Hector Navarro Cabrera

Correlation of MGMT promoter methylation status with gene and protein expression levels in glioblastoma

OBJECTIVES: 1) To correlate the methylation status of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter to its gene and protein expression levels in glioblastoma and 2) to determine the most reliable method for using MGMT to predict the response to adjuvant therapy in patients with glioblastoma. BACKGROUND: The MGMT gene is epigenetically silenced by promoter hypermethylation in gliomas, and this modification has emerged as a relevant predictor of therapeutic response. METHODS: Fifty-one cases of glioblastoma were analyzed for MGMT promoter methylation by methylation-specific PCR and pyrosequencing, gene expression by real time polymerase chain reaction, and protein expression by immunohistochemistry. RESULTS: MGMT promoter methylation was found in 43.1% of glioblastoma by methylation-specific PCR and 38.8% by pyrosequencing. A low level of MGMT gene expression was correlated with positive MGMT promoter methylation (p = 0.001). However, no correlation was found between promoter methylation and MGMT protein expression (p = 0.297). The mean survival time of glioblastoma patients submitted to adjuvant therapy was significantly higher among patients with MGMT promoter methylation (log rank = 0.025 by methylation-specific PCR and 0.004 by pyrosequencing), and methylation was an independent predictive factor that was associated with improved prognosis by multivariate analysis. DISCUSSION AND CONCLUSION: MGMT promoter methylation status was a more reliable predictor of susceptibility to adjuvant therapy and prognosis of glioblastoma than were MGMT protein or gene expression levels. Methylation-specific polymerase chain reaction and pyrosequencing methods were both sensitive methods for determining MGMT promoter methylation status using DNA extracted from frozen tissue.

Cortical mapping with navigated transcranial magnetic stimulation in low-grade glioma surgery.

Transcranial magnetic stimulation (TMS) is a promising method for both investigation and therapeutic treatment of psychiatric and neurologic disorders and, more recently, for brain mapping. This study describes the application of navigated TMS for motor cortex mapping in patients with a brain tumor located close to the precentral gyrus. Materials and methods In this prospective study, six patients with low-grade gliomas in or near the precentral gyrus underwent TMS, and their motor responses were correlated to locations in the cortex around the lesion, generating a functional map overlaid on three-dimensional magnetic resonance imaging (MRI) scans of the brain. To determine the accuracy of this new method, we compared TMS mapping with the gold standard mapping with direct cortical electrical stimulation in surgery. The same navigation system and TMS-generated map were used during the surgical resection procedure. Results The motor cortex could be clearly mapped using both methods. The locations corresponding to the hand and forearm, found during intraoperative mapping, showed a close spatial relationship to the homotopic areas identified by TMS mapping. The mean distance between TMS and direct cortical electrical stimulation (DES) was 4.16 ± 1.02 mm (range: 2.56–5.27 mm). Conclusion Preoperative mapping of the motor cortex with navigated TMS prior to brain tumor resection is a useful presurgical planning tool with good accuracy.

Cognitive impairments in patients with low grade gliomas and high grade gliomas

OBJECTIVE The relationship between brain tumors and cognitive deficits is well established in the literature. However, studies investigating the cognitive status in low and high-grade gliomas patients are scarce, particularly in patients with average or lower educational level. This study aimed at investigating the cognitive functioning in a sample of patients with low and high-grade gliomas before surgical intervention. METHOD The low-grade (G1, n=19) and high-grade glioma (G2, n=8) patients underwent a detailed neuropsychological assessment of memory, executive functions, visuo-perceptive and visuo-spatial abilities, intellectual level and language. RESULTS There was a significant impairment on verbal and visual episodic memory, executive functions including mental flexibility, nominal and categorical verbal fluency and speed of information processing in G2. G1 showed only specific deficits on verbal and visual memory recall, mental flexibility and processing speed. CONCLUSION These findings demonstrated different levels of impairments in the executive and memory domains in patients with low and high grade gliomas.

Use of intraoperative MRI for resection of gliomas

UNLABELLED Literature has shown that extent of tumor resection has an impact on quality of life and survival of patients with gliomas. Intraoperative MRI has been used to increase resection while preserving procedures safety. METHOD The first five patients with gliomas operated on at the University of São Paulo using intraoperative MRI are reported. All but one patient had Karnofsky Performance Status of 100% before surgery. Presentation symptoms were progressive headache, seizures, behavior disturbance, one instance of hemianopsia, and another of hemiparesis. RESULTS Gross total removal was achieved in two patients. Surgical resection was limited by tumor invasion of critical areas like the internal capsule or the mesencephalon in the remaining patients. CONCLUSION Intra-operative MRI is an important tool that helps surgeons to remove glial tumors, however, knowledge of physiology and functional anatomy is still fundamental to avoid morbidity.