IDH1/2 Mutation and MGMT Promoter Methylation - the Relevant Survival Predictors in Czech Patients with Brain Gliomas.

Gliomas are a heterogeneous group of tumours varying in prognosis, treatment approach, and overall survival. Recently, novel markers have been identified which are linked to patient prognosis and therapeutic response. Especially the mutation of the enzyme isocitrate dehydrogenase 1 or 2 (IDH1/2) gene and the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status seem to be the most important predictors of survival. From 2012 to 2015, 94 Czech patients with primary brain tumours were enrolled into the study. The IDH1/2 mutation was detected by denaturing capillary electrophores.The methylation status of the MGMT gene and other 46 genes was revealed by MS-MLPA. In all 94 patients, the clinical data were correlated with molecular markers by Kaplan-Meier analyses and Cox regression model. The MGMT promoter methylation status was established and compared to clinical data. In our study eight different probes were used to elucidate the MGMT methylation status; hypermethylation was proclaimed if four and more probes were positive. This 3 : 5 ratio was tested and confirmed by Kaplan-Meier and Cox analyses. The study confirmed the importance of the IDH1/2 mutation and hypermethylation of the MGMT gene promoter being present in tumour tissue. Both markers are independent positive survival predictors; in the Cox model the IDH hazard ratio was 0.10 and in the case of MGMT methylation it reached 0.32. The methylation analysis of the panel of additional 46 genes did not reveal any other significant epigenetic markers; none of the candidate genes have been confirmed in the Cox regression analyses as an independent prognostic factor.

Carotid endarterectomy and carotid artery stenting: changing paradigm during 10 years in a high-volume centre.

BACKGROUND: We analysed the results of internal carotid artery (ICA) stenosis treatment at our institution over the last 10 years according to treatment modalities (carotid endarterectomy [CEA] vs carotid artery stenting [CAS]). Furthermore, we compared our results of treatment prior to the EVA-3S study being implemented into our practice (2003-2007) and after that (2008-2012). METHOD: During the years 2003-2012, a total of 1,471 procedures were performed for ICA stenosis. CEA was done in 815 cases and CAS in 656 cases. The primary outcome was disabling stroke (mRS > 2) or myocardial infarction (MI) within 30 days after treatment. Secondary outcomes were frequency of transient ischaemic attacks (TIAs), minor strokes (stroke without impaired activities of daily living [ADL]) and any other significant complication. Comparisons of the results before and after 2008 were performed. RESULTS: Major mortality and morbidity were divided according to treatment groups; reached 1.0 % in the CEA group and 3.0 % in the CAS group, p = 0.004. Minor stroke was recorded at 1.8 % and 2.7 % in the CEA and CAS, p = 0.245. TIAs in 1.0 % (CEA) and 4.7 % (CAS), p < 0.001. Any complication in 11.9 % (CEA) and 13.3 % (CAS), p = 0.401. In the overall results (i.e. CEA and CAS together), we found in 2008-2012 a decrease of incidence of TIAs (from 30/840 to 9/631, p = 0.011) and any complications (from 120/840 to 64/631, p = 0.017). CONCLUSIONS: CEA performed in a high-volume centre is a safe procedure in properly indicated patients. In all subgroup analyses, CEA fared better than or at least of equal benefit as CAS. Since 2008, the frequency of TIAs and other complications decreased significantly. This study supports an idea of CEA being the first choice of treatment and CAS being reserved for strictly selected cases, such as re-stenosis after a previous carotid procedure, carotid dissection, ICA stenosis after radiotherapy, previous major neck surgery, contralateral cranial nerve palsy or tandem stenosis.

[Molecular cytogenetic analysis of chromosomal aberrations in cells of low grade gliomas and its contribution for tumour classification]. / Molekulárne cytogenetická analýza chromozomových aberací v bunkách nízkostupnových gliomu a její prínos pro klasifikaci nádoru.

