Feasibility, Contrast Sensitivity and Network Specificity of Language fMRI in Presurgical Evaluation for Epilepsy and Brain Tumor Surgery.

Language fMRI has become an integral part of the planning process in brain surgery. However, fMRI may suffer from confounding factors both on the patient side, as well as on the provider side. In this study, we investigate how patient-related confounds affect the ability of the patient to perform language fMRI tasks (feasibility), the task sensitivity from an image contrast point of view, and the anatomical specificity of expressive and receptive language fMRI protocols. 104 patients were referred for language fMRI in the context of presurgical procedures for epilepsy and brain tumor surgery. Four tasks were used: (1) a verbal fluency (VF) task to map vocabulary use, (2) a semantic description (SD) task to map sentence formation/semantic integration skills, (3) a reading comprehension (RC) task and (4) a listening comprehension (LC) task. Feasibility was excellent in the LC task (100%), but in the acceptable to mediocre range for the rest of the tasks (SD: 87.50%, RC: 85.57%, VF: 67.30%). Feasibility was significantly confounded by age (p = 0.020) and education level (p = 0.003) in VF, by education level (p = 0.004) and lesion laterality (p = 0.019) in SD and by age (p = 0.001), lesion laterality (p = 0.007) and lesion severity (p = 0.048) in RC. All tasks were comparable regarding sensitivity in generating statistically significant image contrast (VF: 90.00%, SD: 92.30%, RC: 93.25%, LC: 88.46%). The lobe of the lesion (p = 0.005) and the age (p = 0.009) confounded contrast sensitivity in the VF and SD tasks respectively. Both VF and LC tasks demonstrated unilateral lateralization of posterior language areas; only the LC task showed unilateral lateralization of anterior language areas. Our study highlights the effects of patient-related confounding factors on language fMRI and proposes LC as the most feasible, less confounded, and efficiently lateralizing task in the clinical presurgical context.

Volumetric and MGMT parameters in glioblastoma patients: survival analysis.

BACKGROUND: In this study several tumor-related volumes were assessed by means of a computer-based application and a survival analysis was conducted to evaluate the prognostic significance of pre- and postoperative volumetric data in patients harboring glioblastomas. In addition, MGMT (O6-methylguanine methyltransferase) related parameters were compared with those of volumetry in order to observe possible relevance of this molecule in tumor development. METHODS: We prospectively analyzed 65 patients suffering from glioblastoma (GBM) who underwent radiotherapy with concomitant adjuvant temozolomide. For the purpose of volumetry T1 and T2-weighted magnetic resonance (MR) sequences were used, acquired both pre- and postoperatively (pre-radiochemotherapy). The volumes measured on preoperative MR images were necrosis, enhancing tumor and edema (including the tumor) and on postoperative ones, net-enhancing tumor. Age, sex, performance status (PS) and type of operation were also included in the multivariate analysis. MGMT was assessed for promoter methylation with Multiplex Ligation-dependent Probe Amplification (MLPA), for RNA expression with real time PCR, and for protein expression with immunohistochemistry in a total of 44 cases with available histologic material. RESULTS: In the multivariate analysis a negative impact was shown for pre-radiochemotherapy net-enhancing tumor on the overall survival (OS) (p = 0.023) and for preoperative necrosis on progression-free survival (PFS) (p = 0.030). Furthermore, the multivariate analysis confirmed the importance of PS in PFS and OS of patients. MGMT promoter methylation was observed in 13/23 (43.5%) evaluable tumors; complete methylation was observed in 3/13 methylated tumors only. High rate of MGMT protein positivity (> 20% positive neoplastic nuclei) was inversely associated with pre-operative tumor necrosis (p = 0.021). CONCLUSIONS: Our findings implicate that volumetric parameters may have a significant role in the prognosis of GBM patients. Furthermore, volumetry could help not only to improve the prediction of outcome but also the outcome itself by identifying patients at high risk of treatment failure and, thus, seek alternative treatment for these patients. In this small series, MGMT protein was associated with less aggressive tumor characteristics.

Pilomyxoid astrocytoma of the cervical spinal cord in a child with rapid progression into glioblastoma: case report and literature review.

