Sporadic and NF2-associated vestibular schwannoma surgery and simultaneous cochlear implantation: a comparative systematic review.

PURPOSE: Cochlear implantation (CI) in patients with sensorineural hearing loss caused by a vestibular schwannoma (VS) represents a unique subtype of hearing rehabilitation, as the outcome may be compromised by vestibulocochlear nerve injury as part of the natural VS history or due to iatrogenic trauma induced by surgical tumor removal. This paper aims to review and report contemporary knowledge and practice regarding feasibility and outcomes of simultaneous vestibular schwannoma resection and cochlear implantation to serve as a reference and guide for future surgery and studies. METHODS: The current literature was searched systematically according to the PRISMA guidelines and after criteria-based selection, 29 studies were identified, including a total of 86 patients who had undergone surgical resection of a vestibular schwannoma and subsequent cochlear implantation in a single procedure. RESULTS: The postoperative outcomes were reported with a high degree of heterogeneity, hindering a proper meta-analysis. However, pooling those cases with reported speech discrimination outcomes demonstrated mean scores equivalent to moderate-to-high performance. A few cases had no audibility. A positive cochlear nerve test result was not a secure positive predictor of success. Complications were rare. CONCLUSION: NF2-associated and sporadic VS had good and comparable postoperative outcomes despite significant differences in tumor size, location and surgical approach.

Ocular alterations, molecular findings, and three novel pathological mutations in a series of NF2 patients.

PURPOSE: To evaluate ophthalmological and molecular findings in eight patients with a clinical diagnosis of neurofibromatosis type 2 (NF2). New pathological mutations are described and variability in the ophthalmic phenotype and NF2 allelic heterogeneity are discussed. METHODS: Eye examination was performed in eight NF2 patients, and it included the measurement of the visual acuity, biomicroscopy, dilated fundus examination, color fundus photography, infrared photography, and spectral domain optical coherence tomography (SD-OCT). Molecular analysis was performed with whole-exome sequencing using DNA derived from peripheral blood mononuclear cells from each individual. RESULTS: Ophthalmological features were present in all patients, ranging from subtle retinal alterations identified only using SD-OCT to severe ocular damage present at birth. Six mutations were observed: two patients with stop codon mutation as shown on table 1 and result section, three patients with frameshift mutation as shown on table 1 and result section. Three novel mutations were found among them. CONCLUSIONS: It is a descriptive study of a rare disease, with poor previous literature. Clinical and genetic data are shown, reviving the need to further studies to clarify the genotype-phenotype correlations in NF2.

Deregulation of the Hippo Pathway Promotes Tumor Cell Proliferation Through YAP Activity in Human Sporadic Vestibular Schwannoma.

OBJECTIVE: Vestibular schwannomas (VSs) can cause serious neurological defects including hearing loss and facial paralysis. The aim of this study is to identify whether Hippo signaling could be a potential targetable pathway for clinical treatment in VSs. METHODS: Gene expression profiling was performed in 10 sporadic VSs and 4 normal nerves to identify aberrant genes expression of the Hippo pathway. Western blotting and immunohistochemical staining were used to examine the expression of Hippo core components in 20 VS samples. Neurofibromatosis type 2 (NF2) gene sequencing was also performed in all tumors using sanger sequencing. Verteporfin, inhibitor of yes-associated protein (YAP)-TEA domain family member, was used to assess the effect of proliferation inhibition in human primary VS cells and RT4-D6P2T cell line. RESULTS: We found 51 differentially expressed genes of the Hippo pathway between VSs and healthy controls. Unsupervised analysis identified the 2 molecular variants that significantly related with distinct NF2 mutation status. The phosphorylation levels of large tumor suppressor 1 and YAP were significantly decreased in NF2-mutated VSs compared with wild-type VSs and normal nerves. Immunohistochemical staining showed that increased nuclear YAP expression in VSs was positively correlated with high Ki-67 index and low Merlin expression. Verteporfin reduced viability of primary VS cells and RT4-D6P2T cells. CONCLUSIONS: Our findings implicate that deregulation of the Hippo pathway as a molecular mechanism of pathogenesis in human VSs, and suggest inhibition of this pathway as a potential treatment strategy.

CASP8, XRCC1, WRN, NF2, and BRIP1 Polymorphisms Analysis Shows Their Genetic Susceptibility for Meningioma Risk and the Association with Tumor-Related Phenotype in a Chinese Population.