BACKGROUND: Low-grade gliomas represent a heterogeneous group of primary brain malignancies. The current diagnostics of these tumors rely strongly on histological classification. With the development of molecular cytogenetic methods several genetic markers were described, contributing to a better distinction of glial subtypes. The aim of this study was to assess the frequency of acquired chromosomal aberrations in lowgrade gliomas and to search for new genomic changes associated with higher risk of tumor progression. PATIENTS AND METHODS: We analysed biopsy specimens from 41 patients with histological dia-gnosis of low-grade glioma using interphase fluorescence in situ hybridization (I FISH) and single nucleotide polymorphism (SNP) array techniques (19 females and 22 males, medium age 42 years). RESULTS: Besides notorious and most frequent finding of combined deletion of 1p/ 19q (81.25% patients) several other recurrent aberrations were described in patients with oligodendrogliomas: deletions of p and q arms of chromosome 4 (25% patients), deletions of the short arms of chromosome 9 (18.75% patients), deletions of the long arms of chromosome 13 and monosomy of chromosome 18 (18.75% patients). In bio-psy specimens from patients with astrocytomas, we often observed deletion of 1p (24% patients), amplification of the long arms of chromosome 7 (16% patients), deletion of the long arm of chromosome 13 (20% patients), segmental uniparental disomy (UPD) of the short arms of chromosome 17 (60% patients) and deletion of the long arms of chromosome 19 (28% patients). In one patient we detected a shuttered chromosome 10 resulting from chromothripsis. CONCLUSION: Using a combination of I FISH and SNP array, we detected not only known chromosomal changes but also new or less frequent recur-rent aberrations. Their role in cancer  cell progression and their impact on low grade gliomas classification remains to be elucidated in a larger cohort of patients.

[The significance of biological intracranial meningioma behaviour for their long-term management]. / Význam biologického chování nitrolebních meningiomu pro jejich dlouhodobý management.

INTRODUCTION: From the histological point of view, most meningiomas are benign tumours. Nevertheless, their recurrence is quite frequent, and identifying the risk factors for recurrent disease is of utmost importance. MATERIAL AND METHODS: Prospective study, patients operated on in the period 2/2008-9/2009. Inclusion criteria for enrolment into the study: age 18-70 years, good health status, and previously untreated solitary intracranial meningioma. Evaluation of clinical, surgical, MRI findings and vascular endothelial growth factor serum levels (prior to procedure, 3 months after, 12 months after, 24 months after procedure and at the time of the last follow-up in 11/2011) was performed. Immunohistochemical analysis of histological samples was carried out. Further treatment (wait and see, redo surgery, treatment with radiation using the Leksell Gamma Knife, external radiotherapy) was recorded in case of a positive follow-up MRI finding (recurrent disease, progression of residual tumour). RESULTS: A total of 50 consecutive patients (34 women and 16 men) were included into the study. Average age at the time of surgery was 59.2 years (range 27-75 years). Radical resection with no residual tumour left was achieved in 35 cases. Histological analysis showed grade I meningioma in 45 cases and grade II (atypical) meningioma in 5 cases. Correlation between E-cadherin expression and recurrent meningioma was proved by immunohistochemical examinations; in the remaining investigations, however, such a correlation was not found. No correlation was detected between the serum vascular endothelial growth factor level and the expression of vascular endothelial growth factor in immunohistochemical investigation. A correlation was found between the expression of vascular endothelial growth factor in immunohistochemical investigation and peritumoural oedema. The tumour recurred in 5 cases. CONCLUSIONS: On the basis of our results as well as literature findings we can conclude that all the patients after meningioma surgery need to be carefully followed for the rest of their life by repeated MRI invetigations.

Chordoid meningioma: presentation of two case reports, review of the literature, and plea for data standardisation.

Chordoid meningioma is a rare variant of meningioma with histological features resembling those of chordoma. This tumour should have a greater risk of recurrence and aggressive growth (WHO grade II). So far, 92 such tumours have been described in the literature. We report two cases of chordoid meningioma occurring in adult female patients. In our two patients (aged 28 and 60 years with chordoid meningioma of the convexity and left-sided outer sphenoid wing, respectively) we centred on some rarely discussed aspects of the tumour. MRI scans showed no edema in the vicinity of either of the two meningiomas, whereas selective angiography of ACI and ACE revealed a dural type of vascular supply to the two neoplasms. In both cases, the tumour was removed by radical surgery (Simpson grade I resection) with a normal post-operative course. Both women (one 2 years post-surgery and one 4 years post-surgery) are now free from any signs of relapse on MRI and with normal neurological findings. The vascular endothelial growth factor (VEGF) expression was low in either case (5 and 40%, respectively). We regard the factors under consideration in our study (i.e. absence of edema, dural supply, low VEGF expression and radical Simpson grade I resection) as an important contribution to the discussion of the biological behaviour of chordoid meningioma.

