Minocycline reduces glioma expansion and invasion by attenuating microglial MT1-MMP expression.

Glioma cells release soluble factors, which induce the expression of membrane type 1 matrix metalloprotease (MT1-MMP) in tumor associated microglia and then exploit MT1-MMP mediated matrix degradation for invasion. Here, we show that minocycline blocked the increase in MT1-MMP expression and activity in cultivated microglia stimulated with glioma conditioned medium. Glioma growth within an organotypic brain slice preparation was reduced by minocycline and this reduction depended on the presence of microglia. Glioma growth in an experimental mouse model was strongly reduced by the addition of minocycline to drinking water, compared to untreated controls. Coherently, we observed in our orthotopic glioma implantation model, that MT1-MMP was abundantly expressed in glioma associated microglia in controls, but was strongly attenuated in tumors of minocycline treated animals. Overall, our study indicates that the clinically approved antibiotic minocycline is a promising new candidate for adjuvant therapy against malignant gliomas.

Completely ossified pseudomeningocele, a rare complication after spinal surgery.

BACKGROUND: We report the rare case of an ossified pseudomeningocele following laminectomy. The extradural pseudocyst has completely ossified without an overt communication to the subarachnoid space. CASE REPORT: In 1986, a 41 year-old woman suffered from spinal stenosis at levels L3-5 and was treated by laminectomy. A cerebrospinal fluid (CSF) leakage was observed postoperatively. A follow-up CT scan eleven years after surgery showed an ossified pseudomeningocele in the operated region. However, in our case no surgical resection was performed since the patient suffered only from diffuse back pain without sciatica or any neurological deficit. In 2009 the patient continues to be neurologically intact without a change in clinical complaints. Hence, the file was closed after 23 years without neurosurgical intervention. DISCUSSION: Seven cases of ossified pseudomeningocele have been previously described in the literature and all were operated on. However, our case shows that ossified extradural pseudocysts do not require operation in every case.

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion.

Diffuse infiltration of glioma cells into normal brain tissue is considered to be a main reason for the unfavorable outcomes of patients with malignant gliomas. Invasion of glioma cells into the brain parenchyma is facilitated by metalloprotease-mediated degradation of the extracellular matrix. Metalloproteases are released as inactive pro-forms and get activated upon cleavage by membrane bound metalloproteases. Here, we show that membrane type 1 metalloprotease (MT1-MMP) is up-regulated in glioma-associated microglia, but not in the glioma cells. Overexpression of MT1-MMP is even lethal for glioma cells. Glioma-released factors trigger the expression and activity of MT1-MMP via microglial toll-like receptors and the p38 MAPK pathway, as deletion of the toll-like receptor adapter protein MyD88 or p38 inhibition prevented MT1-MMP expression and activity in cultured microglial cells. Microglial MT1-MMP in turn activates glioma-derived pro-MMP-2 and promotes glioma expansion, as shown in an ex vivo model using MT1-MMP-deficient brain tissue and a microglia depletion paradigm. Finally, MyD88 deficiency or microglia depletion largely attenuated glioma expansion in 2 independent in vivo models.

Cerebral aneurysms associated with von Recklinghausen's neurofibromatosis: report of a case and review of the literature.

The authors report a case of an intracranial aneurysm associated with von Recklinghausen's neurofibromatosis. A 34-year-old woman presented with a history of headaches, unconsciousness and neck rigidity. Widespread cutaneous neurofibromas were found. Investigations revealed an aneurysm of the anterior communicating artery. The authors discuss this case and review the relevant literature.

Embolization of indirect carotid-cavernous sinus fistulas using the superior ophthalmic vein approach.

OBJECTIVES: In indirect carotid-cavernous sinus fistulas (CCF), abnormal connections exist between tiny dural branches of the external and/or internal carotid system and the cavernous sinus. Usually this kind of fistula occurs spontaneously and is characterized by a low shunt volume. Alternative vascular approaches for embolization are required when standard interventional neuroradiological access via arterial or transfemoral venous routes is not feasible. PATIENTS AND METHODS: Two symptomatic patients with indirect CCFs are described. Transarterial and transfemoral venous approach was unsuccessful or resulted in incomplete occlusion of the CCF. Therefore, the superior ophthalmic vein (SOV) was surgically exposed and retrograde catheterized to allow the delivery of platinum coils to the fistula point via a microcatheter. RESULTS: Complete fistula obliteration was accompanied by recovery of the clinical symptoms. CONCLUSION: The surgical SOV approach might be sufficient when standard neuroradiological procedures do not succeed. The technique is safe and effective when performed by an interdisciplinary team.

