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Objective: To report our initial experience with a novel device, designed to provide portable, noninvasive, transcutaneous stimulation of the vagus nerve, both acutely and preventively, as a treatment for cluster headache. Methods: Patients with cluster headache (11 chronic, 8 episodic), from 2 centers, including 7 who were refractory to drug treatment, had sufficient data available for analysis in this open-label observational cohort study. The device, known as the gammaCore , was used acutely to treat individual attacks as well as to provide prevention. Patient-estimated efficacy data were collected by systematic inquiry during follow-up appointments up to a period of 52 weeks of continuous use. Results: Fifteen patients reported an overall improvement in their condition, with 4 reporting no change, providing a mean overall estimated improvement of 48%. Of all attacks treated, 47% were aborted within an average of 11 ± 1 minutes of commencing stimulation. Ten patients reduced their acute use of high-flow oxygen by 55% with 9 reducing triptan use by 48%. Prophylactic use of the device resulted in a substantial reduction in estimated mean attack frequency from 4.5/24 hours to 2.6/24 hours ( p Conclusion: These data suggest that noninvasive vagus nerve stimulation may be practical and effective as an acute and preventive treatment in chronic cluster headache. Further evaluation of this treatment using randomized sham-controlled trials is thus warranted. Classification of evidence: This study provides Class IV evidence that for patients with cluster headache, transcutaneous stimulation of the vagus nerve aborts acute attacks and reduces the frequency of attacks.

Germ line and somatic mutations in the neurofibromatosis Type 2 (NF2) tumor suppressor gene predispose individuals to tumors of the nervous system, including schwannomas and meningiomas. Since identification of the NF2 gene more than a decade ago, a large body of information has been collected on the nature and consequences of these alterations in patients with NF2 and in individuals in whom sporadic tumors associated with NF2 develop. The catalog of mutations identified thus far has facilitated extensive genetic analysis, including studies of patients with mosaicism and phenotype–genotype correlations, and has also led to experiments that have begun to unravel the molecular biology of the NF2 gene and its role in tumorigenesis. The authors describe some of the most significant findings in NF2 genetics and biology over the last decade.

Central nervous system (CNS) tumours are the most common solid tumours in children. Cytogenetic and molecular genetic studies of these neoplasms have previously shown abnormalities of chromosome 17, implicating genes on this autosome in tumorigenesis. To identify mutations in the TP53 tumour suppressor gene (17p13.1), we have sequenced the five highly conserved regions of this gene in 29 mixed paediatric CNS tumors. No mutations were detected by this analysis. In order to identify other candidate disease loci on chromosome 17, we have carried out a detailed deletion mapping analysis using 16 polymorphic DNA markers on 19 of the above tumours and an additional four cases. Abnormalities of chromosome 17 occurred in nine cases (39%), six of which were primitive neuroectodermal tumour (PNET)-medulloblastomas. These findings suggest that it is unlikely that the TP53 gene is directly involved in the development of common paediatric brain tumours. This is in contrast to findings from adult brain and other tumour types. Moreover, the frequency of chromosome 17 aberrations, especially in PNET-medulloblastomas, suggests that other genes on this chromosome contribute to tumourigenesis.

Meningioma is a common, usually benign, sporadic and solitary tumor of the meninges covering the central nervous system. Meningiomas can become malignant, and such anaplastic tumors are associated with a high rate of recurrence and death from the disease. We analyzed 16 sporadic, anaplastic meningiomas for loss of alleles on the majority of chromosomal arms, in order to define regions in the genome which may be important for tumor progression. Loss of genetic material was observed on all but 2 chromosomes studied. While loss of heterozygozity (LOH) from chromosome 22 was the most frequent finding, LOH from the short arm of chromosome I was the second most common lesion occurring preferentially in tumors from men, and at a frequency almost as high as for LOH on chromosome 22. This suggests the existence of a tumor-suppressor locus on Ip involved in meningioma carcinogenesis. Three tumor samples from one large, anaplastic tumor, each with distinct histopathological characteristics, were studied. All 3 samples showed deletions on 22q and Ip. However, only one tumor sample, with the most malignant histopathological phenotype, displayed, in addition to 22q and Ip, deletions on 9q and 17p. This case suggests that the latter 2 chromosomal regions may harbor genes which contribute to the progression of meningioma.

A 140 kb homozygous deletion from 22q12 in one meningioma directed us towards the cloning and characterization of a new member of the human beta-adaptin gene family (named BAM22). Adaptins are essential for the formation of clathrin coated vesicles in the course of intracellular transport of receptor-ligand complexes. The BAM22 gene is totally inactivated in the tumor with homozygous deletion. Northern blot analysis of 70 sporadic meningiomas showed specific loss of expression in 8 tumors, suggesting inactivation of BAM22. Based on this, we propose BAM22 as a second chromosome 22 locus important in meningioma development, after the neurofibromatosis type 2 gene.