Preoperative neuroimage findings as a predictor of postoperative neurological deficit in intracranial meningiomas.

BACKGROUND: The present study aimed to find radiological parameters that can provide indirect information on the invasive growth of meningioma relevant enough to predict the likely risk of postoperative neurological deficit. MATERIAL/METHODS: The cohort consisted of 40 consecutive adult patients (from January 2004 till May 2005) with comparable general condition parameters (age 18-75 years, KRS 70-100, ASA 1-2) with meningiomas solely attacking brain tissue with the whole of their volume. The Pearson chi-square test was used for statistical evaluation. RESULTS: Radical resection of the meningioma was attained in 33 (82.5%) patients and subtotal resection in 7 (17.5%). Ten (25%) patients at 7 days after the operation had neurological findings which were worse than before. Seven were found to have a new neurological deficit and there were three cases of progression of the existing neurological symptoms. Three patients (7.5%) were worse off neurologically than before the operation as long as 3 months after surgery, while seven had their neurological condition restored ad integrum. All of the ten patients with postoperatively worsened neurological findings had their meningiomas localised in the eloquent area. A correlation was found between the eloquent area and neurological deficits, and also between the presence of peritumoral oedema (small, medium, large) and neurological deficits. Interdependence was detected between a discernible tumour-brain interface and the absence of oedema, between a discernible tumour-brain interface and a dural type of vascular supply, and between the dural type of vascularisation and an absence of oedema. CONCLUSIONS: As follows from the outcomes, meningioma growth in the eloquent area and the presence of peritumoral oedema are the two adverse parameters predicting the development of postoperative neurological deficits. In contrast, dural types of vascularisation, a visible tumour-brain interface, meningioma growing in a non-eloquent area, and the absence of peritumoral oedema are favourable predictive parameters. To go by the results, in the presence of the last two parameters the patient need not be exposed to the risks of invasive selective angiography.

Hypercapnia impact on vascular and neuronal reactivity in patients before and after carotid endarterectomy.

HYPOTHESIS: Regional cerebral blood flow (rCBF) and vascular reactivity strongly affect neuronal function. The restoration of blood flow values in the cerebral vascular system may be another benefit of carotid endarterectomy (CEA) in a specific group of patients. Animal experiments in dogs have provided evidence of neuronal reactivity depending on rCBF and vascular reactivity. However, as yet, there are no reports on neuronal reactivity changes related to altered perfusion parameters in humans. MATERIAL AND METHODS: The cohort under study consisted of 41 patients after transient ischaemic attack (TIA) or reversible ischaemic neurological deficit (RIND) whose neurological findings were normal (group A) and 17 patients after minor stroke with a mild degree of hemiparesis or hemihypesthesia (mRS

Experience of 500 cases of neurophysiological monitoring in carotid endarterectomy.

BACKGROUND: Experience with Intraoperative monitoring using neurophysiological and haemodynamic indices in 500 operations for carotid endarterectomy is reported. METHODS: Transcranial Doppler technique (TCD), electroencephalogram (EEG) and bilateral median somatosensory evoked potentials (SEP) were performed. Latency and amplitude of SEP, spectral analysis of EEG signal and blood flow velocity in the medial cerebral artery (MCA) were continuously measured. FINDINGS: After two consecutive drops of N20/P25 complex of more than 50%, a warning was given, and when the decrease continued, an the alarm raised. Abnormal EEG changes, if any, appeared after a significant decrease in the N20/P25 amplitude. A mean blood flow velocity drop below 40% of the reference value after cross clamping was rated as a significant warning event.A warning as a result of a decrease in N20/P25 amplitude occurred in 80 operations (16.0%), after an spectral edge frequency decrease in 2 cases (0.4%) and after a V(mean) decrease in 21 cases (4.2%). False negative results were experienced in 2 patients (0.4%). A shunt was inserted in 2.8% of the operations. The overall mortality/morbidity rate was 2.4%. CONCLUSION: A decrease of more than 50% in the amplitude of the thalamocortical somatosensory evoked potential complex N20/P25 proved to be the most reliable warning of danger of ischaemia during carotid endarterectomy.