INTRODUCTION: Pilomyxoid astrocytoma (PMA) is a recently described glial tumor with similarities to pilocytic astrocytomas, yet with distinct histopathological characteristics and a more aggressive behavior. It occurs predominantly in the hypothalamic/chiasmatic region. Only four patients with spinal cord PMA have been reported in the pediatric population. The 2007 WHO Working Group recognized PMA as a new variant and recommended an assignment to WHO grade II. OBJECTIVE: The purpose of this paper was to report a rare location, address the aggressive behavior and rapid progression, and based on the specific patient, to review the literature and discuss current treatment strategies. CASE PRESENTATION: A 12-year-old girl presented with motor and sensory deficits of the left side as well as gait disturbance. Imaging revealed an intramedullary tumor extending from C2 to C7. The patient improved impressively after surgical resection. Histopathological findings were consistent with PMA. Three months later, the patient presented with rapid neurological deterioration. Histopathology after the second operation was consistent with glioblastoma. The outcome was fatal 12 months after initial diagnosis, despite adjuvant therapy. CONCLUSIONS: This is the fifth pediatric spinal cord PMA in literature. Furthermore, it is the only documented patient with rapid recurrence and progression within 3 months into a glioblastoma. The question of a sampling error affecting initial pathology is raised. Based on contemporary literature data, we discuss the further treatment options, as there are no guidelines yet. Efforts towards registries should be encouraged, as the documentation of PMA might lead to more evidence based treatment strategies.

Atomic Force Microscope Nanoindentation Analysis of Diffuse Astrocytic Tumor Elasticity: Relation with Tumor Histopathology.

This study aims to investigate the influence of isocitrate dehydrogenase gene family (IDH) mutations, World Health Organization (WHO) grade, and mechanical preconditioning on glioma and adjacent brain elasticity through standard monotonic and repetitive atomic force microscope (AFM) nanoindentation. The elastic modulus was measured ex vivo on fresh tissue specimens acquired during craniotomy from the tumor and the peritumoral white matter of 16 diffuse glioma patients. Linear mixed-effects models examined the impact of tumor traits and preconditioning on tissue elasticity. Tissues from IDH-mutant cases were stiffer than those from IDH-wildtype ones among anaplastic astrocytoma patients (p = 0.0496) but of similar elasticity to IDH-wildtype cases for diffuse astrocytoma patients (p = 0.480). The tumor was found to be non-significantly softer than white matter in anaplastic astrocytomas (p = 0.070), but of similar elasticity to adjacent brain in diffuse astrocytomas (p = 0.492) and glioblastomas (p = 0.593). During repetitive indentation, both tumor (p = 0.002) and white matter (p = 0.003) showed initial stiffening followed by softening. Stiffening was fully reversed in white matter (p = 0.942) and partially reversed in tumor (p = 0.015). Tissue elasticity comprises a phenotypic characteristic closely related to glioma histopathology. Heterogeneity between patients should be further explored.

Distal middle cerebral artery dissection with concurrent completely thrombosed aneurysm manifesting as cerebral ischemia. A case report and review of the literature.

We report the case of a 70-year-old woman who presented with an acute ischemic stroke involving the left frontal operculum secondary to an M2 dissection and a concomitant completely thrombosed aneurysm of the left distal middle cerebral artery. Initial imaging work-up was inconclusive due to the lack of typical radiographic features and only repeated imaging studies pointed towards the presence of an arterial dissection combined with a completely thrombosed aneurysm. The aneurysm was partially clipped and wrapped with excellent clinical result at 1-year follow-up. The clinical, imaging and therapeutic challenges of this rare entity are discussed.

Mechanical properties of human glioma.

Brain gliomas represent some of the most aggressive tumors encountered by modern medicine and, despite major efforts to optimize early diagnosis and treatment, the prognosis remains poor. Due to the complex structure of the brain and the unique mechanical properties of the extracellular matrix, gliomas invade and expand into the brain parenchyma, along white matter tracts and within perivascular spaces, usually sparing normal vessels. Different methods have been developed to study the mechanical properties of gliomas in a wide range of scales, from cells and the microscale to tissues and the macroscale. In this review, the current view on glioma mechanics is presented and the methods used to determine glioma mechanical properties are outlined. Their principles and current state of affairs are discussed.

Is There an Independent Role of TERT and NF1 in High Grade Gliomas?

BACKGROUND: High grade glioma molecular profiling is of particular interest in neurooncology. The role of telomerase reverse transcriptase (TERT) varies dependent upon other molecular parameters. We explored the role of TERT in 101 high-grade gliomas. METHODS: A total of 101 patients (pts) with grade III-IV gliomas treated with standard of care and informative tumor genotypes were included in the present study. Of 55 genes targeted with the next-generation sequencing panel, mutations (muts) were found in 37; these were included in the analysis. TERT mut were tested with Sanger sequencing. MGMT promoter methylation status was determined by methylation specific PCR. RESULTS: 270 mut were detected in 92/101 tumors (91.1%). TERT was the most frequently mutated gene (74.3%). IDH1/2 mut were mutually exclusive with mut in the neurofibromin 1 (NF1) gene. Mutated TERT was associated with wild-type (wt) IDH1/2 (p = 0.025). The 12-month overall survival (OS) rate was 74.3% (median OS: 22 months). Pts with TERT and NF1 wt had a median OS of 40.8 months, while among pts with NF1 wt/TERT mutant, the median OS was 18.5 months. NF1 and TERT mut univariately conferred shorter OS (HR = 3.19; p = 0.004 and HR = 2.28; p = 0.002). Upon multivariate analysis, mutated TERT showed marginal unfavorable prognostic significance for OS (p = 0.049), while NF1 lost its unfavorable significance (p = 0.151). CONCLUSIONS: TERT is herein proven to confer poor prognosis in high grade gliomas, independent of IDH and MGMT. NF1 seems to also confer poor prognosis although our small numbers do not allow for firm conclusions.