OBJECTIVE: To investigate 10 candidate single nucleotide polymorphisms (SNPs) in 5 genes (CASP8, XRCC1, WRN, NF2, and BRIP1) to confirm the association between the 5 genes and the meningioma risk in a Chinese population. METHODS: We examined 10 candidate SNPs in 5 genes (CASP8, XRCC1, WRN, NF2, and BRIP1) to confirm the association between the 5 genes and the meningioma risk and tumor-related phenotype in 433 individuals, including 215 patients with meningioma and 218 controls. RESULTS: The polymorphisms rs4968451T>G in BRIP1 were significantly associated with the risk of meningioma (TT vs. TG vs. GG additive, P = 0.005; TT+TG vs. GG dominant, P = 0.015; TT/GT+GG recessive, P = 0.034). The significant association was found only in females for BRIP1 rs4968451T>G (TT+TG vs. GG dominant, P = 0.001; TT/GT+GG recessive, P = 0.044). We observed no significant association between genotypes and the meningioma risk for the other 9 SNPs. Through genotype-phenotype analysis, the genotype of BRIP1 rs4968451T>G was also strongly associated with tumor-related phenotypes, including the tumor grade and tumor subtypes. BRIP1 rs4968451T>G was associated with markedly grade I meningioma risk (TT+TG vs. GG dominant, P = 0.008; TT/GT+GG recessive, P = 0.020). In addition, BRIP1 rs4968451T>G was associated with markedly meningothelial and transitional meningioma risk. Furthermore, the genotype of CAPS8, XRCC1, and NF2 was associated with different subtype of meningioma risk. CONCLUSIONS: This study indicated a role for BRIP1 gene variations in meningioma and may be informative for future genetic or biological studies of meningioma. These findings will assist in further understanding the genetic cause for meningiomas and guide more effective biological interventions to facilitate meningiomas.

Neurofibromatosis type 2 French cohort analysis using a comprehensive NF2 molecular diagnostic strategy.

OBJECTIVE: Neurofibromatosis type 2 (NF2) affects about one in 25,000 to 40,000 people. Most NF2 patients have private loss-of-function mutations scattered along the NF2 gene. Here, we present our NF2 investigation strategy. MATERIAL AND METHODS: We report a comprehensive NF2 mutation analysis of 221 NF2 French patients: 134 unrelated typical NF2 patients fulfilling the Manchester criteria and 87 unrelated patients presenting symptoms that partially fulfilled the Manchester criteria. RESULTS: A NF2 mutation was identified in 56 of the 221 patients, giving a global mutation detection rate of 25%. This rate reached 37% (49/134) for typical NF2 patients fulfilling the Manchester criteria and only 8% (7/87) for patients presenting symptoms suggestive of NF2. Six of these seven patients were under 25 of age. Our approach showed that 77% of NF2 identified variants were detected by coding exons sequencing. Multiplex ligation-dependent probe amplification allowed the identification of restricted rearrangements (23% of NF2 identified variants corresponding to complete deletion or partial deletion/duplication of NF2). CONCLUSION: High mutation detection rate can be achieved if well phenotyped NF2 patients are studied with multiple complementary and optimized techniques. NF2 somatic mosaicism detection was improved by frozen tumor samples molecular analysis.

ß1 integrin-dependent Rac/group I PAK signaling mediates YAP activation of Yes-associated protein 1 (YAP1) via NF2/merlin.

Cell adhesion to the extracellular matrix or to surrounding cells plays a key role in cell proliferation and differentiation and is critical for proper tissue homeostasis. An important pathway in adhesion-dependent cell proliferation is the Hippo signaling cascade, which is coregulated by the transcription factors Yes-associated protein 1 (YAP1) and transcriptional coactivator with PDZ-binding motif (TAZ). However, how cells integrate extracellular information at the molecular level to regulate YAP1's nuclear localization is still puzzling. Herein, we investigated the role of ß1 integrins in regulating this process. We found that ß1 integrin-dependent cell adhesion is critical for supporting cell proliferation in mesenchymal cells both in vivo and in vitro ß1 integrin-dependent cell adhesion relied on the relocation of YAP1 to the nucleus after the down-regulation of its phosphorylated state mediated by large tumor suppressor gene 1 and 2 (LATS1/2). We also found that this phenotype relies on ß1 integrin-dependent local activation of the small GTPase RAC1 at the plasma membrane to control the activity of P21 (RAC1)-activated kinase (PAK) of group 1. We further report that the regulatory protein merlin (neurofibromin 2, NF2) interacts with both YAP1 and LATS1/2 via its C-terminal moiety and FERM domain, respectively. PAK1-mediated merlin phosphorylation on Ser-518 reduced merlin's interactions with both LATS1/2 and YAP1, resulting in YAP1 dephosphorylation and nuclear shuttling. Our results highlight RAC/PAK1 as major players in YAP1 regulation triggered by cell adhesion.