Molecular cytogenetic stratification of recurrent oligodendrogliomas: utility of interphase fluorescence in situ hybridization (I-FISH).

In oligodendroglial brain tumours, losses of chromosomal material of the short arm of chromosome 1 and long arm of chromosome 19 have been shown to predict responsiveness to chemotherapy and prolonged patients' survival. Therefore, the correct diagnosis of these genetic alterations in tumours of oligodendroglial origin is particularly important. To detect deletions of 1p36 and/or 19q13.3 in oligodendroglial cells we used dual-colour I-FISH with locus-specific DNA probes. I-FISH was performed on isolated whole cell nuclei, prepared from fresh non-fixed tumour tissue samples resuspended in media and processed using a standard cytogenetic procedure, thus bypassing the problem of nuclear truncation. We examined 16 patients with histologically proved oligodendrogliomas (5x oligodendroglioma, 9x anaplastic oligodendroglioma, 2x anaplastic oligoastrocytoma). The results of molecular cytogenetic analyses were correlated with morphological and clinical findings. Molecular cytogenetic analyses were successful in 15 patients and, due to a non-adequate tissue specimen, were uninformative in one patient only. Combined deletions 1p36/19q13 were proved in 13 patients. However, in six of them additional genetic alterations typical for high-grade astrocytoma were found, which could have negative influence on the prognosis. One patient had isolated deletion of 1p36 and another had a normal genetic pattern without any chromosomal alterations. In summary, I-FISH on isolated cell nuclei is a powerful tool for detecting chromosomal aberrations in tumour cells. A systematic molecular cytogenetic analysis may advance diagnosis, prognostic stratification, and targeted treatment of patients with brain tumours.

Intracranial meningioma surgery outcome--the impact of preoperative neuroimaging.

The present study is aimed at finding radiological parameters which could provide indirect information on invasive growth of meningioma, relevant enough to predict the possible risk of postoperative neurological deficit development. The cohort was composed of 40 consecutive adult patients of comparable general condition parameters (age 18-75 years, KRS 70-100, ASA 1-2) with meningiomas attacking with the whole of their volume solely the brain tissue. As follows from the outcome, meningioma growth in the eloquent area and the presence of peritumoral oedema are the two adverse parameters predicting the development of postoperative neurological deficit. In contrast, dural type of vascularisation, visible tumour-brain interface, meningioma growing in a non-eloquent area and the absence of peritumoral oedema are favourable predictive parameters. According to our results, if the last two of those parameters are present, the patient need not to be exposed to the risks of invasive selective angiography.

[Intracranial meningiomas; standard diagnostic procedure and results of surgical treatment]. / Nitrolební meningiomy; standardní diagnostický postup a vý1sledky operacní lécby.

The aim of the study is to define radiological parameters which may indirectly indicate invasive expansion of a meningioma and thus forecast potential risks of postoperative neurological deficits. The study group includes 40 adult patients in comparable physical conditions (age 18-75, CRS 70-100, ASA 1-2) with meningiomas, affecting the brain tissue only. The results indicate that unfavorable parametres, predicting potential postoperative neurological deficits include: growth of a meningioma in eloquent regions and presence of a peritumoral oedema. Positive parametres, indicating that no neurological deficit would arise, include: dural supply, visible brain-tumor barrier, non-eloquent location of a meningioma and absence of a peritumoral oedema. The study results suggest that provided the two last parametres are present, a patient need not be exposed to risks of invasive selective angiography.

[Intracranial meningiomas--criteria for selection of the optimum therapeutic modality]. / Nitrolební meningiomy; kritéria pro výber optimální léebné modality.

The authors present their own proposal for a standard diagnostic procedure algorithm in intracranial meningiomas, which they used in their prospective, non-randomized longitudinal study in a group of 30 subjects within a year. The following four criteria were assessed in each patient: age, physical condition according the ASA classification, location of the meningioma on the MRI (superficial, the scull base) and the growth invasivity using selective DSA (ACI+ACE) and MRI (the vascularization type, the oedema index and the change in the oedema signal intensity in 3.5 hours). The criteria helped to establish the optimum therapeutic procedure for each patient: embolisation without a follow-up surgery (2 subjects), observation (2 subjects), pre-operative embolisation (5 subjects) and surgery without preceeding embolisation (21 subjects). This study did not assess the intracranial meningiomas treatment outcome. It highlights significance of the diagnostic procedures standardization in order to establish their optimum therapeutic modality.

