[show abstract][hide abstract] ABSTRACT: Hemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged, malformed cerebral hemisphere, typically causing epilepsy that requires surgical resection. We studied resected HMG tissue to test whether the condition might reflect somatic mutations affecting genes critical to brain development. We found that two out of eight HMG samples showed trisomy of chromosome 1q, which encompasses many genes, including AKT3, a gene known to regulate brain size. A third case showed a known activating mutation in AKT3 (c.49G→A, creating p.E17K) that was not present in the patient's blood cells. Remarkably, the E17K mutation in AKT3 is exactly paralogous to E17K mutations in AKT1 and AKT2 recently discovered in somatic overgrowth syndromes. We show that AKT3 is the most abundant AKT paralog in the brain during neurogenesis and that phosphorylated AKT is abundant in cortical progenitor cells. Our data suggest that somatic mutations limited to the brain could represent an important cause of complex neurogenetic disease.
[show abstract][hide abstract] ABSTRACT: Low grade tumors are associated with a high risk of seizures. Prolonged use of antiepileptic drugs (AEDs) is associated with morbidity. Determining which patients can safely discontinue AEDs perioperatively is difficult. We examined patients with low grade supratentorial brain tumors to determine characteristics of patients who underwent AED withdrawal. A retrospective chart review was performed in patients who underwent resection between 1/1/2004 and 12/31/2005 at a single center. Data were collected regarding the use of postoperative AEDs, occurrence of postoperative seizures, and patient/tumor characteristics. We examined 169 patients with a median follow-up of 3.1 years. AEDs were withdrawn or never started in 111 patients; post-withdrawal seizures occurred in 11 (9.9%). The rate was similar between meningiomas and primary brain tumors. No independent risk factors for post-withdrawal seizures were found. Of 58 patients whose AEDs were not withdrawn, postoperative seizures occurred in 28 (48%). Predictors of AED continuation included existence of preoperative seizures, temporal tumor location, tumor recurrence, incomplete resection, and male sex. The decision to continue AEDs was predictive for postoperative seizures even after controlling for known risk factors. Although clinicians are able to identify patients at high risk for postoperative seizures, treatment with AEDs is ineffective in many patients.
Journal of Neuro-Oncology 01/2012; 107(3):565-70. · 3.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mutations of the NF2 gene on chromosome 22q are thought to initiate tumorigenesis in nearly 50% of meningiomas, and 22q deletion is the earliest and most frequent large-scale chromosomal abnormality observed in these tumors. In aggressive meningiomas, 22q deletions are generally accompanied by the presence of large-scale segmental abnormalities involving other chromosomes, but the reasons for this association are unknown. We find that large-scale chromosomal alterations accumulate during meningioma progression primarily in tumors harboring 22q deletions, suggesting 22q-associated chromosomal instability. Here we show frequent codeletion of the DNA repair and tumor suppressor gene, CHEK2, in combination with NF2 on chromosome 22q in a majority of aggressive meningiomas. In addition, tumor-specific splicing of CHEK2 in meningioma leads to decreased functional Chk2 protein expression. We show that enforced Chk2 knockdown in meningioma cells decreases DNA repair. Furthermore, Chk2 depletion increases centrosome amplification, thereby promoting chromosomal instability. Taken together, these data indicate that alternative splicing and frequent codeletion of CHEK2 and NF2 contribute to the genomic instability and associated development of aggressive biologic behavior in meningiomas.
Neoplasia (New York, N.Y.) 01/2012; 14(1):20-8. · 5.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: The treatment of skull base tumors has undergone a tremendous change within the past decade. This change has been largely
technology driven, but also secondary to advances in surgical technique and instrumentation.A new subspecialty has been created,
bringing neurosurgeons together with otologists, head and neck surgeons, and plastic surgeons to specifically address these
very complex problems with a level of expertise not seen before. Teams of skull base surgeons have been formed dedicated to
helping patients with problems previously thought to harbor little hope of recovery. The surgical techniques which have been
developed to treat such lesions are without question of the highest level of complexity and sophistication in modern medicine.