[Bladder dysfunction due to spinal cord compression. Treatment modes and results]. / Blasendysfunktion bei spinaler Kompression.Therapieformen und Ergebnisse.

Bladder dysfunction is often observed in cases of spinal compression and is commonly caused by spinal tumors, trauma, or degenerative spine disease. Microsurgical decompression is the most important therapy. The earlier microsurgery is performed, the better the chances are for recovery of bladder function.

GABA(A)-receptor expression in glioma cells is triggered by contact with neuronal cells.

The expression of functional GABA(A)-receptors in glioma cells correlates with low malignancy of tumours and cell lines from glioma lack these receptors. Here we show that contact with neurons induces the expression of functional GABA(A)-receptors. C6 and F98 glioma cell lines were labelled by recombinant expression of enhanced green fluorescent protein injected into rat brain and studied in acute slices after two to three weeks of tumour growth. The cells responded to GABA or the specific agonist, muscimol with a current typical for GABA(A)-receptors, as studied with the patch-clamp technique. To get insight into the mechanism of GABA(A) receptor induction, the C6 or F98 cells were co-cultured with neurons, astrocytes, oligodendrocytes and microglia. Glioma cells expressed functional GABA(A) receptors within 24 h only in cultures where physical contact to neurons occurred. Activation of GABA(A)-receptors in the co-cultures attenuated glioma cell metabolism while blockade of the receptors increased metabolism. We conclude that with this form of interaction, neurons can influence tumour behaviour in the brain.

Focal cortical dysplasia of the temporal lobe with late-onset partial epilepsy: serial quantitative MRI.

We describe serial studies of focal cortical dysplasia causing temporal lobe seizures and progressive aphasia in a 54-year-old woman. Initially, MRI volumetry of the temporal lobes showed significant left cortical thickening corresponding to an elevated amino-acid uptake in the left temporoparietal and inferior frontal cortex on SPECT using 3-[123I]iodo-alpha-methyl-L-tyrosine (IMT). After 1 year there was severe shrinkage of the left temporal lobe, possibly the result of recurrent complex partial seizures.

Comparison of iodotyrosines and methionine uptake in a rat glioma model.

UNLABELLED: This study compares brain tumor imaging with 3-[123I]iodo-alpha-methyl-L-tyrosine (IMT) and 3-[123I/125I]iodo-O-methyl-alpha-methyl-L-tyrosine (OMIMT) to that with [methyl-3H]-L-methionine (Met) in a rat glioma model by double-tracer autoradiography. METHODS: Cells of the glioma clone F-98 were implanted stereotactically into the right basal ganglia of 22 Fischer 344 rats. After 8 days of tumor growth, the animals simultaneously were injected with a mixture of either 123I-IMT and 3H-Met (n=5), 123I-OMIMT and 3H-Met (n=8) or 123I-IMT and 125I-OMIMT (n=9). The animals were killed 15 min after the tracer injection and cryosections of the tumor-bearing brain area were exposed to phosphor-imaging plates both immediately and after the decay of 123I. Tumor-to-brain ratios (T/B) and intratumoral distribution of the different tracers and of the cresyl violet staining of the tissue were compared. RESULTS: There was a significant correlation of the T/B ratios between all tracers (IMT versus Met: r=0.97, n=5, p < 0.01; OMIMT versus Met: r=0.94, n=8, p < 0.001; OMIMT versus IMT: r=0.95, n=9, p < 0.001). Intratumoral tracer distribution was similar for all tracers and the extent of tumor labeling was identical to that of the histological tumor extent. Mean values of the T/B ratios, however, were lower for IMT (2.81+/-0.78, n=14, mean+/-s.d., p < 0.01 compared with Met) and for OMIMT (2.03+/-0.57, n=17, p < 0.01 compared with Met) than for Met (3.86+/-1.12, n=13). CONCLUSION: This study confirms that tumor imaging with IMT is similar to that of Met but T/B ratios of IMT are lower. OMIMT intratumoral tracer distribution and tumor size are similar to Met and IMT, but the T/B contrast is rather low and makes this amino acid less suitable for clinical application.