Comparison between degree of carotid stenosis observed at angiography and in histological examination.

BACKGROUND: The generally accepted indications for carotid endarterectomy are the clinical picture and degree of per cent stenosis of the carotid artery. Despite the fact that stenosis measurement is defined, the methods vary considerably. The correlation of particular methods, especially angiography and duplex sonography, has been repeatedly demonstrated. However, the correlation between any technique and true anatomical stenosis, as evaluated on the surgical specimen, has been only anecdotally reported. METHOD: During carotid endarterectomy, the atherosclerotic plaque was removed in one piece and subsequently stored and histologically processed. The histological slides were evaluated under an optical microscope, scanned and the slide with maximum stenosis was determined using a planimetric program. Both the minimal lumen area and the area of the whole plaque were measured. The stenosis was calculated using the planimetric method. On the maximum stenosis slice, the minimal diameter and the diameter of the whole plaque were also measured. Angiographic images were scanned and the per cent stenoses were remeasured, according to the NASCET and ECST criteria. In total, of 147 cases, all above-mentioned parameters were obtained. Student's t tests for paired samples were used to evaluate the results. FINDINGS: The t-tests indicated significant differences between the per cent stenosis as measured on the anatomical specimen and on the angiogram (p<0.05). The results indicate that the angiographic measurement underestimates the degree of in-situ anatomical stenosis. The underestimation was more marked the less the degree of stenosis. CONCLUSIONS: Our study finds that per cent stenosis measurement obtained by angiography with NASCET or ECST methods does not reliably reflect the anatomical degree of per cent stenosis, which makes questionable the rigorous following of percentage stenosis using angiography as the sole indicator for carotid endarterectomy in all cases.

[Anterior cervical corpectomy in the treatment of multilevel degenerative stenoses with spondylotic myelopathy. Personal experience with therapy and a literature review]. / Prední krcní korpektomie pri resení víceetázových degenerativních stenóz se spondylogenní myelopatií. Zkusenosti s lécbou a prehled literatury.

The authors use as a basis experience with a group of 389 patients operated in 1989-1997 on account of degenerative diseases of the cervical spine with neurological manifestations. The results are compared with experience assembled in 1998-1999. In the new group (188 patients with the same diagnosis) the same indication criteria were used but in case of myelopathy associated with multisegmetal cervical stenosis not only multilevel discectomy was performed (as in the previous group) but in addition also 1-3 segmental corpectomy (somatectomy). The results were evaluated separately for both methods used. The authors emphasize the necessity of a radical approach during decompression of neurological structures incl. removal of uncovertebral osteophytes which must be combined with suitable stabilization of the fusions or possibly be supported by instrumentation. In the discussion the authors illustrate in the form of a review the development of anterior cervical corpectomy as one of the methods of an anterior approach to the cervical spine used at first in traumatic and oncological conditions, later extended to operations on account of degenerative, dysplastic conditions and other diseases. The authors wish to help to define criteria for application of corpectomy when treating stenoses of the spinal canal in the cervical region. The indication will be defined in a perspectively followed up group where a detailed clinical and electrophysiological algorithm for examination was submitted as well as postoperative follow-up and processing of the resulting data.

[Doppler scanning in aneurysm surgery]. / Doppler scanning v chirurgii aneuryzmat.

Subarachnoid hemorrhage still represents important medical problem, from both, ineffective prevention and high morbidity and mortality rate of the condition. On the other hand, majority of patients who survive initial hemorrhage and successful clipping of their aneurysm can live without major medical restrictions. Apart from surviving the initial attack the most important condition is properly clipped aneurysm. Doppler scanning control allows precise placement of the clip on the neck of an aneurysm. Since January 1997 through December 1999 the authors have surgically treated 204 aneurysms in 181 patient. In 40 surgeries the Doppler scanning was employed after the aneurysm complex was dissected free. Using 20 MHz PW Doppler probe the flow within the aneurysm and in the involved arteries was measured (usual depth 1.5 mm, range 1-2.5 mm). After the clipping the flow was evaluated again, to ensure proper exclusion of an aneurysm and good flow in involved arteries. The authors consider the Doppler scanning to be important technical aid in aneurysm surgery, especially in anatomically complex situations.