The importance of tumor volume in the prognosis of patients with glioblastoma: comparison of computerized volumetry and geometric models.

BACKGROUND AND PURPOSE: The importance of tumor volume as a prognostic factor in high-grade gliomas is highly controversial and there are numerous methods estimating this parameter. In this study, a computer-based application was used in order to assess tumor volume from hard copies and a survival analysis was conducted in order to evaluate the prognostic significance of preoperative volumetric data in patients harboring glioblastomas. PATIENTS AND METHODS: 50 patients suffering from glioblastoma were analyzed retrospectively. Tumor volume was determined by the various geometric models as well as by an own specialized software (Volumio). Age, performance status, type of excision, and tumor location were also included in the multivariate analysis. RESULTS: The spheroid and rectangular models overestimated tumor volume, while the ellipsoid model offered the best approximation. Volume failed to attain any statistical significance in prognosis, while age and performance status confirmed their importance in progression-free and overall survival of patients. CONCLUSION: Geometric models provide a rough approximation of tumor volume and should not be used, as accurate determination of size is of paramount importance in order to draw safe conclusions in oncology. Although the significance of volumetry was not disclosed, further studies are definitely required.

Demyelinating plaque imitates an intramedullary tumour.

An isolated spinal demyelinating lesion is very rare and almost always associated with multiple sclerosis. There are only a few reports of biopsy or resection of MS-associated lesions. Sometimes the radiological and the histopathological findings can lead to a false diagnosis of a tumour. A 15-year-old girl presented with a progressive spastic tetraparesis and various associated clinical symptoms. Magnetic resonance imaging (MRI) suggested a possible intramedullary tumour extending from C4 to C7 and the need for surgical intervention. There was no previous neurological or other history and the brain MRI was normal. The performing surgeons based their procedures on oncological criteria. The extracted lesion was finally diagnosed as a demyelinating plaque. The postoperative course was uneventful without deterioration of the neurological status and the young patient improved completely after 4-months of rehabilitation. After an 8-year follow-up, the patient remains in remission and free of neurological defects. Apart from the radiological findings, the CSF exam as well as the evoked potentials does not suggest a diagnosis of MS. A demyelinating plaque in the cervical spinal cord can occasionally imitate a cervical intramedullary tumour leading to an operation. Such lesions underscore the sensitivity of present-day lesion detection procedures. An addition of a MS work up could be beneficial in some cases of intramedullary tumours without a typical history, although in the case presented this type of workup was negative.

Post-operative combined radiation and chemotherapy with temozolomide and irinotecan in patients with high-grade astrocytic tumors. A phase II study with biomarker evaluation.

BACKGROUND: Clinical studies have shown that temozolomide (TMZ) and irinotecan demonstrate activity in high grade astrocytic tumors (HGAT). However, the optimal schedule of administration is unknown. PATIENTS AND METHODS: In the present study, a total of 45 HGAT patients, 38 with glioblastoma multiforme (GBM) and 7 with anaplastic astrocytoma (AA), were treated with TMZ, 150 mg/m(2) on days 1-5, followed by irinotecan, 150 mg/m(2) on days 6 and 17, every 4 weeks for 6 cycles or until the occurrence of unacceptable toxicity or disease progression. Radiation therapy (60 Gy) was initiated on the first day of treatment. RESULTS: Twenty-two patients completed six cycles of treatment. Most frequently recorded side-effects included neutropenia (37%), nausea/vomiting (66%), diarrhea (31%) and infection (44%). Five episodes of vaso-occlusive disease, all of them fatal, were observed. After a median follow-up of 49.8 months, median progression-free survival for patients with GBM was 7.7 months, while median overall survival was 12.8 months. There were six long-term survivors, three of them with GBM. Two out of the five biomarkers studied, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor-C (VEGF-C), were found to be overexpressed in 74% of the tumors, however they had no predictive value for progression-free or overall survival. CONCLUSION: The combination of TMZ and irinotecan, as administered in this study, was accompanied by high rates of toxicity, especially myelotoxicity and infection. Further development of this regimen in the treatment of HGAT is not recommended.

DARPP32, STAT5 and STAT3 mRNA expression ratios in glioblastomas are associated with patient outcome.