In vivo MRI thermometry using a phase-sensitive sequence: preliminary experience during MRI-guided laser-induced interstitial thermotherapy of brain tumors.

The purpose of this study was the application of the proton-resonance-frequency method to monitor laser-induced interstitial thermotherapy (LITT) in a patient with an astrocytoma WHO II. A phase-sensitive two-dimensional (2D) fast low-angle shot (FLASH) sequence was used to determine the temperature-related phase shifts during LITT. Temperature maps were displayed during therapy with a temporal resolution of 20 seconds. Irradiation was discontinued as soon as the 60 to 65 degrees C isotherm reached the margin of the tumor. A contrast-enhanced MRI study performed immediately after therapy showed a good correlation of the size of an enhancing rim around the lesion with the 60 to 65 degrees C isotherm. The preliminary results of our study indicate that MRI guidance of LITT may be improved by temperature quantification based on the proton-resonance-frequency method.

Precentral glioma location determines the displacement of cortical hand representation.

OBJECTIVE: Low-grade brain tumors may remain asymptomatic in contrast to malignant gliomas. The mechanisms underlying the preservation of cerebral function in such gliomas are not well understood. METHODS: We used positron emission tomography and transcranial magnetic stimulation for presurgical monitoring of motor hand function in six patients with gliomas of the precentral gyrus. All patients were able to perform finger movements of the contralesional hand. RESULTS: Movement-related increases of the regional cerebral blood flow occurred only outside the tumor in surrounding brain tissue. Compared with the contralateral side, these activations were shifted by 20 +/- 13 mm (standard deviation) within the dorsoventral dimension of the precentral gyrus. This shift of cortical hand representation could not be explained by the deformation of the central sulcus as determined from the spatially aligned magnetic resonance images but was closely related to the location of the maximal tumor growth. Dorsal tumor growth resulted in ventral displacement of motor hand representation, leaving the motor cortical output system unaffected, whereas ventral tumor growth leading to dorsal displacement of motor hand representation compromised the motor cortical output, as evident from transcranial magnetic stimulation. In two patients, additional activation of the supplementary motor area was present. CONCLUSION: Our data provide evidence for the reorganization of the human motor cortex to allow for preserved hand function in Grade II astrocytomas.

Whole-body kinetics and dosimetry of L-3--123I-iodo-alpha-methyltyrosine.

The synthetic amino acid L-3--123I-iodo-alpha-methyltyrosine (IMT) is currently under clinical evaluation as a single-photon emission tomography (SPET) tracer of amino acid uptake in brain tumours. So far, dosimetric data in respect of IMT are not available. Therefore we investigated the whole-body distribution of IMT in six patients with cerebral gliomas and the radiation doses were estimated. Whole-body scans were acquired at 1.5, 3 and 5 h after i.v. injection of 370-550 MBq IMT. The bladder was voided prior to each scan and the radioactivity excreted in the urine was measured. Based on the MIRD-11 method and the updated MIRDOSE3, the mean absorbed doses for various organs and the effective dose were calculated from geometric means of the anterior and posterior whole-body scans using seven source organs and the residence time. IMT was predominantly excreted by the kidneys (52.8%+/-11.5% at 1.5 h p.i., 63.0%+/-15.7% at 3 h p.i. and 74.6%+/-9.8% at 5 h p.i.). No organ system other than the urinary tract showed significant retention of the tracer. Early whole-body scans revealed slightly increased tracer uptake in the liver and in the bowel. Highest absorbed doses were found for the urinary bladder wall (0.047 mGy/MBq), the kidneys (0.010 mGy/MBq), the lower large intestinal wall (0.011 mGy/MBq) and the upper large intestinal wall (0.008 mGy/MBq). The effective dose according to ICRP 60 was estimated to be 0.0073 mSv/MBq for adults. This leads to an effective dose of 3.65 mSv in a typical brain SPET study using 500 MBq IMT. The MIRDOSE3 scheme yielded similar results. Thus, in spite of the relatively high tracer dose required for optimal brain scanning, radiation exposure in SPET studies with IMT is in the normal range of routine nuclear medicine investigations.