Likewise, adjuvant therapies for these patients also take advantage of the latest technology. In particular for skull base
tumors, stereotactic radiosurgery plays a major adjuvant role in many cases. Despite the demonstrated successes of conventional
radiotherapy in limiting further tumor growth, lesions at the skull base have mandated a different approach. This is largely
owing to the complex anatomy involved and therelative inability to completely shield adjacent structures, such as sensitive
cranial nerves or the brainstem. The importance of the different elements of the treatment strategy mean that an optimal outcome
is more likely to be achieved when treatment is delivered by a multidisciplinary team who treat such lesions frequently.
Handbook of Clinical Neurology 01/2012; 105:657-64.
[show abstract][hide abstract] ABSTRACT: The most common neurological symptom of tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) is early life refractory epilepsy. As previous studies have shown enhanced excitatory glutamatergic neurotransmission in TSC and FCD brains, we hypothesized that neurons associated with these lesions may also express altered γ-aminobutyric acid (GABA)(A) receptor (GABA(A)R)-mediated inhibition.
Expression of the GABA(A)R subunits α1 and α4, and the Na(+)-K(+)-2Cl(-) (NKCC1) and the K(+)-Cl(-) (KCC2) transporters, in human TSC and FCD type II specimens were analyzed by Western blot and double label immunocytochemistry. GABA(A) R responses in dysplastic neurons from a single case of TSC were measured by perforated patch recording and compared to normal-appearing cortical neurons from a non-TSC epilepsy case.
TSC and FCD type IIb lesions demonstrated decreased expression of GABA(A)R α1, and increased NKCC1 and decreased KCC2 levels. In contrast, FCD type IIa lesions showed decreased α4, and increased expression of both NKCC1 and KCC2 transporters. Patch clamp recordings from dysplastic neurons in acute slices from TSC tubers demonstrated excitatory GABA(A)R responses that were significantly attenuated by the NKCC1 inhibitor bumetanide, in contrast to hyperpolarizing GABA(A)R-mediated currents in normal neurons from non-TSC cortical slices.
Expression and function of GABA(A)Rs in TSC and FCD type IIb suggest the relative benzodiazepine insensitivity and more excitatory action of GABA compared to FCD type IIa. These factors may contribute to resistance of seizure activity to anticonvulsants that increase GABAergic function, and may justify add-on trials of the NKCC1 inhibitor bumetanide for the treatment of TSC and FCD type IIb-related epilepsy.
Annals of Neurology 12/2011; 71(4):539-51. · 11.19 Impact Factor
[show abstract][hide abstract] ABSTRACT: Human mesenchymal stromal cells (hMSC) can be used as a drug delivery vehicle for the treatment of GBM. However, tracking the migration and distribution of these transplanted cells is necessary to interpret therapeutic efficacy. We compared three labeling techniques for their ability to track the migration of transplanted hMSC in an orthotopic mouse xenograft model. hMSC were labeled with three different imaging tags (fluorescence, luciferase or ferumoxide) for imaging by fluorescence, bioluminescence or magnetic resonance imaging (MRI), respectively. hMSC were labeled for all imaging modalities without the use of transfection agents. The labeling efficacy of the tags was confirmed, followed by in vitro and in vivo migration assays to track hMSC migration towards U87 glioma cells. Our results confirmed that the labeled hMSC retained their migratory ability in vitro, similar to unlabeled hMSC. In addition, labeled hMSC migrated towards the U87 tumor site, demonstrating their retention of tumor tropism. hMSC tumor tropism was confirmed by all three imaging modalities; however, MRI provides both real time assessment and the high resolution needed for clinical studies. Our findings suggest that ferumoxide labeling of hMSC is feasible, does not alter their migratory ability and allows detection by MRI. Non invasive tracking of transplanted therapeutic hMSC in the brain will allow further development of human cell based therapies.
