Quantitative profiling of genes associated with cancer pathways in brain tumors.

BACKGROUND: Brain tumors are a heterogeneous group of malignancies characterized by inter- and intratumoral heterogeneity. Among them, the most aggressive and, despite advances in medicine, still incurable remains glioblastoma. One of the reasons is the high recurrence rate of the disease and resistance to temozolomide, a golden standard in chemotherapy of brain tumors. Therefore, mapping the pathways responsible for tumorigenesis at the transcriptional level may help to determine the causes and aggressive behavior among different glial tumors. PATIENTS AND METHODS: Biopsies from patients with astrocytoma (N = 6), glioblastoma (N = 22), and meningioma (N = 14) were included in the sample set. A control group consisted of RNA isolated from healthy human brain (N = 3). The reverse-transcribed cDNAs were analyzed using the Human Cancer PathwayFinder™ real-time PCR Array in a 96-well format. The expression of 84 genes belonging to 9 signaling pathways (angiogenesis, apoptosis, cell cycle and senescence, DNA damage and repair, epithelial-to-mesenchymal transition, hypoxia, overall metabolism, and telomere dynamics) was determined for each sample. RESULTS: By determining the relative expression of selected genes, we characterized the transcriptomic profile of individual brain malignancies in the context of signaling pathways involved in tumorigenesis. We observed deregulation in 50, 52.4 and 53.6% % of the genes in glioblastomas, meningiomas and astrocytomas, respectively. The most pronounced changes with statistical significance compared to control were observed in the genes associated with epithelial-to-mesenchymal transition (CDH2, FOXC2, GSC, SNAI2, and SOX10), cellular senescence (BMI1, ETS2, MAP2K1, and SOD1), DNA repair (DDB2, ERCC3, GADD45G, and LIG4), and dynamic of telomeres (TEP1, TERF2IP, TNKS, and TNKS2). CONCLUSION: Based on the obtained data, we can conclude that individual diagnoses differ in transcriptomic profile. An individual molecular approach is therefore necessary in order to provide comprehensive and targeted therapy on multiple metabolic pathways in the diagnosis of brain tumors.

Stereotactic stimulation of the anterior lobe of the cerebellum in cerebral palsy from a suboccipital approach.

The anatomical connections of the anterior lobe of the cerebellum with the reticular formation in the brainstem, upper motor neurons and the limbic system, as well as the results of experimental and clinical observations indicate that this region is a proper area for modulation of certain types of central motor disorders but also of limbic functions. Through a direct stereotacticaly suboccipital approach electrodes were introduced into the anterior lobe of the cerebellum in four patients (3 females and one male, 24, 29, 45 and 19 years old, respectively) suffering from cerebral palsy and being confined to a wheelchair with severe spastic choreoathetoid movements, with minimal hand function, but in good mental state. After a period of test stimulation (up to 10 days), the pulse generators were implanted and chronic high-frequency stimulation was applied (for 37, 58, 9 and 32 months, respectively). In agreement with our previous experience (transtentorial approach in 30 patients), noticeable improvements in spasticity were immediate and a gradual reduction in choreoatetoid movements was observed in the following days to weeks. Improvements in speech, swallowing, respiration, posture, ambulation, and mood states were combined with development of new motor skills. Caution with the proper positioning of the electrode in the target and the selection of optimal program for stimulation are of paramount importance.

In vitro study of astrocytic tumour metabolism by proton magnetic resonance spectroscopy.

In vivo magnetic resonance spectroscopy (MRS) studies of glial brain tumours reported that higher grade of astrocytoma is associated with increased level of choline-containing compounds (Cho) and decreased levels of N-acetylaspartate (NAA) and creatine and phosphocreatine (Cr). In this work, we studied the metabolism of glioma tumours by in vitro proton magnetic resonance spectroscopy (1H-MRS). 1H-MR spectra were recorded in vitro from perchloric acid extracts of astrocytoma (WHO II) and glioblastoma multiforme (WHO IV) samples. We observed differences between astrocytoma and glioblastoma multiforme in the levels of Cho, alanine, lactate, NAA, and glutamate/glutamine. In astrocytoma samples, we found higher MR signal of NAA and lower signal of Cho and alanine. MR spectra of glioblastoma samples reported significantly higher levels of lactate and glutamate/glutamine. In contrast, levels of Cr were the same in both tumour types. We also determined NAA/Cr and Cho/Cr ratios in the tumour samples. The NAA/Cr ratio was higher in astrocytomas than in glioblastomas multiforme. Conversely, the Cho/Cr ratio was higher in glioblastoma multiforme. The results indicate that MRS is a promising method for distinguishing pathologies in human brain and for pre-surgical grading of brain tumours.

Effect of stereotactic high-frequency stimulation in the anterior lobe of the cerebellum in cerebral palsy: a new suboccipital approach.

The direct stereotactic suboccipital approach to the anterior lobe of the cerebellum was applied for deep high-frequency stimulation in three patients (for 29, 8 and 3 months) suffering from cerebral palsy. In agreement with our previous experience with a transtentorial approach in 30 patients, spasticity, dyskinesias and behavior were improved during chronic intermittent stimulation (frequency 185 Hz, pulse width 210 micros, voltage individually altered according to motor response at 0.5-4.0 V, 15 min on, 2-6 h off). Patients attained useful motor skill improvements. The results indicate that the method is safe, effective and reasonable.

