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.

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.

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.

Tomographic studies of rCBF with [99mTc]-HM-PAO SPECT in patients with brain tumors: comparison with C15O2 continuous inhalation technique and PET.

In 10 patients with malignant gliomas, the intracerebral distribution of [99mTc]-hexamethylpropylene-amine oxime [( 99mTc]-HM-PAO) was studied with single photon emission computed tomography (SPECT) in comparison with C15O2 steady-state inhalation technique to measure cerebral blood flow using positron emission tomography (PET). In all instances, the cerebral [99mTc]-HM-PAO distribution was comparable with the regional pattern of cerebral blood flow (rCBF) observed with PET. This was confirmed by a significant correlation of tumor to cortex and tumor to white matter ratios between these two experimental methods. However, the contrast between high and low activity regions in the SPECT scans was significantly less than that in the PET scans. Contrast enhancement of the SPECT scans was accomplished using a correction formula proposed by Lassen.

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.

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.

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.

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.

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.

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.

RG2 glioma growth in rat cerebellum after subdural implantation.

The nitrosourea-induced rat glioma clone RG2 was tested for its capacity to form multicellular tumor spheroids (MTS's). Resulting spheroids were investigated by light and electron microscopy with regard to their proliferation patterns and morphological features. Using microsurgical techniques and avoiding mechanical injury of the brain tissue, the authors successfully transplanted avascular MTS's under the dura of the cerebellum, above the vermis, in 43 adult syngeneic Fischer CD rats. The rate of tumor establishment was 93%, and the tumors that were solid and spheroid in shape grew exponentially. Neovascularization could be observed at 3 days after implantation, and invasion of the cerebellum occurred by 3 to 5 days. Neurological deterioration, including ataxia, impairment of walking, and apathy, could be observed after 10 days. The mean survival time was approximately 16 days. The subdural cerebellar tumors were studied by histological techniques, and two morphometric methods were applied to check the growth of implanted spheroids. All tumors were deeply stained with the Evans blue dye-albumin complex, demonstrating disturbance of the blood-brain barrier. The easy accessibility of the cerebellar vermis in rats, the microsurgical implantation of glioma spheroids under the dura avoiding nerve tissue disruption, and the high percentage of reproducible establishment of tumors favor this experimental brain-tumor model. This should be an excellent model for study of experimental therapies.

Effects of recombinant human tumor necrosis factor on rodent gliomas and normal brain.

In a study examining the possible therapeutic effects of recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) on malignant gliomas without expression of tumor necrosis factor (TNF)-receptors, RG-2 glioma cells were tested in vitro as well as in a rat experimental glioma model. A growth inhibition assay revealed no inhibiting effect in vitro up to a concentration of 20 micrograms/ml rHuTNF-alpha. Receptor-binding studies showed that RG-2 cells did not present specific receptors for rHuTNF-alpha. The pharmacokinetics of rHuTNF-alpha after intravenous injection were studied with respect to serum, tissue, and brain tumor concentrations and showed increased glioma concentrations of (mean +/- standard error of the mean) 0.47 +/- 0.18 ng TNF/mg brain compared to 0.15 +/- 0.05 ng TNF/mg brain in the normal contralateral hemisphere. No therapeutic effect on solid RG-2 gliomas could be observed after stereotactic injection of 7.3 micrograms rHuTNF/10 microliter buffer solution into the tumor in 10 animals. Immunohistochemical studies after stereotactic injection of rHuTNF-alpha showed total disappearance of the substance after 24 hours without internalization into tumor cells. Stereotactic injection of 7.3 micrograms rHuTNF 10 microliters into normal brain resulted in marked inflammatory response around the injection track, including microvascular thrombosis. These results demonstrate that rHuTNF has neither direct nor indirect cytotoxic activity on RG-2 glioma cells. Furthermore, before clinical use of rHuTNF-alpha in malignant gliomas, the authors suggest that receptor studies be done in each patient. In receptor-positive patients undergoing treatment with rHuTNF-alpha, precautions should be taken to prevent local encephalitic reactions.

