Mitochondrial DNA haplogroups J and T increase the risk of glioma.

The presence of different sets of mitochondrial polymorphisms generated by the accumulation of mutations in different maternal lineages has allowed differentiating mitochondrial haplogroups in human populations. These polymorphisms, in turn, may have effects at the phenotypic level, considering a possible contribution of these germinal mutations to the development of certain diseases such as cancer. The main goal of the present study is to establish a possible association between mitochondrial haplogroups and the risk of suffering glioma. Blood samples were obtained from 32 patients from Catalonia (Spain) diagnosed with different grades of glioma (II, III and IV), according to the World Health Organization. The mitochondrial genome was amplified and sequenced using MiSeq 2000 (Illumina). The HaploGrep tool implemented in mtDNA-Server v.1.0.5 was used for the identification of mitochondrial haplogroups. Data obtained in the present study was further pooled with data from previous European studies including glioma patients from Galicia (Spain) and Italy. Results for the Catalonian samples showed an association between individuals with haplogroup J and the increased risk of suffering glioma, with a significant increase of the frequency of individuals with this haplogroup (25%) regarding the general population (7%). Combining different sets of patients with European origin, it appears that individuals with haplogroups J and T have a significantly higher risk of suffering glioma (p < 0.001; OR: 2.407 and p = 0.007; OR: 1.82, respectively). This is the first study that establishes an association between different mitochondrial haplogroups and the risk of suffering glioma, highlighting the role of mitochondrial variants in this disease.

Evaluation of a novel software application for magnetic resonance distortion correction in cranial stereotactic radiosurgery.

This study aimed to validate a novel commercially available software for correcting spatial distortion in cranial magnetic resonance (MR) images. This software has been used to assess the dosimetric impact of MR distortion in stereotactic radiosurgery (SRS) treatments of vestibular schwannomas (VSs). Five MR datasets were intentionally distorted. Each distorted MR dataset was corrected using the Cranial Distortion software, obtaining a new corrected MR dataset (MRcorr). The accuracy of the correction was quantified by calculating the target registration error (TRE) for 6 anatomical landmarks identified in the co-registered MRcorr and planning computed tomography (pCT) images. Nine VS cases were included to investigate the impact of the MR distortion in SRS plans. Each SRS plan was calculated on the pCT (1 × 1 × 1 mm3 voxel) with the target and organs at risk (OARs) delineated using the planning MR dataset. This MR dataset was then corrected (MRcorr) using the Cranial Distortion software. Geometrical agreement between the original target and the corresponding corrected target was assessed using several metrics: MacDonald criteria, mean distance to agreement (MDA), and Dice similarity coefficient (DSC). Target coverage (D99%) and maximum doses (D2%) to ipsilateral cochlea and brainstem resulting on the MRcorr dataset were compared with the original values. TRE values (0.6 mm ± 0.3 mm) and differences found in Macdonald criteria (0.3 mm ± 0.4 mm and 0.3 mm ± 0.3 mm) and MDA (0.8 mm ± 0.2 mm) were mostly within the voxel size dimension of the pCT scan (1 × 1 × 1 mm3). High similarity (DSC > 0.7) between the original and corrected targets was found. Small dose differences for the original and corrected structures were found: 0.1 Gy ± 0.1 Gy for target D99%, 0.2 Gy ± 0.3 Gy for cochlea D2%, and 0.1 Gy ± 0.1 Gy for brainstem D2%. Our study shows that Distortion Correction software can be a helpful tool to detect and adequately correct brain MR distortions. However, a negligible dosimetric impact of MR distortion has been detected in our clinical practice.

Electrical stimulation mapping of nouns and verbs in Broca's area.

Electric stimulation mapping (ESM) is frequently used during brain surgery to localise higher cognitive functions to avoid post-chirurgical disabilities. Experiments with brain imaging techniques and neuropsychological studies showed differences in the cortical representation and processing of nouns and verbs. The goal of the present study was to investigate whether electric stimulation in specific sites in the frontal cortex disrupted noun and verb production selectively. We found that most of the stimulated areas showed disruption of both verbs and nouns at the inferior frontal gyrus. However, when selective effects were obtained, verbs were more prone to disruption than nouns with important individual differences. The overall results indicate that selective impairments can be observed at inferior and middle frontal regions and the action naming task seems to be more suitable to avoid post-chirurgical language disabilities, as it shows a greater sensitivity to disruption with ESM than the classical object naming task.

