showed similar sensitivity to anti-angiogenic therapy induced changes in VS. Modeling studies confirmed the benefits of averaging baseline signal from multiple images for normalized SQ metrics and demonstrated poor noise tolerance in the widely used signal enhancement ratio, which is corrected by removal of outlier values.

Assessment of antiangiogenic effect of imatinib mesylate on vestibular schwannoma tumors using in vivo corneal angiogenesis assay.

OBJECT: Angiogenesis and the platelet-derived growth factor (PDGF) pathway are active in the pathogenesis of vestibular schwannomas (VSs). The purpose of this study was to test whether imatinib mesylate (Gleevec), a PDGF receptor (PDGFR) blocker, reduces angiogenic capacity in sporadic VS and in VS associated with neurofibromatosis Type 2 (NF2) using a corneal angiogenesis assay. METHODS: From 121 VS tissue samples stored in the tumor bank at the Marmara University Institute of Neurological Sciences, 10 samples (6 from sporadic cases, 4 from NF2-associated cases) were selected at random for use in this study. Expression of PDGF-A and PDGF-B and their receptors was evaluated in sporadic and NF2-associated VS as well as in glioblastoma (GBM) and normal brain tissue by means of immunohistochemistry and Western blot analysis. Corneal angiogenesis assay was then used to evaluate the angiogenic capacity of tissue specimens from sporadic and NF2-associated VS with and without imatinib treatment as well as positive and negative controls (GBM and normal brain tissue). RESULTS: The angiogenic potential of the sporadic and NF2-associated VS tumor tissue differed significantly from that of the positive and negative control tissues (p <0.05). Furthermore, NF2-associated VS showed significantly lower angiogenic potential than sporadic VS (p <0.05). Imatinib treatment significantly reduced the angiogenic potential in both the sporadic VS and the NF2-associated VS groups. The level of PDGF-A and PDGFR-α as well as PDGF-B and PDGFR-ß expression in sporadic VS and NF2-associated VS also differed significantly (p <0.05) from the levels in controls. Additionally the level of PDGFR-ß was significantly higher in sporadic VS than in NF2-associated VS (p <0.05). CONCLUSIONS: The findings of this study indicate that NF2-associated VS has significantly more angiogenic potential than sporadic VS and normal brain tissue. Additionally, imatinib reduces the angiogenic activity of both sporadic and NF2-associated VS. The authors conclude that imatinib may be a potential treatment for VS, especially for NF2-associated lesions that cannot be cured with resection or radiosurgery.

New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment.

Malignant pleural mesothelioma (MPM) is a highly lethal cancer with limited therapeutic options. Recent work has focused on the frequent somatic inactivation of two tumor suppressor genes in MPM-NF2 (Neurofibromatosis type 2) and the recently identified BAP1 (BRCA associated protein 1). In addition, germline mutations in BAP1 have been identified that define a new familial cancer syndrome, which includes MPM, ocular melanoma, and other cancers. These recent advances may allow screening of high-risk individuals and the development of new therapies that target key pathways in MPM.

Quantitative assessment of whole-body tumor burden in adult patients with neurofibromatosis.

PURPOSE: Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis are at risk for multiple nerve sheath tumors and premature mortality. Traditional magnetic resonance imaging (MRI) has limited ability to assess disease burden accurately. The aim of this study was to establish an international cohort of patients with quantified whole-body internal tumor burden and to correlate tumor burden with clinical features of disease. METHODS: We determined the number, volume, and distribution of internal nerve sheath tumors in patients using whole-body MRI (WBMRI) and three-dimensional computerized volumetry. We quantified the distribution of tumor volume across body regions and used unsupervised cluster analysis to group patients based on tumor distribution. We correlated the presence and volume of internal tumors with disease-related and demographic factors. RESULTS: WBMRI identified 1286 tumors in 145/247 patients (59%). Schwannomatosis patients had the highest prevalence of tumors (P = 0.03), but NF1 patients had the highest median tumor volume (P = 0.02). Tumor volume was unevenly distributed across body regions with overrepresentation of the head/neck and pelvis. Risk factors for internal nerve sheath tumors included decreasing numbers of café-au-lait macules in NF1 patients (P = 0.003) and history of skeletal abnormalities in NF2 patients (P = 0.09). Risk factors for higher tumor volume included female gender (P = 0.05) and increasing subcutaneous neurofibromas (P = 0.03) in NF1 patients, absence of cutaneous schwannomas in NF2 patients (P = 0.06), and increasing age in schwannomatosis patients (p = 0.10). CONCLUSION: WBMRI provides a comprehensive phenotype of neurofibromatosis patients, identifies distinct anatomic subgroups, and provides the basis for investigating molecular biomarkers that correlate with unique disease manifestations.