Journal of Neuro-Oncology 11/2011; 107(2):257-67. · 3.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recent advents in magnetic resonance spectroscopy (MRS) techniques permit subsequent microarray analysis over the entire human transcriptome in the same tissue biopsies. However, extracting information from such immense quantities of data is limited by difficulties in recognizing and evaluating the relevant patterns of apparent gene expression in the context of the existing knowledge of phenotypes by histopathology. Using a quantitative approach derived from a knowledge base of pathology findings, we present a novel methodology used to process genome-wide transcription and MRS data. This methodology was tested to examine metabolite and genome-wide profiles in MRS and RNA in 55 biopsies from human subjects with brain tumors with ~100% certainty. With the guidance of histopathology and clinical outcome, 15 genes with the assistance of 15 MRS metabolites were able to be distinguished by tumor categories and the prediction of survival was better than when either method was used alone. This new method, combining MRS, genomics, statistics and biological content, improves the typing and understanding of the complexity of human brain tumors, and assists in the search for novel tumor biomarkers. It is an important step for novel drug development, it generates testable hypotheses regarding neoplasia and promises to guide human brain tumor therapy provided improved in vivo methods for monitoring response to therapy are developed.
International Journal of Oncology 04/2011; 38(4):1113-27. · 2.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: OBJECTIVE: Postcraniotomy infections have generally been treated by debridement of infected tissues, disposal of the bone flap, and delayed cranioplasty several months later to repair the resulting skull defect. Debridement followed by retention of the bone flap has also been advocated. Here we propose an alternative operative strategy for the treatment of postcraniotomy infections. METHODS: Two patients presenting with clinical and radiographic signs and symptoms of postcraniotomy infections were treated by debridement, bone flap disposal, and immediate titanium mesh cranioplasty. The patients were subsequently administered antibiotics, and their clinical courses were followed. RESULTS: The patients treated in this fashion did not have recurrence of their infections during 3-year follow-up periods. CONCLUSIONS: Surgical debridement, bone flap disposal, and immediate titanium mesh cranioplasty may be a suitable option for the treatment of postcraniotomy infections. This treatment strategy facilitates the eradication of infectious sources and obviates the risks and costs associated with a second surgical procedure.
[show abstract][hide abstract] ABSTRACT: Change detection is a critical component in the diagnosis and monitoring of many slowly evolving pathologies.
This article describes a semiautomatic monitoring approach using longitudinal medical images. We test the method on brain scans of patients with meningioma, which experts have found difficult to monitor because the tumor evolution is very slow and may be obscured by artifacts related to image acquisition.
We describe a semiautomatic procedure targeted toward identifying difficult-to-detect changes in brain tumor imaging. The tool combines input from a medical expert with state-of-the-art technology. The software is easy to calibrate and, in less than 5 minutes, returns the total volume of tumor change in mm. We test the method on postgadolinium, T1-weighted magnetic resonance images of 10 patients with meningioma and compare our results with experts' findings. We also perform benchmark testing with synthetic data.
Our experiments indicated that experts' visual inspections are not sensitive enough to detect subtle growth. Measurements based on experts' manual segmentations were highly accurate but also labor intensive. The accuracy of our approach was comparable to the experts' results. However, our approach required far less user input and generated more consistent measurements.
The sensitivity of experts' visual inspection is often too low to detect subtle growth of meningiomas from longitudinal scans. Measurements based on experts' segmentation are highly accurate but generally too labor intensive for standard clinical settings. We described an alternative metric that provides accurate and robust measurements of subtle tumor changes while requiring a minimal amount of user input.
[show abstract][hide abstract] ABSTRACT: Meningioma, the most frequent tumor in the central nervous system, has few recognized risk factors. We explored the role of allergies in a population-based case-control consortium study of meningioma in five geographic areas. We also studied serum levels of a marker of atopic allergy (IgE) in a subset of study participants, a first for a study on meningioma. Participants (N = 1,065) with surgically resected, pathologically confirmed meningioma and controls (N = 634) selected via random-digit dialing were recruited and interviewed. Cases were less likely than controls to report history of physician-diagnosed allergy [odds ratio (OR) = 0.64; 95% confidence interval (95% CI): 0.51-0.80]. Also, cases (N = 295) had lower total serum IgE than controls [N = 192; OR = 0.85, 95% CI: 0.75-0.98 for each unit of Ln(IgE)]. Similar to glioma and cancers at several other sites, meningioma appears to have an inverse relationship with history of allergies and a biomarker of atopic allergy. As some common opposing predisposition or developmental processes for allergy and meningioma may exist, further research into immune processes that can affect the incidence and natural history of meningioma is warranted.