A mosaic pattern of INI1/SMARCB1 protein expression distinguishes Schwannomatosis and NF2-associated peripheral schwannomas from solitary peripheral schwannomas and NF2-associated vestibular schwannomas.

BACKGROUND: The INI1/SMARCB1 gene protein product has been implicated in the direct pathogenesis of schwannomas from patients with one form of schwannomatosis [SWNTS1; MIM # 162091] showing a mosaic pattern of loss of protein expression by immunohistochemistry [93% in familial vs. 55% in sporadic cases]. AIM OF STUDY: To verify whether such INI1/SMARCB1 mosaic pattern could be extended to all schwannomas arising in the sporadic and familial schwannomatoses [i.e. to SMARCB1-related (SWNTS1) or LZTR1-related (SWNTS2) schwannomatosis or to SMARCB1/LZTR1-negative schwannomatosis] and whether it could be involved in classical NF2 or solitary peripheral schwannomas METHODS: We blindly analysed schwannoma samples obtained from a total of 22 patients including (a) 2 patients (2 males; aged 38 and 55 years) affected by non-familial SMARCB1-associated schwannomatosis (SWTNS1); (b) 1 patient (1 female; aged 33 years) affected by familial schwannomatosis (SWTNS1/ SMARCB1 germ line mutations); (c) 5 patients (3 males, 2 females; aged 33 to 35 years) affected by non-familial (sporadic) LZTR1-associated schwannomatosis (SWNTS2); (d) 3 patients (3 males; aged 35 to 47 years) affected by familial schwannomatosis (SWTNS2/ LZTR1 germ line mutations); (e) 2 patients (1 male, 1 female; aged 63 and 49 years, respectively) affected by non-familial schwannomatosis (SWTNS, negative for SMARCB1, LZTR1 and NF2 gene mutations); (f) 4 patients (3 males, 1 females; aged 15 to 24 years) affected by classical NF2 (NF2: harbouring NF2 germ line mutations; and (g) 5 patients (3 males, 2 females; aged 33 to 68 years) who had solitary schwannomas. [follow-up = 15-30 years; negative for constitutional/somatic mutation analysis for the SMARCB1, LZTR1 and NF2 genes] were (blindly) analyzed. The INI1/SMARCB1 immunostaining pattern was regarded as (1) diffuse positive nuclear staining [= retained expression] or (2) mosaic pattern [mixed positive/negative nuclei = loss of expression in a subset of tumour cells]. RESULTS: All solitary peripheral schwannomas and NF2-associated vestibular schwannomas showed diffuse nuclear INI1/SMARCB1 staining in 97-100% of neoplastic cells; schwannomas obtained from all cases of non-familial and familial schwannomatosis and NF2-associated non-vestibular schwannomas showed a mosaic pattern ranging from 10 to 70% of INI1/SMARCB1-positive expression. We did not record a complete lack of nuclear staining. CONCLUSIONS: The present data suggests that (a) mosaic loss of immunohistochemical INI1/SMARCB1 expression, despite the interlesional variability, is a reliable marker of schwannomatosis regardless of the involved gene and it might help in the differential diagnosis of schwannomatosis vs. solitary schwannomas and (b) INI1/SMARCB1 expression is not useful in the differential with mosaic NF2, since NF2-associated peripheral schwannomas show the same immunohistochemical pattern.

Genomic Characterization of Renal Cell Carcinoma with Sarcomatoid Dedifferentiation Pinpoints Recurrent Genomic Alterations.