Based on recent developments in glioblastoma subtyping, we examined DARPP32 (PPP1R1B), a neuronal marker against STAT5 and STAT3 that are pro-oncogenic in glioblastoma. mRNA ratios of DARPP32, STAT1, STAT3, STAT5A and STAT5B were assessed in routinely diagnosed gliomas s including a series of glioblastomas from patients (n = 67) treated with chemoradiotherapy (temozolomide), out of which 88 % had sequencing validated IDH-negative disease. DARPP32/STAT1 (p = 0.0007), DARPP32/STAT3 (p = 0.0004) and DARPP32/STAT5B (p = 0.0039) ratios were significantly higher in grade II and III as compared to grade IV tumours. The same high ratios were also associated with absence of immunohistochemically assessed AKT/PKB phosphorylation and survivin protein expression. High DARPP32/STAT3, DARPP32/STAT5B, and STAT5B/STAT3 ratios were associated with longer patient progression free (PFS) and overall survival (OS). Upon multivariate analysis, total/subtotal removal of the tumour (HR:0.431; 95%CI:0.241-0.771, Wald p = 0.005), high DARPP32/STAT5B (HR:0.341; 95%CI:0.169-0.690; Wald p = 0.003) and STAT5B/STAT3 mRNA ratios (HR:0.480; 95%CI:0.280-0.824; Wald p = 0.008) were independent favorable parameters for prolonged PFS. Extent of surgery (HR:0.198; 95%CI:0.101-0.390; p < 0.001) and high DARPP32/STAT5A ratios (HR:0.320; 95%CI:0.160-0.638, p = 0.001) were independently predictive for longer OS. The presented approach is applicable for prospective validation and appears promising towards an effective glioblastoma patient stratification in addition to IDH mutations. These data may contribute to understanding the biology of gliomas with respect to their potential neuronal characteristics and justify STAT-inhibiting therapeutic interventions in the same tumour system.

Biopsy versus resection in the management of malignant gliomas: a systematic review and meta-analysis.

OBJECT: The aim of this study was to answer the question whether quality of life and progression-free and overall survival are increased in adults with supratentorial malignant glioma who are treated with cytoreductive resection as compared with those who only undergo biopsy. METHODS: A literature search of the electronic databases MEDLINE, EMBASE, and CENTRAL was performed to identify relevant studies published before May 2008. Hand-searching of reference lists of the identified studies and relevant review articles was also performed. A study was considered eligible, regardless of study design (prospective or retrospective), if: 1) quality of life and/or progression-free and/or overall survival was compared among adult patients undergoing biopsy or resection, and 2) patient age and Karnofsky Performance Scale scores were not significantly different among the 2 groups compared. RESULTS: One randomized controlled trial and 4 retrospective studies (involving a total of 1111 patients) were found eligible for this systematic review. A meta-analysis of the eligible studies demonstrated a significant increase in overall survival in the patients treated with resection instead of biopsy (hazard ratio 0.61, 95% CI 0.52-0.71, p < 0.0001, fixed-effect model). Although statistical pooling was not feasible, the available data suggest that quality of life was increased in patients treated with resection rather than biopsy, while there did not seem to be any significant difference in progression-free survival between the 2 groups. CONCLUSIONS: Based on the best available evidence, it appears that cytoreductive resection in adults with supratentorial malignant glioma is associated with improved overall survival as compared with biopsy. However, well-designed prospective studies are needed for more solid conclusions to be drawn.

Spontaneous spinal cord herniation: recurrence after 10 years.

BACKGROUND CONTEXT: Transdural spontaneous spinal cord herniation is a very rare nosological entity, which despite recent reports in the medical literature remains often misdiagnosed preoperatively. Usually it affects the thoracic segment, protrudes ventrally, presents clinically as a progressive Brown-Séquard syndrome and carries a favorable surgical outcome. PURPOSE: To describe a rare case of delayed recurrence of spontaneous spinal cord herniation despite excellent outcome for 10 years, and discussion of management and observation issues. STUDY DESIGN/SETTING: Case report/University Hospital. METHODS: We describe the management of a patient with spontaneous spinal cord herniation that presented initially with a Brown-Séquard syndrome and has been treated successfully with surgery. After 10 years free of symptoms, the patient developed progressive paraparesis and urinary incontinence because of recurrence of the herniation at the same level. RESULTS: Despite technical challenges, during the second operation the enlarged ventral dural defect was meticulously closed and the patient's neurological condition presents 9-month postsurgery considerable improvement. To our best knowledge, recurrences of spontaneous spinal cord herniation are extremely rare. CONCLUSIONS: The reported case underlines the necessity to be aware of this rare but treatable spinal disease, notify the possibility of late recurrences and the need of long-term follow-up even if initial outcome is favorable.