Pleomorphic xanthoastrocytoma with desmoplastic reaction: angiomatous variant. Report of two cases.

Two cases of cerebral pleomorphic xanthoastrocytomas (PXA-s) with prominent vascularity and desmoplastic changes occurring in young subjects are presented. The tumors displayed the marked pleomorphism characteristic of PXA-s and had variable cellularity. The cytoplasm of many tumor cells contained an abundance of lipid droplets. Most tumor cells were positive for glial fibrillary acidic protein. The unusual feature about these tumors was the presence of very large numbers of tiny blood vessels with variable thickness of their walls. In many areas the small vessels and the neoplastic astrocytes were in close proximity to each other, with capillaries adjacent to or protruding into tumor cell cytoplasm, reminiscent of the pattern seen in highly vascularized or "angiomatous" meningiomas. In other areas extensive fibrosis was seen. We feel that the latter, as in the cases of comparably vascular meningiomas, had its origin in congelation and secondary organization of plasma proteins that have exuded through leaky walls of newly formed blood vessels. These are the first reported cases of PXA with an angiogliomatous pattern.

[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.

Early effects of intra-arterial chemotherapy in patients with brain tumours studied with PET: preliminary results.

In ten patients with malignant gliomas the regional cerebral metabolic rate for glucose (rCMRGlc) was studied with positron emission tomography (PET) using 2-18F-deoxyglucose (18FDG) before and within 1 to 7 days after intra-arterial chemotherapy with the nitrosourea derivative ACNU (iaACNU). Three patients were studied before and after two iaACNU courses and one patients before and after three iaACNU courses. The early effects of iaACNU on tumour rCMRGlc were highly variable and appeared to be more pronounced after the first course of iaACNU than in later iaACNU courses, i.e. more pronounced in untreated patients. Although there was no clear correlation between the change of rCMRGlc following the first course of iaACNU and the clinical outcome in this small group of patients, the patient with the most pronounced decrease of tumour metabolism (-16.5%) after the first course of iaACNU exhibited full tumour remission for 12 months, while the patient with the most pronounced increase of tumour metabolism (+65%) after the first course of iaACNU developed rapid tumour progression. The first results indicate that early effects of intra-arterial chemotherapy may be observed with 18FDG PET, especially following the first course of iACNU. Further studies are needed to evaluate the predictive value of such studies for therapy response.

Investigations of brain tumours with 99Tcm-HMPAO SPECT.

The cerebral uptake of 99Tcm-hexamethylpropyleneamine oxime (99Tcm-HMPAO) as measured with the use of single photon emission computed tomography (SPECT) was studied in 66 patients with various types of brain tumours and quantified by tumour-to-cerebellum ratios. The uptake of 99Tcm-HMPAO by gliomas and meningiomas showed wide ranges of values. There were no significant differences among primary malignant gliomas (0.75 +/- 0.27, n = 25), recurrent malignant gliomas (0.81 +/- 0.25, n = 14) and benign gliomas (0.77 +/- 0.21, n = 9). Compared to gliomas, meningiomas exhibited a significantly higher 99Tcm-HMPAO uptake (1.14 +/- 0.31, n = 13, p less than 0.001) while the remaining four patients with tumours of various histopathology showed a low 99Tcm-HMPAO uptake. Three of the 66 patients were scanned immediately and again 2 h after injection and they revealed a decrease in tumour activity. No changes in the pattern of uptake were observed in two patients with gliomas which were studied before and after intra-arterial chemotherapy, but a decrease in tumour uptake was found in the glioma patient who was studied before and after radiotherapy. The results obtained with 99Tcm-HMPAO SPECT are in agreement with those on regional cerebral blood flow (rCBF) in brain tumours reported in the literature.

Osteoclastomas of the petrous bone.

Two cases of osteoclastoma of the petrous bone are presented that were clinically taken for tumors of the glomus jugulare. The petrous bone is a very uncommon location for such tumors, and only six cases have been reported in the English literature. The histopathological features as well as the clinical course are described, and the literature is critically reviewed.

[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.

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.