BACKGROUND: The genomic features underpinning renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) are not well understood, and at present, there are no specific or effective therapies for sRCC. OBJECTIVE: To identify genomic alterations in patients with sRCC. DESIGN, SETTING, AND PARTICIPANTS: We conducted genomic profiling on paired epithelial and sarcomatoid areas of three sRCC cases. Genomic profiling was performed on another 23 sRCC patients harboring diverse epithelial components (total of 26 cases). Genomic profiling was conducted using a hybrid capture DNA next-generation sequencing assay of 236 cancer-related genes plus 19 genes frequently rearranged in cancer. Results were compared with 56 similarly sequenced cases of clear cell RCC (ccRCC) devoid of a sarcomatoid component, and with clear cell, papillary, and chromophobe renal cell carcinoma datasets from The Cancer Genome Atlas. Four additional ccRCC cases underwent whole exome sequencing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Genomic alterations in patients with sRCC and ccRCC were described, and their frequencies were compared using the Fisher exact test. RESULTS AND LIMITATIONS: Two of three patients with sRCC who underwent genomic profiling of both their epithelial and sarcomatoid components demonstrated identical mutational profiles, and a third case demonstrated commonly disrupted genes. Of the 26 sRCCs, TP53 (42.3%), VHL (34.6%), CDKN2A (26.9%), and NF2 (19.2%) were the most frequently altered genes. NF2 mutations were mutually exclusive with TP53 but not with VHL mutations. Limitations include the small sample size. CONCLUSIONS: We found that sRCC contains different driver mutations than ccRCC. The epithelial and sarcomatoid components of sRCC largely contain the same genomic features. On the basis of harboring either TP53 or NF2 mutations, sRCC can be divided into two groups. These findings may have implications for understanding the oncogenesis of sarcomatoid renal tumors and for defining systemic treatment options. PATIENT SUMMARY: Next-generation sequencing of tumors from patients with sarcomatoid kidney cancer reveals mutations that differ from those in nonsarcomatoid patients. These findings have implications in understanding the pathobiology of sarcomatoid kidney cancer and indicate the need for a different treatment approach in these patients.

Alterations in the NF2/LATS1/LATS2/YAP Pathway in Schwannomas.

Schwannomas are benign nerve sheath tumors composed of well-differentiated Schwann cells. Other than frequent NF2 (neurofibromatosis type 2) mutations (50%-60%), their molecular pathogenesis is not fully understood. LATS1 and LATS2 are downstream molecules of NF2 and are negative regulators of the yes-associated protein (YAP) oncogene in the Hippo signaling pathway. We assessed mutations of the NF2, LATS1, and LATS2 genes, promoter methylation of LATS1 and LATS2, and expression of YAP and phosphorylated YAP in 82 cases of sporadic schwannomas. Targeted sequencing using the Ion Torrent Proton instrument revealed NF2 mutations in 45 cases (55%), LATS1 mutations in 2 cases (2%), and LATS2 mutations in 1 case (1%) of schwannoma. Methylation-specific polymerase chain reaction showed promoter methylation of LATS1 and LATS2 in 14 cases (17%) and 25 cases (30%), respectively. Overall, 62 cases (76%) had at least 1 alteration in the NF2, LATS1, and/or LATS2 genes. Immunohistochemistry revealed nuclear YAP expression in 18 of 42 cases of schwannoma (43%) and reduced cytoplasmic phosphorylated YAP expression in 15 of 49 cases of schwannoma (31%), all of which had at least 1 alteration in the NF2, LATS1, and/or LATS2 genes. These results suggest that an abnormal Hippo signaling pathway is involved in the pathogenesis of most sporadic schwannomas.

Tumor suppressor alterations cooperate to drive aggressive mesotheliomas with enriched cancer stem cells via a p53-miR-34a-c-Met axis.