Loss of genetic information from chromosome 22 has been implicated in the development of neurofibromatosis type 2, meningioma, and several other neoplasia. Molecular studies indicate that genes within chromosomal band 22q12 may be involved in tumorigenesis. We have mapped 29 loci into 16 groups in this region, using pulsed-field gel electrophoresis, fluorescence in situ suppression hybridization, and somatic cell hybrid mapping. The region spans more than 5 Mb of genomic DNA and contains the genes for neurofibromatosis type 2 and meningioma. The order of loci presented here provides the framework for the fine mapping of this region using cosmids and yeast artificial chromosomes, and it facilitates the speedy cloning of novel genes from 22q12.

Schwannomas are tumors arising from schwann cells surrounding peripheral nerves. Although most schwannomas are sporadic, they are seen in approximately 90% of individuals with neurofibromatosis type 2 (NF2), an autosomal dominantly inherited disease with an incidence of 1:40000 live births. The NF2 gene has recently been isolated on chromosome 22 and encodes a putative membrane organizing protein named schwannomin. It is believed to act as a tumor suppressor gene based on the high frequency of loss of heterozygosity (LOH) on this autosome in both sporadic and NF2 associated schwannomas and meningiomas and the identification of inactivating mutation in NF2 patients. In this study we examined 61 schwannomas including 48 sporadic schwannomas (46 of which are vestibular schwannomas) and 12 schwannomas obtained from NF2 patients, for mutations in 10 of the 16 coding exons of the NF2 gene. Twelve inactivating mutations were identified, 8 in sporadic tumours and 4 in tumors from people with NF2. These results support the hypothesis that loss of function of schwannomin is a frequent and fundamental event in the genesis of schwannomas.

In order to permit detailed characterization of meningioma cases showing deletions within chromosomal band 22q12 and further systematically clone genes located within this region, we established a genomic YAC and cosmid contig which encompasses a region in excess of 1000 kb of 22q12. The YAC contig consists of 6 YAC clones arranged into 5 overlapping steps covering more than 1100 kb. Two corresponding cosmid contigs consisting of 40 steps of overlapping groups of cosmids encompasses 900-1000 kb. This set of genomic clones provides a detailed physical map of this part of chromosome 22 and constitutes a basis for the isolation and characterization of genes that may be located within this chromosomal region. Employing the exon-amplification method on two cosmids from the contig, we cloned a novel, anonymous gene, pK1.3, which potentially encodes a protein of 683 amino acids with a predicted molecular weight of of 78.5 kD. Its 2.7 kb mRNA is expressed ubiquitously. We estimated the genomic size of this gene to 100-150 kb, and it is located in the immediate centromeric vicinity of the neurofibromatosis 2 (NF2) tumor suppressor gene.

A series of 195 random chromosome 22-specific probes, equivalent to approximately 1% of the size of this chromosome, have been isolated from a chromosome 22-specific bacteriophage lambda genomic library. These probes were mapped to four different regions of chromosome 22 on a panel of five somatic cell hybrids. Restriction fragment length polymorphisms were detected by 28 of the probes mapping to 22q12-qter. Evolutionarily conserved sequences in human, mouse, and Chinese hamster DNA were detected by 12% of the isolated probes.

Women who carry a mutation in the BRCA1 gene (on chromosome 17q21), have an 80% risk of breast cancer and a 40% risk of ovarian cancer by the age of 70 (ref. 1). The variable penetrance of BRCA1 suggests that other genetic and non-genetic factors play a role in tumourigenesis in these individuals. The HRAS1 variable number of tandem repeats (VNTR) polymorphism, located 1 kilobase (kb) downstream of the HRAS1 proto-oncogene (chromosome 11p15.5) is one possible genetic modifier of cancer penetrance. Individuals who have rare alleles of the VNTR have an increased risk of certain types of cancers, including breast cancer (2-4). To investigate whether the presence of rare HRAS1 alleles increases susceptibility to hereditary breast and ovarian cancer, we have typed a panel of 307 female BRCA1 carriers at this locus using a PCR-based technique. The risk for ovarian cancer was 2.11 times greater for BRCA1 carriers harbouring one or two rare HRAS1 alleles, compared to carriers with only common alleles (P = 0.015). The magnitude of the relative risk associated with a rare HRAS1 allele was not altered by adjusting for the other known risk factors for hereditary ovarian cancer (5). Susceptibility to breast cancer did not appear to be affected by the presence of rare HRAS1 alleles. This study is the first to show the effect of a modifying gene on the penetrance of an inherited cancer syndrome.