International Journal of Cancer 02/2011; 129(8):1932-9. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: This study sought to compare objectively the complexity and diversity of the certification process in neurological surgery in member societies of the World Federation of Neurosurgical Societies (WFNS) in the African and Middle Eastern regions.
This report centers on two geographic regions: Africa and the Middle East. We provide a subgroup analysis based on the responses provided to the 13-item survey sent in Part I of this study. The data received were analyzed, and three Regional Complexity Scores (RCS) were designed. To compare national board experience, eligibility requirements to access the certification process, and the obligatory nature of the examinations, a RCS-Organizational score was created (RCS-O, 20 points maximum). To analyze the complexity of the examination, a RCS-Components was designed (RCS-C, 20 points maximum). The sum of both is presented in a global RCS (RCS-G). In addition, a descriptive summary of the certification process per responding society is also provided.
Based on the data provided by our RCS system, the highest RCS-G was obtained by South Africa (19 of 40 points), followed by Egypt (18 of 40 points), countries of the Gulf Neurosurgical Society (16 of 40 points), and the Neurosurgical Society of East and Central Africa (16 of 40 points).
This grading system allows societies to compare their process of certification within their continental region and worldwide, potentially identifying aspects for further improvement or development.
World Neurosurgery 01/2011; 76(1-2):18-27; discussion 54-6. · 1.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is still challenging. Alzheimer's disease (AD), along with vascular dementia, the most important differential diagnosis for iNPH, has several potential cerebrospinal fluid (CSF) biomarkers which might help in the selection of patients for shunt treatment. The aim of this study was to compare a battery of CSF biomarkers including well-known AD-related proteins with CSF from patients with suspected iNPH collected from the external lumbar drainage test (ELD). A total of 35 patients with suspected iNPH patients were evaluated with ELD. CSF was collected in the beginning of the test, and the concentrations of total tau, ptau(181), Aβ(42), NFL, TNF-α, TGFβ1, and VEGF were analysed by ELISA. Twenty-six patients had a positive ELD result-that is, their gait symptoms improved; 9 patients had negative ELD. The levels of all analyzed CSF biomarkers were similar between the groups and none of them predicted the ELD result in these patients. Contrary to expectations lumbar CSF TNF-α concentration was low in iNPH patients.
International journal of Alzheimer's disease. 01/2011; 2011:312526.
[show abstract][hide abstract] ABSTRACT: To objectively compare the complexity and diversity of the certification process in neurological surgery in member societies of the World Federation of Neurosurgical Societies.
This study centers in continental Asia. We provide here an analysis based on the responses provided to a 13-item survey. The data received were analyzed, and three Regional Complexity Scores (RCS) were designed. To compare national board experience, eligibility requirements for access to the certification process, and the obligatory nature of the examinations, an RCS-Organizational score was created (20 points maximum). To analyze the complexity of the examination, an RCS-Components score was designed (20 points maximum). The sum of both is presented in a Global RCS score. Only those countries that responded to the survey and presented nationwide homogeneity in the conduction of neurosurgery examinations could be included within the scoring system. In addition, a descriptive summary of the certification process per responding society is also provided.
On the basis of the data provided by our RCS system, the highest global RCS was achieved by South Korea and Malaysia (21/40 points) followed by the joint examination of Singapore and Hong-Kong (FRCS-Ed) (20/40 points), Japan (17/40 points), the Philippines (15/40 points), and Taiwan (13 points). The experience from these leading countries should be of value to all countries within Asia.
World Neurosurgery 01/2011; 75(3-4):325-34. · 1.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine the complexity and diversity of the neurosurgery certification and recertification process in member societies of the World Federation of Neurosurgical Societies.