Robustness of equations that define molecular subtypes of glioblastoma tumors based on five transcripts measured by RT-PCR.

Glioblastoma (Gb) is one of the most deadly tumors. Its molecular subtypes are yet to be fully characterized while the attendant efforts for personalized medicine need to be intensified in relation to glioblastoma diagnosis, treatment, and prognosis. Several molecular signatures based on gene expression microarrays were reported, but the use of microarrays for routine clinical practice is challenged by attendant economic costs. Several authors have proposed discriminant equations based on RT-PCR. Still, the discriminant threshold is often incompletely described, which makes proper validation difficult. In a previous work, we have reported two Gb subtypes based on the expression levels of four genes: CHI3L1, LDHA, LGALS1, and IGFBP3. One Gb subtype presented with low expression of the four genes mentioned, and of MGMT in a large portion of the patients (with anticipated high methylation of its promoter), and mutated IDH1. Here, we evaluate the robustness of the equations fitted with these genes using RT-PCR values in a set of 64 cases and importantly, define an unequivocal discriminant threshold with a view to prognostic implications. We developed two approaches to generate the discriminant equations: 1) using the expression level of the four genes mentioned above, and 2) using those genes displaying the highest correlation with survival among the aforementioned four ones, plus MGMT, as an attempt to further reduce the number of genes. The ease of equations' applicability, reduction in cost for raw data, and robustness in terms of resampling-based classification accuracy warrant further evaluation of these equations to discern Gb tumor biopsy heterogeneity at molecular level, diagnose potential malignancy, and prognosis of individual patients with glioblastomas.

Supratentorial brain schwannomas: an uncommon location for a common tumour.

INTRODUCTION: Intracranial schwannomas not related to cranial nerves are uncommon brain tumours. Such tumours account for less than 1% of all surgically treated schwannomas. Only 79 cases have been reported in the literature. METHODS: We describe two cases treated in our centre. The patients are young women with seizures as a presenting symptom. Both underwent surgery with the presumptive diagnosis of benign brain tumour. Histopathological examination revealed the certain diagnosis of Schwannoma. RESULTS: Good outcome was achieved with total excision of the tumour. Based on the literature, demographic data, clinical aspects, imaging features and theories on the possible origin of this rare tumour are discussed. CONCLUSIONS: These tumours should be included in the differential diagnosis of supratentorial benign tumours in young adults. Total excision, whenever possible, is the treatment of choice.

Surgical versus conservative treatment in patients with cerebral cavernomas and non refractory epilepsy.

PURPOSE: The optimal therapy of patients with cerebral cavernoma (CCs) and new onset epilepsy, sporadic seizures, or non well established refractory epilepsy is still not clear. The aim of this study was to compare the incidence of seizures in patients with CCs both operated and non operated, in order to obtain more information on the correct management of these patients. MATERIALS AND METHODS: We studied retrospectively 43 patients with non refractory epilepsy secondary to CCs. Twenty-six of them (60.5%) underwent surgery and made up the surgical group, and 17 patients were treated medically and constituted the medical group. Seizure frequency and other clinical variables were compared between both groups. RESULTS: At two years, out of the 26 operated patients, 19 (73%) remained seizure free, 4 (15%) had less than a seizure per month, and one patient (4%) had more than one seizure per month. At five years, 15 patients of the surgical group remained for analysis. Of them, 11 (73.3%) were seizure free, and 4 (26.7%) had less than one seizure a month. In the medical group, 12 out of 17 patients were seizure free (70.6%). There were no significant differences between the two groups (p=0.2 and p=0.3, respectively). Seven patients had postoperative neurological sequelae. CONCLUSION: Surgical treatment of patients with non refractory epilepsy due to CCs did not significantly reduce the likelihood of seizures when compared to medical treatment. It must also be considered that surgery carries serious risks. A prospective and randomized study must be carried out to further clarify our findings.

Prospective diagnostic performance evaluation of single-voxel 1H MRS for typing and grading of brain tumours.