Malignant mesothelioma is a highly aggressive, asbestos-related cancer frequently marked by mutations of both NF2 and CDKN2A. We demonstrate that germline knockout of one allele of each of these genes causes accelerated onset and progression of asbestos-induced malignant mesothelioma compared with asbestos-exposed Nf2(+/-) or wild-type mice. Ascites from some Nf2(+/-);Cdkn2a(+/-) mice exhibited large tumor spheroids, and tail vein injections of malignant mesothelioma cells established from these mice, but not from Nf2(+/-) or wild-type mice, produced numerous tumors in the lung, suggesting increased metastatic potential of tumor cells from Nf2(+/-);Cdkn2a(+/-) mice. Intraperitoneal injections of malignant mesothelioma cells derived from Nf2(+/-);Cdkn2a(+/-) mice into severe combined immunodeficient mice produced tumors that penetrated the diaphragm and pleural cavity and harbored increased cancer stem cells (CSC). Malignant mesothelioma cells from Nf2(+/-);Cdkn2a(+/-) mice stained positively for CSC markers and formed CSC spheroids in vitro more efficiently than counterparts from wild-type mice. Moreover, tumor cells from Nf2(+/-);Cdkn2a(+/-) mice showed elevated c-Met expression/activation, which was partly dependent on p53-mediated regulation of miR-34a and required for tumor migration/invasiveness and maintenance of the CSC population. Collectively, these studies demonstrate in vivo that inactivation of Nf2 and Cdkn2a cooperate to drive the development of highly aggressive malignant mesotheliomas characterized by enhanced tumor spreading capability and the presence of a CSC population associated with p53/miR-34a-dependent activation of c-Met. These findings suggest that cooperativity between losses of Nf2 and Cdkn2a plays a fundamental role in driving the highly aggressive tumorigenic phenotype considered to be a hallmark of malignant mesothelioma.

Advances in the treatment of neurofibromatosis-associated tumours.

Neurofibromatosis (NF) comprises two distinct genetic disorders-neurofibromatosis type 1 and 2 (NF1 and NF2)-in which affected individuals develop both benign and malignant tumours. NF1 results from germline mutations in the NF1 gene that encodes neurofibromin, while NF2 results from germline mutations in the NF2 gene that encodes merlin (or schwannomin). The major tumour types arising in individuals with NF1 include neurofibromas, malignant peripheral nerve sheath tumours, and gliomas, whereas NF2 is characterized by the formation of schwannomas, meningiomas, and ependymomas. With the identification of the NF1 and NF2 genes and the generation of robust preclinical mouse models of NF-associated neoplasms, novel treatments that specifically target the growth control pathways deregulated in these tumours have been discovered, some of which are now being tested in clinical trials in individuals with NF1 and NF2. In this Review, we will highlight the key clinical features of NF1 and NF2 and the advances in future clinical management based on an improved understanding of the function of the NF1 and NF2 genes and the development of small-animal models.

Intracranial meningiomas and neurofibromatosis type 2.

PURPOSE: In spite of the few clinical studies regarding the occurrence of intracranial meningiomas, their prognosis in neurofibromatosis type 2 (NF2) has not been accurately assessed and their management remains controversial. This study aims to compare NF2 patients with intracranial meningiomas to those without, and consequently to identify prognostic factors in attempt to improve the management of these tumors. METHODS: This retrospective study includes a total of 80 NF2 patients followed at Lille Hospital Center between 1987 and 2011. The diagnosis of NF2 was confirmed either because the patient met the Manchester criteria or by the presence of genetic mutation. Clinical, radiological and genetic data were retrospectively recorded and analyzed. Patients underwent annual cranial and spinal MRI. Both location and size of each tumor were reported. RESULTS: The mean follow-up period was 8.8 years (range 1-24 years; SD: ±0.8) and the mean age at diagnosis was 27.2 years (range 6-73 years; SD: ±1.7). Among all patients, 34 harbored intracranial meningiomas. Patients with intracranial meningiomas had a higher number of intracranial schwannomas, spinal tumors and cutaneous tumors (p < 0.05). They underwent more surgical procedures (p < 0.012). Twenty five intracranial meningiomas were surgically removed in 17 patients. The decision to perform surgery was taken in 10 cases for symptomatic tumors and in 15 cases for growing asymptomatic tumors determined by radiology. The histological analysis found a high rate of fibroblastic, transitional or grade 2 meningiomas preferentially located at the cerebri falx. CONCLUSION: Intracranial meningiomas are common in NF2. They are associated with poor prognosis factors. Clinical and radiological monitoring could lead to early treatment of these tumors both when clinical symptoms are present and in case of proven radiological evolution, and thus trying to maintain a favorable functional prognosis for as long as possible.

mTORC1 inhibitors suppress meningioma growth in mouse models.