A qualitative study of the impact of living with neurofibromatosis type 2.

Neurofibromatosis type 2 (Nf2) is an inherited autosomal dominant syndrome characterised by the development of nervous system tumours, ocular abnormalities and skin tumours. Symptoms of Nf2 can vary depending on the size and location of the tumour and include hearing loss, balance deficits and facial palsy. This study explored the physical, emotional and social impact of Nf2. Six patients were recruited through a neurofibromatosis clinic and underwent a semi-structured interview. Interviews were recorded and analysed using Framework analysis. Participants spoke of the negative impact of Nf2 on daily activities, including work. Social isolation resulted from the avoidance of social situations and was often a consequence of difficulties with communication due to loss of hearing. Patients expressed a range of negative emotional reactions in response to their diagnosis and the impact of the disease. Furthermore, the findings highlighted the important role of partners and family who were relied on for physical as well as emotional and psychological support. Patients also expressed frustration at the limited awareness of Nf2 among health professionals and a desire for improved access to information on Nf2 within their local community.

Neurofibromatosis.

Neurofibromatosis is a heritable disease characterized by disordered growth of ectodermal tissues.

Management of the patient and family with neurofibromatosis 2: a consensus conference statement.

A consensus conference on neurofibromatosis 2 (NF2) was held in 2002 at the request of the United Kingdom (UK) Neurofibromatosis Association, with particular emphasis on vestibular schwannoma (VS) surgery. NF2 patients should be managed at specialty treatment centres, whose staff has extensive experience with the disease. All NF2 patients and their families should have access to genetic testing because presymptomatic diagnosis improves the clinical management of the disease. Some clinical manifestations of NF2, such as ocular abnormalities, can be detected in infancy; therefore, clinical screening for at-risk members of NF2 families can start at birth, with the first magnetic resonance (MRI) scan at 10-12 years of age. Minimal interference, maintenance of quality of life, and conservation of function or auditory rehabilitation are the cornerstones of NF2 management, and the decision points to achieve these goals for patients with different clinical presentations are discussed.

Mutation scanning of the NF2 gene: an improved service based on meta-PCR/sequencing, dosage analysis, and loss of heterozygosity analysis.

We describe the development and implementation of a neurofibromatosis type 2 (NF2) mutation scanning service based on novel techniques. All 17 exons of the NF2 gene are amplified in four polymerase chain reaction (PCR) reactions, using the meta-PCR technique to link the NF2 exons into chimeric concatamers. The meta-PCR products are then scanned for point mutations by direct sequencing. A four-exon dosage assay is used to test for large deletion/duplication mutations. In certain cases when tumour studies are necessary, these techniques are also combined with loss of heterozygosity analysis with three highly polymorphic microsatellite markers located within or close to the NF2 gene. Over a period of 2 years, we have applied these techniques in a service setting to the analysis of 271 patient samples (245 lymphocyte DNA; 26 schwannoma DNA). Meta-PCR and sequencing identified 90 point mutations in the 271 blood and tumor samples, 48 of which have not been reported previously. Dosage analysis identified large deletions in 12 of the lymphocyte DNA samples. In addition, over 84% of mutations were identified in 23 schwannoma DNA samples in which complete analysis was possible. Adoption of this novel strategy has increased the overall mutation detection rate in familial NF2 cases to 88% and sporadic NF2 cases to 59%. It has also allowed us to decrease our reporting turnaround times, and because of a low overall failure rate, permitted the running of an efficient and cost-effective service.