Different effect of chronic electrical stimulation of the region of the superior cerebellar peduncle and the nucleus ventralis intermedius of the thalamus in the treatment of movement disorders.

The stereotactic target for essential tremor is usually restricted to the nucleus ventralis intermedius of the thalamus, where total immediate suppression of tremor is obtained by continuous chronic electrical stimulation. According to authors' experience in cerebral palsy, chronic stimulation of the region of the superior cerebellar peduncle can diminish spasticity and dyskinesias. The effect of this stimulation is gradual and persists, so stimulation is applied 3-8 times daily for 15-20 min, and is accompanied by a feeling of pleasure. After interruption of chronic stimulation, the effects last for days or weeks. It is suggested that the changes in synaptic connections--reactive synaptogenesis--can also contribute.

[Personal experience with surgical treatment of the lumbo-ischiadic syndrome]. / Nase skúsenosti s chirurgickou liecbou lumboischiadického syndrómu.

A prospective investigation of 200 patients with lumboischiadic syndrome, who were operated in the Regional Institute of National Health, Banska Bystrica. Before operation 176 patients had CT examinations and 70 perimyelographic examinations. Only patients where the clinical finding and CT or perimyelographic finding correlated were indicated for operation. Attention was focused on comparison of the findings on operation and findings of the CT examination. Noninvasive CT examinations which are aimed and follow a detailed clinical analysis and incl. sagittal reconstruction pictures give a reliable idea of morphological changes in the examined LS portion of the spine. They make it possible to localize herniation of intervertebral disc and to differentiate reliably compression of spinal roots by osseous structure in the area of facet, the narrow lateral recess or narrow spinal canal. Thus selective surgery is possible. Invasive perimyelographic examination is the method of choice where CT is not available or when the CT finding does not correlate with the clinical finding.

Behavioural responses to cerebellar stimulation in cerebral palsy.

Stereotactic placement of stimulating electrodes (TESLA) into deep regions of the cerebellum (Fischer instruments) was analyzed in respect to its organization into sagittaly oriented zones. This was done after imaging of the trajectory and target area and verification of the position of electrodes by CT (Siemens). A correlation was observed between the position of the stimulating electrode from the midline laterally and localization of induced responses on the body--from bilateral to ipsilateral. The combination of deep cerebellar stimulation and destructive method in the supratentorial region could be the optimal approach to relieve spasticity and to improve motor function in some cases of cerebral palsy.

Motor and psychological responses to deep cerebellar stimulation in cerebral palsy (correlation with organization of cerebellum into zones).

The study includes 68 cases of cerebral palsy stereotaxically operated on from 1977. Deep cerebellar stimulation treatment was performed. The motor and psychological responses to electrical stimulation of 305 points of subcortical regions of cerebellum, mostly lobus anterior were analysed. The characteristic response--slight motor jerk immediately--followed by relaxation and feeling of pleasure, even laughing, to the electrical stimulation from selected points was always found. The level of stimulating current must be adjusted individually. The higher current increased pathological posture, muscular tonus and was conducted with the state of fear. The lower current was without detectable influence on the patient. On the trajectory of electrode, nearly perpendicular to the sagittal plane were narrow areas, which recurred as the strips, from where it was possible or not to elicit characteristic response. The most convenient target is in the region of brachia conjunctiva cerebelli. Localization of the point of stimulation in respect to organization of cerebellum into sagittally oriented zones and the parameters of stimulation seem to contribute to the diversity of responses to cerebellar stimulation.

Stereotactic approach to therapeutic stimulation of cerebellum for spasticity.

A Stereotactic approach for transtentorial implantation of deep wire electrodes directly into the anterior lobe of cerebellum has been shown as a beneficial method for the treatment of cerebral palsy in 9 patients. Proper placement of the electrodes especially into the central lobule were checked by evoked potentials and by choosing an optimal program of therapeutic stimulation which appears to be essential. With its favourable effect particularly on axial musculature stimulation seems to promote physiologic maturation of functional mechanisms in the brain, which were delayed in the course of development.

Combined transtentorial dentatotomy with pulvinarotomy in cerebral palsy.

For frequently associated spasticity with involuntary movements in cerebral palsy operations on cerebellar nuclei or on the pulvinar of the thalamus are recommended. We combined both approaches in 45 patients. The combination was possible after experiences with transtentorial dentatotomy, in which the electrodes are introduced into the deep structures of the cerebellum from a burr-hole on the lambdoid suture. The same lambdoid approach may equally well be applied for introducing electrodes into the pulvinar of the thalamus. The lesion in the pulvinar may moreover be combined with the target in the centrum medianum or in the nuclei VIM-VCP or VOP. Lesions are always asymmetric and multilocular. Their influence on the clinical picture is quite favourable.

Some observations in treatment stimulation of epilepsy.

In a group of 10 patients suffering from epilepsy therapeutic stimulation was applied by means of chronic electrodes and a technical stimulator three times in nucleus dentatus, five times in nucleus caudatus, once in both structures simultaneously. Once chronic electrodes were introduced into the amygdalo-hippocampal complex and non-specific thalanic system bilaterally. One patient was stimulated by means of a pacemaker and once by normal rhythm from the hypothalamus of the same patient using magnetic tape. The patients were subjected to stimulations once a day for a period of 1-8 days. The results obtained are being discussed with respect to Goddard's kindling phenomenon.