PURPOSE: To evaluate the mTORC1 (mammalian target of rapamycin complex 1) pathway in meningiomas and to explore mTORC1 as a therapeutic target in meningioma cell lines and mouse models. EXPERIMENTAL DESIGN: Tissue microarrays (53 meningiomas of all WHO grades) were stained for phosphorylated polypeptides of mTOR, Akt, and the mTORC1 targets 4EBP1 and p70S6K, the latter being the consensus marker for mTORC1 activity. Expression of proteins and mRNAs was assessed by Western blotting and real-time PCR in 25 tumors. Cell lines Ben-Men-1 (benign), IOMM-Lee and KT21 (malignant), and pairs of merlin-positive or -negative meningioma cells were used to assess sensitivity toward mTORC1 inhibitors in methyl-tetrazolium and bromodeoxyuridine (BrdUrd) assays. The effect of temsirolimus (20 mg/kg daily) on tumor weight or MRI-estimated tumor volume was tested by treatment of eight nude mice (vs. 7 controls) carrying subcutaneous IOMM-Lee xenografts, or of eight (5) mice xenotransplanted intracranially with IOMM-Lee (KT21) cells in comparison to eight (5) untreated controls. RESULTS: All components of the mTORC1 pathway were expressed and activated in meningiomas, independent of their WHO grade. A significant dosage-dependent growth inhibition by temsirolimus and everolimus was observed in all cell lines. It was slightly diminished by merlin loss. In the orthotopic and subcutaneous xenograft models, temsirolimus treatment resulted in about 70% growth reduction of tumors (P < 0.01), which was paralleled by reduction of Ki67 mitotic index (P < 0.05) and reduction of mTORC1 activity (p70S6K phosphorylation) within the tumors. CONCLUSION: mTORC1 inhibitors suppress meningioma growth in mouse models, although the present study did not measure survival.

Natural history of neurofibromatosis type 2 with onset before the age of 1 year.

Neurofibromatosis type 2 (NF2) with onset before the first year of life has been anecdotally reported in the literature. We (a) prospectively (years 1997-2012) followed up three unrelated NF2 children, all harbouring NF2 gene mutations whose onset of disease was before age 1 year, and (b) systematically reviewed published reports on NF2 in the youngest age group (i.e. onset <1 year). The present three children had (1) small (<1 cm), bilateral vestibular schwannomas (VSs) detected (as an incidental finding) at magnetic resonance imaging (MRI) by the age of 4 to 5 months that were asymptomatic for 10 to 14 years, with sudden and rapid (<12 months) progression in two cases at the age of 11 and 15 years, respectively; (2) development of large numbers of skin NF2 plaques mainly in atypical locations (i.e. face, hands, legs and knees), which reverted to normal skin appearance at the time of VSs progression; (3) lens opacities (n = 1) and NF2 retinal changes (n = 2) detected as early as age of 3-4 months; (4) diffuse (asymptomatic) high signal lesions at brain MRI in the periventricular regions (alike cortical dysplasia); and (5) unaffected first-degree relatives who did not harbour NF2 gene abnormalities. This represents the youngest NF2 group with the longest prospective follow-up so far reported. NF2 may present as a congenital form with bilateral VSs presenting as early as the first months of life and with natural history different to that which occurs in classical NF2.

Prognostic value and management of spinal tumors in neurofibromatosis type 2 patients.

PURPOSE: Neurofibromatosis type 2 (NF2) is a well-studied disease. Although spinal tumors are frequent, many issues concerning their prognosis and management still have to be clarified. The authors studied the clinical impact and radiological progression of spinal tumors in patients with NF2 to determine their prognostic value. METHODS: A total of 80 NF2 patients were followed in the Lille University Hospital between 1987 and 2011. Clinical, radiological and genetic data were retrospectively recorded and analyzed. Patients underwent annual cranial and spinal MRI. Both the location and size of each tumor were reported. The diagnosis of NF2 was confirmed either because the patient met the Manchester criteria or by the presence of genetic mutation. RESULTS: The mean follow-up period was 8.8 years (range 1 to 24 years; SD: ±0.8), and the mean age at diagnosis was 27.2 years (range 6 to 73 years; SD: ±1.7). Among all patients, 48 harbored spinal tumors. Twenty of them were symptomatic, and 21 were operated on. Patients with spinal tumors had a lower age at diagnosis (p = 0.02), a higher number of intracranial meningiomas (p = 0.028) and schwannomas (p = 0.03), and more nonsense and frameshift mutations (p = 0.04). CONCLUSION: Spinal tumors are common in NF2, and all patients should be regularly monitored by spinal MRI. The presence of spinal tumors seems to be a factor indicating poor prognosis. Clinical and radiological monitoring of spinal tumors could lead to early treatment both when clinical symptoms are present and in case of proven radiological evolution, maintaining a favorable functional prognosis as long as possible.