3-[123I]iodo-alpha-methyltyrosine and [methyl-11C]-L-methionine uptake in cerebral gliomas: a comparative study using SPECT and PET.

UNLABELLED: This study compares the uptake of the nonmetabolizable amino acid analog 3-[123I]iodo-alpha-methyltyrosine (IMT) and of [methyl-11C]-L-methionine (MET) in cerebral gliomas. METHODS: In 14 patients with cerebral gliomas, IMT uptake was measured using SPECT (10 dynamic, 4 static SPECT acquisitions) and, on the same day, MET uptake by dynamic PET. The IMT and MET data were compared with respect to tracer kinetics, tumor to brain ratios (T/B) and tumor size after converting the resolution of the PET scans to that of the SPECT scans (14 mm FWHM). RESULTS: All gliomas showed increased uptake of both tracers in relation to normal brain tissue. Visual comparison of the scans yielded no differences in tumor size and shape with both methods. IMT showed a maximal tracer uptake in brain and in tumors at about 15 min postinjection which was followed by a washout of 45.0% +/- 13.5% in gliomas (mean +/- s.d., p < 0.001, n = 10) and 35.3% +/- 5.4% in normal brain (p < 0.001, n = 10) at 60 min postinjection. MET concentration in tumor tissue or brain tissue between 15 and 60 min remained constant. T/B ratios of IMT SPECT and MET PET showed a significant correlation at 15 min postinjection (r = 0.69, n = 10, p = 0.03), a low correlation for the mean values of the scans from 15-60 min postinjection (r = 0.54, n = 14, p = 0.05) and no correlation at 60 min postinjection (r = 0.09, n = 10, n.s.). CONCLUSION: IMT and MET uptake in gliomas is similar in the early, transport dominated phase. There are some differences in tumor to brain ratios between both tracers within the first hour postinjection that are mainly caused by variable washout of IMT. Imaging of tumor extent with IMT SPECT is comparable to MET PET. Thus, amino acid SPECT using IMT is a promising tool to evaluate the biological activity and intracerebral infiltration of gliomas.

Somatosensory evoked potentials modified by laser-induced lesions of the rat cortex.

The effect of focal application of laser energy on the modification of somatosensory evoked potentials (SEPs) was studied in sensory cortical fields of the rat. This article describes the methodological set-up for recording of SEPs and for determining location and size of the laser-induced lesion. The results show that both the size of the lesion of the somatosensory cortex, and the suppression and time of recovery of cortical SEPs varied depending on the laser energy dose. It remains to be analyzed by further experiments if the recovery of SEPs is due to a transient dysfunction of the somatosensory cortex or if it reflects cortical plasticity.

Survival in malignant glioma: analysis of prognostic factors with special regard to cytoreductive surgery.

Although the question of optimal treatment for malignant gliomas has been addressed in many retrospective papers, no clear answer has been found to what extent surgical removal of tumor tissue should be performed. We conducted a retrospective analysis in 274 unselected patients, admitted to our institution with the diagnosis of malignant supratentorial glioma. Median survival time after surgery was analyzed with respect to the following defining variables: Age, pre- and postoperative Karnofsky Performance Scale (KPS), tumor location, histology, sex, pre- and postoperative tumor volume and volumetrically measured extent of resection. All these defining variables with exception of sex and preoperative tumor volume were of significant influence on the median survival time of glioma patients (Kolmogoroff-Smirnoff test, Log-Rank test, Breslow test and Tarone-Ware test p < 0,05). To exclude covariant influences of these variables on patients survival and to answer the question of the best surgical option, a matched pair analysis between 40 patients undergoing stereotactic biopsy and 40 patients undergoing cytoreductive surgery was performed. Median survival time (MST) in the biopsy group was 184 days whereas the cytoreductive surgery group had a MST of 292 days (p < 0,05). In addition median postoperative KPS at the point of discharge in patients with tumor resection was slightly better (KPS 58%) in comparison with the biopsy group (KPS 53%) but not on a significant level. It is concluded from these data that patients harbouring malignant gliomas clearly benefit from cytoreductive surgery compared with stereotactic biopsy regarding life expectancy and mildly regarding life quality.