The purpose of this study was to evaluate whether single-voxel (1)H MRS could add useful information to conventional MRI in the preoperative characterisation of the type and grade of brain tumours. MRI and MRS examinations from a prospective cohort of 40 consecutive patients were analysed double blind by radiologists and spectroscopists before the histological diagnosis was known. The spectroscopists had only the MR spectra, whereas the radiologists had both the MR images and basic clinical details (age, sex and presenting symptoms). Then, the radiologists and spectroscopists exchanged their predictions and re-evaluated their initial opinions, taking into account the new evidence. Spectroscopists used four different systems of analysis for (1)H MRS data, and the efficacy of each of these methods was also evaluated. Information extracted from (1)H MRS significantly improved the radiologists' MRI-based characterisation of grade IV tumours (glioblastomas, metastases, medulloblastomas and lymphomas) in the cohort [area under the curve (AUC) in the MRI re-evaluation 0.93 versus AUC in the MRI evaluation 0.85], and also of the less malignant glial tumours (AUC in the MRI re-evaluation 0.93 versus AUC in the MRI evaluation 0.81). One of the MRS analysis systems used, the INTERPRET (International Network for Pattern Recognition of Tumours Using Magnetic Resonance) decision support system, outperformed the others, as well as being better than the MRI evaluation for the characterisation of grade III astrocytomas. Thus, preoperative MRS data improve the radiologists' performance in diagnosing grade IV tumours and, for those of grade II-III, MRS data help them to recognise the glial lineage. Even in cases in which their diagnoses were not improved, the provision of MRS data to the radiologists had no negative influence on their predictions.

Activation of p53 by nutlin-3a induces apoptosis and cellular senescence in human glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. Despite concerted efforts to improve current therapies and develop novel clinical approaches, patient survival remains poor. As such, increasing attention has focused on developing new therapeutic strategies that specifically target the apoptotic pathway in order to improve treatment responses. Recently, nutlins, small-molecule antagonists of MDM2, have been developed to inhibit p53-MDM2 interaction and activate p53 signaling in cancer cells. Glioma cell lines and primary cultured glioblastoma cells were treated with nutlin-3a. Nutlin-3a induced p53-dependent G1- and G2-M cell cycle arrest and apoptosis in glioma cell lines with normal TP53 status. In addition, nutlin-arrested glioma cells show morphological features of senescence and persistent induction of p21 protein. Furthermore, senescence induced by nutlin-3a might be depending on mTOR pathway activity. In wild-type TP53 primary cultured cells, exposure to nutlin-3a resulted in variable degrees of apoptosis as well as cellular features of senescence. Nutlin-3a-induced apoptosis and senescence were firmly dependent on the presence of functional p53, as revealed by the fact that glioblastoma cells with knockdown p53 with specific siRNA, or cells with mutated or functionally impaired p53 pathway, were completely insensitive to the drug. Finally, we also found that nutlin-3a increased response of glioma cells to radiation therapy. The results provide a basis for the rational use of MDM2 antagonists as a novel treatment option for glioblastoma patients.

Short-term temperature effect on the HRMAS spectra of human brain tumor biopsies and their pattern recognition analysis.

OBJECT: To investigate the effect of temperature (0 versus 37 degrees C) in the high-resolution magic angle spinning spectroscopy (HRMAS) pattern of human brain tumor biopsies and its influence in recognition-based tumor type prediction. This proof-of-principle study addressed the bilateral discrimination between meningioma (MM) and glioblastoma multiforme (GBM) cases. MATERIALS AND METHODS: Forty-three tumor biopsy samples were collected (20 MM and 23 GBM), kept frozen and later analyzed at 0 degrees C and 37 degrees C by HRMAS. Post-HRMAS histopathology was used to validate the tumor type. Time-course experiments (100 min) at both temperatures were carried out to monitor HRMAS pattern changes. Principal component analysis and linear discriminant analysis were used for classifier development with a training set of 20 biopsies. RESULTS: Temperature-dependent, spectral pattern changes mostly affected mobile lipids and choline-containing compounds resonances and were essentially reversible. Incubation of 3 MM and 3 GBM at 37 degrees C during 100 minutes produced irreversible pattern changes below 13% in a few resonances. Classification performance of an independent test set of 7 biopsies was 100% for the pulse-and-acquire, CPMG at echo times (TE) of 30 ms and 144 ms and Hahn Echo at TE 30 ms at 0 degrees C and 37 degrees C. The performance for Hahn Echo spectra at 136 ms was 83.3% at 0 degrees C and 100% at 37 degrees C. CONCLUSION: The spectral pattern of mobile lipids changes reversibly with temperature. HRMAS demonstrated potential for automated brain tumor biopsy classification. No advantage was obtained when acquiring spectra at 37 degrees C with respect to 0 degrees C in most of the conditions used for the discrimination addressed.