The molecular genetic alterations that underlie development of gliomas, the most common neoplasm of the human central nervous system, include activation of cellular proto-oncogenes as well as inactivation of tumor suppressor genes. Although research has identified some affected loci, others clearly remain to be identified. We have investigated loss of heterozygosity on chromosome 22 in a panel of sporadic gliomas, and have assessed the possibility that inactivation of the neurofibromatosis type 2 (NF2) tumor suppressor gene on 22q plays a role in development of sporadic gliomas in humans. Loss of heterozygosity for loci on chromosome 22 loci was observed in 15 of 47 informative blood-tumor pairs, although no common area of loss of heterozygosity shared by all of these tumors could be identified. The most frequently affected segment, distal to the NF2 locus and bounded proximally by D22S15 and distally by a gene for myoglobin, was shared by as many as 11 tumors. Loss of heterozygosity at the NF2 locus was observed in 10 tumors. No rearrangements of the NF2 gene could be detected by Southern analysis of restriction endonuclease-digested genomic DNA, and no abnormally migrating bands were detected on single strand conformation analysis of individual exons of the NF2 gene. Thus, although frequent loss of heterozygosity on chromosome 22 suggests that inactivation of a tumor suppressor gene on this chromosome plays a role in development of gliomas, there is no evidence that inactivation of the NF2 gene is implicated in this process, confirming the results of other studies of the NF2 gene in human gliomas. The identity of the putative tumor suppressor gene on 22q involved in development of gliomas remains unknown.

Meningiomas are the second most common group of primary central nervous system tumors in humans. Cytogenetic and molecular studies imply that genes involved in the primary development of meningioma reside on chromosome 22. The recently characterized neurofibromatosis type 2 gene (NF2) has been shown to be mutated in two cases of sporadic meningioma, suggesting that this is the chromosome 22 gene which is involved in tumorigenesis. We have investigated a series of 170 meningiomas by deletion mapping analysis with 43 markers from chromosome 22 to ascertain if NF2 is the only gene on this autosome that is inactivated. Half of the tumors showed results consistent with monosomy for chromosome 22, whereas 13 cases showed terminal deletions of 22q, including the NF2 region. Homozygous (complete) deletions were detected in tumors from two patients. In one of them complete loss was found at the NF2 locus and cosmid contigs from the region were used to determine the extent of the deletions. The second tumor showed homozygous loss of two large genomic regions outside the NF2 region. These aberrations were confined to only one part of this large tumor, suggesting that they may be involved in the later stages of meningioma development. An additional four tumors had interstitial deletions on chromosome 22, in three of them without overlap with NF2. Our results show that NF2 is completely inactivated in sporadic meningioma but do not rule out the possibility that additional chromosome 22 loci are important in tumorigenesis.

Meningiomas are common central nervous system tumours which present usually in the 4th and 5th decades of life. Loss of constitutional heterozygosity on chromosome 22 in 60% of sporadic meningiomas has implied the involvement of a tumour suppressor gene. The neurofibromatosis type 2 gene (NF2), a prime candidate for involvement in meningioma, was screened for point mutations. After examining eight of the 16 known NF2 exons in 151 meningiomas, 24 inactivating mutations were characterized. Significantly, these aberrations were exclusively detected in tumours which lost the other chromosome 22 allele. These results provide strong evidence that the suppressor gene on chromosome 22, frequently inactivated in meningioma, is the NF2 gene, and suggest that another gene is involved in the development of 40% of meningiomas.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disease which predisposes to the development of schwannomas, meningiomas, ependymomas, and juvenile cataracts. The NF2 gene (NF2) has recently been isolated and maps to chromosome 22q12 between the loci D22S212 and D22S32. Deletion studies in sporadic and NF2 associated schwannomas and meningiomas, and the presence of inactivating mutations in NF2 in patients suggest that it acts as a tumor suppressor gene. A candidate meningioma gene (MEN) has also been isolated from the same interval. A new highly polymorphic (CA)n marker, D22S268, which maps very near to NF2, has allowed us to identify a kindred with three living affected individuals, where the disease is presumably caused by a large germline deletion. Fluorescence in situ hybridization and pulsed field gel electrophoresis confirm the presence of a 700kb deletion which includes the neurofilament heavy chain subunit gene locus (NEFH), D22S268, NF2 and the putative MEN gene. The absence of meningiomas in this pedigree raises doubts as to the existence of a separate MEN locus in this region. These results support the hypothesis that NF2 results from the inactivation of a tumor suppressor gene on chromosome 22q.