[Possibilities of the use of MR tomography-based cerebral blood volume maps in the diagnosis of brain tumors]. / Einsatzmöglichkeiten von kernspintomographischen Parameterbildern des zerebralen Blutvolumens in der Diagnostik von Hirntumoren.

PURPOSE: Today contrast enhanced MR imaging is a reliable method for detecting mostly distinguishing between different histological types of tumours. In this study we use a MR-based method to measure the regional cerebral blood volume (rCBV). Using this technique we try to judge the grading and vitality of the tumours. METHODS: 26 patients with various types of brain tumours were examined. To calculate rCBV-maps of one slice, low-dosed Gd-DTPA was injected as a bolus. Using the relaxation effect the obtained signal intensity-time curves were converted pixel-wise into rCBV images. For the tumours rCBV-ratios were calculated relative to the corresponding area in the contralateral hemisphere. RESULTS: In the investigated group all tumours were detected on the basis of a raised rCBV-ratio. Since only vital parts of the tumour are perfused, the rCBV maps may be used to determine the place of biopsy. CONCLUSIONS: The differential diagnosis of all histological tumour types was not possible on the basis of rCBV values. Distinction between low grade and high grade gliomas was also not significant. However, a low grade glioma can be excluded if the morphological images definitely indicate an astrocytoma and if the rCBV-ratio was higher than 2.

Stiff-person syndrome with anti-glutamic acid decarboxylase autoantibodies: complete remission of symptoms after intrathecal baclofen administration.

A female patient, aged 61 years, who developed a severe immobilizing stiff-person syndrome in conjunction with insulin-dependent diabetes mellitus, is described. In addition to the typical clinical symptoms, diagnosis was proven by the presence of autoantibodies against glutamic acid decarboxylase in serum and cerebrospinal fluid. Symptomatic treatment with continuous intrathecal application of baclofen administered by a subcutaneous pump resulted in rapid clinical improvement so that the patient became ambulatory. Intermittent withdrawal from intrathecal baclofen therapy led to complete remanifestation of stiff-person syndrome within 18 h; after re-introduction of intrathecal therapy stiffness disappeared completely within 48 h. The clinical course has been stable now for over 24 months and stiffness has completely disappeared. The effect of baclofen in this patient is discussed in the light of the suggested pathophysiological mechanisms in stiff-person syndromes.

Reversal of chemoresistance in malignant gliomas by calcium antagonists: correlation with the expression of multidrug-resistant p-glycoprotein.

Resistance to multiple drugs is often observed in malignant gliomas. The authors used a microtiter tetrazolium test to analyze primary in vitro chemoresistance and chemosensitivity of 15 early cultures of human malignant glioma exposed to 50 micrograms/ml (1,4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosoure a (ACNU), 50 micrograms/ml cisplatin, 1 microgram/ml vincristine, or combinations of these chemotherapeutic agents. Primary chemoresistance was observed in 87% of tumors for ACNU, in 87% for cisplatin, and in 83% for vincristine. All tumors were examined for expression of multidrug-resistant p-glycoprotein, a transport protein of 170,000 D, by means of immunohistochemical staining with the JSB-1 antibody on paraffinized tumor sections. Eight of 15 specimens (53%) showed positive staining for the monoclonal antibody. Primary chemoresistance was overcome by addition of the calcium antagonists verapamil or nimodipine to the cultures if the original tumor expressed p-glycoprotein (p < 0.01 for verapamil, p < 0.05 for nimodipine). In tumors not expressing p-glycoprotein, addition of calcium antagonists to the cell cultures did not influence primary chemoresistance. It is concluded from these data that addition of calcium antagonists to the adjuvant chemotherapy of malignant gliomas might overcome primary chemoresistance in tumors expressing the multidrug-resistant phenotype.