Development of a predictor for human brain tumors based on gene expression values obtained from two types of microarray technologies.

Development of molecular diagnostics that can reliably differentiate amongst different subtypes of brain tumors is an important unmet clinical need in postgenomics medicine and clinical oncology. A simple linear formula derived from gene expression values of four genes (GFAP, PTPRZ1, GPM6B, and PRELP) measured from cDNA microarrays (n = 35) have distinguished glioblastoma and meningioma cases in a previous study. We herein extend this work further and report that the above predictor formula showed its robustness when applied to Affymetrix microarray data acquired prospectively in our laboratory (n = 80) as well as publicly available data (n = 98). Importantly, GFAP and GPM6B were both retained as being significant in the predictive model upon using the Affymetrix data obtained in our laboratory, whereas the other two predictor genes were SFRP2 and SLC6A2. These results collectively indicate the importance of the expression values of GFAP and GPM6B genes sampled from the two types of microarray technologies tested. The high prediction accuracy obtained in these instances demonstrates the robustness of the predictors across microarray platforms used. This result would require further validation with a larger population of meningioma and glioblastoma cases. At any rate, this study paves the way for further application of gene signatures to more stringent biopsy discrimination challenges.

Automated brain tumor biopsy prediction using single-labeling cDNA microarrays-based gene expression profiling.

AIMS: Gene signatures obtained from microarray experiments may be of use to improve the prediction of brain tumor diagnosis. Nevertheless, automated and objective prediction with accuracy comparable to or better than the gold standard should be convincingly demonstrated for possible clinician uptake of the new methodology. Herewith, we demonstrate that primary brain tumor types can be discriminated using microarray data in an automated and objective way. METHODS: Postsurgical biopsies from 35 patients [17 glioblastoma multiforme (Gbm) and 18 meningothelial meningioma (Mm)] were stored in liquid nitrogen, total RNA was extracted, and cDNA was labeled with Cy3 fluorochrome and hybridized onto a cDNA-based microarray containing 11,500 cDNA clones representing 9300 loci. Scanned data were preprocessed, normalized, and used for predictor development. The predictive functions were fitted to a subset of samples and their performance evaluated with an independent subset. Expression results were validated by means of real time-polymerase chain reaction. RESULTS: Some gene expression-based predictors achieved 100% accuracy both in training resampling validation and independent testing. One of them, composed of GFAP, PTPRZ1, GPM6B and PRELP, produced a 100% prediction accuracy for both training and independent test datasets. Furthermore, the gene signatures obtained, increased cell detoxification, motility and intracellular transport in Gbm, and increased cell adhesion and cytochrome-family genes in Mm, agree well with the expected biologic and pathologic characteristics of the studied tumors. CONCLUSIONS: The ability of gene signatures to automate prediction of brain tumors through a fully objective approach has been demonstrated. A comparison of gene expression profiles between Gbm and Mm may provide additional clues about patterns associated with each tumor type.

Utilidad de la determinación de la subunidad alfa tras estímulo con TRH como indicador de persistencia y/o recurrencia tumoral en gonadotropinomas / Utility of alpha subunit determination alter thyrotropin-releasing hormone stimulation as an indicator of gonadotropinoma persistente and/or recurrence