A 13-item survey was sent to 88 national and regional societies that are members of the World Federation of Neurosurgical Societies. Variables included in the survey covered a wide range of aspects pertaining to the certification process achieved by cognitive and oral examinations. The data received from 40 responding societies (response rate 45%) were tabulated, and an individual and comparative (global) analysis was performed for all categories, including eligibility and requirements for certification, examination components, use of computer-assisted technology and imaging, performance, validation of foreign degrees, recertification, and maintenance of certification.
We present here the global analysis, which is comparative of all participating societies. Although there is high variability in the structure of certification programs worldwide, performance in knowledge-based examinations is similar. Recertification and maintenance of certification are still under development in many societies.
With the onset of globalization, we anticipate that efforts will be made in the future to obtain homogeneity in the structure of certification, recertification, and in criteria for international reciprocity of postgraduate neurosurgical training. Peer-Review Article.
World Neurosurgery 01/2011; 76(3-4):231-8. · 1.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: Few studies have examined the relationship between human leukocyte antigen (HLA) polymorphisms and adult glioma, particularly at class II loci. We evaluated the association between selected HLA class II polymorphisms and adult glioma in a large, hospital-based case-control study, using unconditional logistic regression. DQB1 06 (OR=1.67, 95% CI=1.17-2.39) and DRB1 13 (OR=1.69, 95% CI=1.08-2.64) alleles were associated with an increased risk of glioma, while the DQB1 05 allele showed an inverse association (OR=0.63, 95% CI=0.43-0.93). These results, which were of borderline significance once controlled for the false discovery rate, suggest a potential role for the DQB1 06, DQB1 05, and DRB1 13 alleles in glioma susceptibility.
Journal of neuroimmunology 12/2010; 233(1-2):185-91. · 2.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: Meningiomas are the most common central nervous system tumors in the population of age 35 and older. WHO defines three grades predictive of the risk of recurrence. Clinical data supporting histologic malignant progression of meningiomas are sparse and underlying molecular mechanisms are not clearly depicted.
We identified genetic alterations associated with histologic progression of 36 paired meningioma samples in 18 patients using 500K SNP genotyping arrays and NF2 gene sequencing.
The most frequent chromosome alterations observed in progressing meningioma samples are early alterations (i.e., present both in lower- and higher-grade samples of a single patient). In our series, NF2 gene inactivation was an early and frequent event in progressing meningioma samples (73%). Chromosome alterations acquired during progression from grade I to grade II meningioma were not recurrent. Progression to grade III was characterized by recurrent genomic alterations, the most frequent being CDKN2A/CDKN2B locus loss on 9p.
Meningiomas displayed different patterns of genetic alterations during progression according to their NF2 status: NF2-mutated meningiomas showed higher chromosome instability during progression than NF2-nonmutated meningiomas, which had very few imbalanced chromosome segments. This pattern of alterations could thus be used as markers in clinical practice to identify tumors prone to progress among grade I meningiomas.
Clinical Cancer Research 08/2010; 16(16):4155-64. · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: This article aims to objectively compare the complexity and diversity of the certification process in neurologic surgery in member societies of the World Federation of Neurosurgical Societies.
This study centers on the certification processes in the geographic regions of North, South, and Central America. It presents a subgroup analysis based on the responses provided to a 13-item survey. The data received were analyzed and three Regional Complexity Scores (RCSs) were designed. To compare national board experience, eligibility requirements to access the certification process, and the degree to which exams were obligatory, an RCS-Organizational score was created (RCS-O, 20 points maximum). To analyze the complexity of the examination, an RCS-Components score was designed (RCS-C, 20 points maximum). The sum of both is presented as the Global RCS (RCS-G) score. In addition, a descriptive summary of the certification process for each responding society is also provided.
On the basis of the data provided by the RCS system, the United States and Brazil seem to have the most developed certification processes in the American continent (20 points each), followed by Canada (18 points) and Mexico (17 points).
The experience from these leading countries should be of value and reference to other countries, allowing future improvement within the region. Peer-Review Article.
World Neurosurgery 07/2010; 74(1):16-27. · 1.77 Impact Factor