The NF2 tumor suppressor regulates microtubule-based vesicle trafficking via a novel Rac, MLK and p38(SAPK) pathway.

Neurofibromatosis type 2 patients develop schwannomas, meningiomas and ependymomas resulting from mutations in the tumor suppressor gene, NF2, encoding a membrane-cytoskeleton adapter protein called merlin. Merlin regulates contact inhibition of growth and controls the availability of growth factor receptors at the cell surface. We tested if microtubule-based vesicular trafficking might be a mechanism by which merlin acts. We found that schwannoma cells, containing merlin mutations and constitutive activation of the Rho/Rac family of GTPases, had decreased intracellular vesicular trafficking relative to normal human Schwann cells. In Nf2-/- mouse Schwann (SC4) cells, re-expression of merlin as well as inhibition of Rac or its effector kinases, MLK and p38(SAPK), each increased the velocity of Rab6 positive exocytic vesicles. Conversely, an activated Rac mutant decreased Rab6 vesicle velocity. Vesicle motility assays in isolated squid axoplasm further demonstrated that both mutant merlin and active Rac specifically reduce anterograde microtubule-based transport of vesicles dependent upon the activity of p38(SAPK) kinase. Taken together, our data suggest loss of merlin results in the Rac-dependent decrease of anterograde trafficking of exocytic vesicles, representing a possible mechanism controlling the concentration of growth factor receptors at the cell surface.

Intracranial clear cell meningioma in two children with blood relations: two case reports and literature review.

Intracranial clear cell meningioma (CCM) is very rare and often has an aggressive clinical course. The predilection site of intracranial CCM in children was cerebellopontine angle where represents challenging tumor resection because of the vicinity of brainstem, vertebral artery, and lower cranial nerve. Therefore, special consideration is required for this tumor.We report two cases with intracranial CCM in a family and reviewed the literature concerning pediatric intracranial CCM. Case 1 is a 4-year-old boy with a tumor at the right posterior fossa. Case 2 is an 8-year-old boy with a left basilar region tumor. Gross total resection and subtotal resection was achieved in case 1 and case 2, respectively. Case 1 had no tumor recurrence at 12 months after the operation. Case 2 received cyber-knife radiosurgery (CKS) after subtotal resection at 4 months, and the residual tumor had gradually shrunk. Comprehensive chromosomal number aberrations in both patients were revealed by array-comparative genomic hybridization, and loss of neurofibromatosis 2 (NF2) gene was the common genetic abnormality in the two patients.To the best of our knowledge, this is the first report concerned two patients with CCM in a family, and the findings in this article suggest that CKS is a safe and effective adjuvant therapy for residual CCM after operation and NF2 gene mutation plays a role in tumorigenesis of pediatric intracranial CCM.

[Expression of Merlin protein in non-small cell lung carcinoma and the clinical significance].

OBJECTIVE: To determine the expression and clinical significance of Merlin protein in non-small cell lung cancer (NSCLC). METHODS: The expression of Merlin protein in 45 cases of NSCLC and adjacent tissue of NSCLC and normal lung tissue was checked by immunohistochemistry. The relation between the expression of Merlin protein and the multiple factors of pathological type, gender, P-TNM stage, differentiation and lymph node metastasis was analyzed. RESULTS: The expression rates of Merlin protein in NSCLC and normal lung tissue sections were 73.33% and 15.56%, respectively (P<0.05). The expression of Merlin protein was not associated with the pathological type, gender, P-TNM stage, differentiation and lymph node metastasis (P>0.05). CONCLUSION: Merlin protein might contribute to the initiation of metastasis of NSCLC.

[Drosophila tumor suppressor Merlin is essential for morphogenesis of mitochondria during sperm formation].

Drosophila Merlin, an ortholog of the merlin protein encoded by the human Neurofibromatosis 2 (NF2) gene, is important for the regulation of cell proliferation and differentiation in the eye and wing. Also, it has been shown to be involved in male fertility in flies. In the present study, we formation using the comparative light and electron microscopic research of merlin mutants (mer3 and mer4) and ectopic expression of the Mer+ construct. Our work defines specific functions for Merlin in the mitochondria association and aggregation during the nebenkern formation and unfurling mitochondrial derivates during spermatid elongation. Possible role of Merlin as an adaptor protein that can link mitochondria with cytoskeleton is discussed.