Objetivo: Los gonadotropinomas son tumores originados en las células gonadotropas de la hipófisis anterior causales de la síntesis y la secreción de gonadotrofinas (folitropina [FSH] y lutropina [LH]). La mayoría de estos tumores tienen una producción alterada de gonadotropinas y de sus subunidades (folitropina beta, subunidad alfa y, con menos frecuencia, lutropina beta). Los gonadotropinomas pueden presentar una respuesta de la subunidad alfa de las gonadotropinas al estímulo con protirrelina (TRH) que podría diferenciar estos tumores de los no funcionantes. De igual forma, esta prueba podría ser de utilidad tras la cirugía para poderdiscernir los posibles restos tumorales respecto a los cambios posquirúrgicos. Sujetos y método: Se estudió a 24 pacientes intervenidos de macroadenoma hipofisario, de los que 14 fueron diagnosticados de gonadotropinoma en el estudio histológico. Se les practicó la prueba de lasubunidad alfa tras la administración de TRH antes y después de la cirugía.Resultados: En el estudio prequirúrgico el 50% de los gonadotropinomas tuvieron una respuesta positiva a dicha prueba y en el posquirúrgico otro 50%. El 83% de los pacientes con gonadotropinoma presentaban signos de recidiva/persistencia tumoral y/o cambios en laresonancia magnética (RM) de control posquirúrgico; el 83% de estos pacientes (41,6% del total) tuvo una respuesta positiva de la subunidad alfa tras el estímulo con TRH. En el grupo de macroadenomas no gonadotropinomas sólo un 33% tuvo respuesta positiva antes de la cirugía y otro 33%, después. En la RM practicada después de la cirugía, todos mostraban signos radiológicos compatibles con cambios inflamatorios posquirúrgicos o signos de persistencia y/o recidivatumoral. Conclusiones: Dicha prueba podría ser de ayuda en el diagnóstico diferencial de los gonadotropinomas, así como en el seguimiento y la valoración posquirúrgica de estos tumores (AU)

Objective: Gonadotropinomas are adenomas of the gonadotropic cells of the anterior pituitary. These cells produce and secrete gonadotropins (follicle-stimulating hormone and luteinizing hormone). Most of these tumors show altered production of gonadotropins and their subunits (the - FSH, and, less frequently, -LH subunits). The thyrotropin-releasing hormone (TRH) stimulation test could differentiate these tumors from nonfunctioning tumors. Equally, this test could be able to distinguish between postsurgical changes and tumoral remnants after surgery. Subjects and method: We studied 24 patients with pituitary macroadenoma, 14 of who had a histological diagnosis of gonadotroph adenoma. The TRH stimulation test was performed before and after surgery. Results: Both before and after surgery, a positive result to the TRH test was obtained in 50% of gonadotropinomas. Magnetic resonance imaging (MRI)performed after surgery revealed that 83% of the patients with gonadotropinoma had signs of tumoral persistence or recurrence and/or postsurgical changes. Of these patients, 83% (41.6% of the total) showed positive (..) (AU)

Cavernous sinus syndrome: a series of 126 patients.

The etiology of cavernous sinus syndrome (CSS) remains difficult to determine in spite of the development of neuroimaging techniques. We conducted the current study to identify clinical and imaging features that allow a reliable approach to the etiologic diagnosis of patients with CSS. We studied a consecutive series of 126 patients with CSS, defined as involvement of 2 or more of the third, fourth, fifth (V1, V2), or sixth cranial nerves, or involvement of only 1 of them in combination with a neuroimaging-confirmed lesion in the cavernous sinus. Tumors were the most common cause of CSS (80 patients). All patients with optic nerve involvement had a tumor. No patient with a normal MRI had a tumor. The lack of pain during the course of the disease (odds ratio [OR], 0.58; 95% confidence intervals [CI], 0.06-0.40), V2 involvement (OR, 12.17; 95% CI, 2.98-49.71), and male sex (OR, 3.2; 95% CI, 1.31-8.14) were independently associated with the presence of a tumor. Pain at the onset of disease (OR, 12.09; 95% CI, 3.14-46.50) and third cranial nerve involvement (OR, 4.9; 95% CI, 1.01-24.60) were independently associated with Tolosa-Hunt syndrome.

[Analysis of early prognostic factors for risk of treatment failure in Cushing's disease treated by trans-sphenoidal pituitary surgery]. / Estudio de factores pronósticos precoces de riesgo de fallo del tratamiento en la enfermedad de Cushing tras la cirugía hipofisaria transesfenoidal.

BACKGROUND AND OBJECTIVE: We performed an analysis of early factors influencing the outcome of Cushing's disease treated by transsphenoidal pituitary surgery. PATIENTS AND METHOD: Prospective study of 29 patients who underwent transsphenoidal pituitary surgery for Cushing's disease. The prognostic value of preoperative and operative variables, histological findings and serum cortisol (measured at 8:00 a.m. the day after surgery) were analyzed. RESULTS: Of the 29 patients included in this study, 26 achieved postoperative remission while in 3 patients treatment failed. Tumor was identified at histology in 92.3% patients in the remission group and in 33.3% in the failure group, this difference being significant (p = 0.03). Median postoperative cortisol levels were 95.8 nmol/l in the remission group and 676 nmol/l in the failure group, this difference being significant (p = 0.024). Serum cortisol of 600 nmol/l correctly classified the remission and failure groups with a sensitivity of 100% and a specificity of 96%. CONCLUSIONS: In our experience, no identification of an adenoma at histology and an early postoperative cortisol level higher than 600 nmol/l after transsphenoidal pituitary surgery for Cushing's disease was associated with a high risk of failed treatment.

Estudio de factores pronósticos precoces de riesgo de fallo del tratamiento en la enfermedad de Cushing tras la cirugía hipofisaria transesfenoidal / Analysis of early factors for treatment failure in Cushing's disease treated by transsphenoidal pituitary surgery

Fundamento y objetivo: Identificar factores pronósticos precoces tras la cirugía transesfenoidal en la enfermedad de Cushing (EC). Pacientes y método: Se estudió prospectivamente a 29 pacientes que fueron intervenidos con cirugía transesfenoidal por EC. Se analizó el valor pronóstico de variables preoperatorias, operatorias, estudio histológico y cortisol sérico a las 8.00 de la mañana siguiente a la intervención. Resultados: Se consiguió la remisión de la enfermedad en 26 pacientes y la enfermedad persistió en 3 pacientes. En el estudio histológico, en el 92,3% de los curados y en el 33,3% de los no curados se identificó un adenoma, diferencias que resultaron ser estadísticamente significativas (p = 0,03). En los pacientes curados, el cortisol mediano postoperatorio fue de 95,8 nmol/l y en los no curados, de 676 nmol/l (p = 0,024). Un cortisol sérico de 600 nmol/l diferencia entre el grupo de pacientes curados y no curados con una sensibilidad del 100% y una especificidad del 96%. Conclusiones: En nuestra experiencia, los pacientes en los que tras la cirugía transesfenoidal por EC no se identifica un adenoma en el estudio histológico y/o el cortisol sérico postoperatorio inmediato es > 600 nmol/l tienen elevado riesgo de no estar curados

Background and objective: We performed an analysis of early factors influencing the outcome of Cushing's disease treated by transsphenoidal pituitary surgery. Patients and method: Prospective study of 29 patients who underwent transsphenoidal pituitary surgery for Cushing's disease. The pronostic value of preoperative and operative variables, histological findings and serum cortisol (measured at 8:00 a.m. the day after surgery) were analyzed. Results: Of the 29 patients included in this study, 26 achieved postoperative remission while in 3 patients treatment failed. Tumor was identified at histology in 92.3% patients in the remission group and in 33.3% in the failure group, this difference being significant (p = 0.03). Median postoperative cortisol levels were 95.8 nmol/l in the remission group and 676 nmol/l in the failure group, this difference being significant (p = 0.024). Serum cortisol of 600 nmol/l correctly classified the remission and failure groups with a sensitivity of 100% and a specificity of 96%. Conclusions: In our experience, no identification of an adenoma at histology and an early postoperative cortisol level higher than 600 nmol/l after transsphenoidal pituitary surgery for Cushing's disease was associated with a high risk of failed treatment

Comparison between neuroimaging classifications and histopathological diagnoses using an international multicenter brain tumor magnetic resonance imaging database.

OBJECT: The aim of this study was to estimate the accuracy of routine magnetic resonance (MR) imaging studies in the classification of brain tumors in terms of both cell type and grade of malignancy. METHODS: The authors retrospectively assessed the correlation between neuroimaging classifications and histopathological diagnoses by using multicenter database records from 393 patients with brain tumors. An ontology was devised to establish diagnostic agreement. Each tumor category was compared with the corresponding histopathological diagnoses by dichotomization. Sensitivity, specificity, positive and negative predictive values (PPVs and NPVs, respectively), and the Wilson 95% confidence intervals (CI) for each were calculated. In routine reporting of MR imaging examinations, tumor types and grades were classified with a high specificity (85.2-100%); sensitivity varied, depending on the tumor type and grade, alone or in combination. The recognition of broad diagnostic categories (neuroepithelial or meningeal lesions) was highly sensitive, whereas when both detailed type and grade were considered, sensitivity diverged, being highest in low-grade meningioma (sensitivity 100%, 95% CI 96.2-100.0%) and lowest in high-grade meningioma (sensitivity 0.0%, 95% CI 0.0-65.8%) and low-grade oligodendroglioma (sensitivity 15%, 95% CI 5.2-36.0%). In neuroepithelial tumors, sensitivity was inversely related to the precision in reporting of grade and cellular origin; "glioma" was a frequent neuroimaging classification associated with higher sensitivity in the corresponding category. The PPVs varied among categories, in general being greater than their prevalence in this dataset. The NPV was high in all categories (69.8-100%). CONCLUSIONS: The PPVs and NPVs provided in this study may be used as estimates of posttest probabilities of diagnostic accuracy using MR imaging. This study targets the need for noninvasively increasing sensitivity in categorizing most brain tumor types while retaining high specificity, especially in the differentiation of high- and low-grade glial tumor classes.

Fractionated stereotactic radiotherapy in the treatment of exclusive cavernous sinus meningioma: functional outcome, local control, and tolerance.

BACKGROUND: Fractionated stereotactic radiotherapy (FSRT) combines the precision of stereotactic positioning with the radiobiologic advantage of dose fractionation. METHODS: From June 1997 to June 2001, 30 patients with cavernous sinus meningiomas were treated with FSRT using fixed noncoplanar conformal fields. Patient skull fixation was achieved using the BrainLAB mask (20 patients) or Beverly frame (10 patients). The Cosman-Roberts-Wells coordinate frame was used for stereotactic space definition. In selected cases before 1999, and in all cases afterward, gadolinium-enhanced MRI for image fusion was performed. The median radiation dose was 52 Gy, with a daily fraction of 2 Gy. Patients were regularly followed up analyzing symptoms, tumor progression, and side effects. Neurocognitive function was evaluated retrospectively for 26 patients using Mini-Mental State Examination. RESULTS: Median follow-up period was 50 months (range, 28.2-74.5 months). Preexisting neurologic symptoms improved in 50% of the patients and worsened in 2 patients. Only 2 patients progressed and the actuarial local progression free survival was 93% at 4 years. Tolerance was good with 2 cases of late radiation toxicity which consisted of moderate short-term memory loss and dysphasia in one case and neuropsychologic deficit with seizures in the other. Postradiotherapy Mini-Mental State Examination results showed a median score of 28 (range, 16-30). CONCLUSIONS: Fractionated stereotactic radiotherapy is a high-precision technique. It is safe and feasible in the primary and adjuvant treatment of cavernous sinus meningiomas. Fractionated stereotactic radiotherapy allowed local control in more than 90% of patients.

Prognostic significance of O6-methylguanine-DNA methyltransferase determined by promoter hypermethylation and immunohistochemical expression in anaplastic gliomas.

PURPOSE: Anaplastic gliomas constitute a heterogeneous group of tumors with different therapeutic responses to adjuvant chemotherapy with alkylating agents. O6-Methylguanine-DNA methyltransferase (MGMT), a DNA repair protein, is one of the implicated factors in glioma chemoresistance. The prognostic value of MGMT remains controversial due in part to the fact that previous published studies included heterogeneous groups of patients with different tumor grades. The aim of this study was to evaluate the prognostic significance of MGMT in patients with anaplastic glioma. EXPERIMENTAL DESIGN: Ninety-three patients with anaplastic glioma were analyzed for MGMT protein expression by immunohistochemistry. In addition, for those patients from whom a good yield of DNA was obtained (n = 40), MGMT promoter methylation profile was analyzed by methylation-specific PCR. MGMT prognostic significance was evaluated together with other well-known prognostic factors. RESULTS: Fifty-one tumors (54.8%) showed nuclear staining of MGMT. There was a trend towards longer overall survival for those patients with negative MGMT immunostaining (hazard ratio, 1.66; P = 0.066). In a secondary analysis including those patients who actually received chemotherapy (n = 72), the absence of MGMT expression was independently associated with better survival (hazard ratio, 2.12; P = 0.027). MGMT promoter methylation was observed in 50% of the analyzed tumors. No statistical correlation between MGMT expression and MGMT promoter hypermethylation was observed. CONCLUSIONS: Unlike previous studies, we did not find a correlation between MGMT promoter methylation and survival. However, we observed a correlation between MGMT protein expression and survival in those patients who received chemotherapy thus suggesting that the absence of MGMT expression is a positive predictive marker in patients with anaplastic glioma.