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Biomedical subjects

O Gratzl

Publications and source records attributed to O Gratzl.

At least 19 recordsLinked to original sources
PubMed2002

Local injection of the 90Y-labelled peptidic vector DOTATOC to control gliomas of WHO grades II and III: an extended pilot study.

We have previously presented preliminary observations on targeting somatostatin receptor-positive malignant gliomas of all grades by local injection of the radiolabelled peptidic vector 90Y-DOTATOC. We now report on our more thorough clinical experience with this novel compound, focussing on low-grade and anaplastic gliomas. Small peptidic vectors have the potential to target invisible infiltrative disease within normal surrounding brain tissue, thereby opening a window of opportunity for early intervention. Five progressive gliomas of WHO grades II and III and five extensively debulked low-grade gliomas were treated with varying fractions of 90Y-DOTATOC. The vectors were locally injected into the resection cavity or into solid tumour. The activity per single injection ranged from 555 to 1,875 MBq, and the cumulative activity from 555 to 7,030 MBq, according to tumour volumes and eloquence of the affected brain area, yielding dose estimates from 76+/-15 to 312+/-62 Gy. Response was assessed by the clinical status, by steroid dependence and, every 4-6 months, by magnetic resonance imaging and fluorine-18 fluorodeoxyglucose positron emission tomography. In the five progressive gliomas, lasting responses were obtained for at least 13-45 months without the need for steroids. Radiopeptide brachytherapy had been the only modality applied to counter tumour progression. Interestingly, we observed the slow transformation of a solid, primarily inoperable anaplastic astrocytoma into a resectable multi-cystic lesion 2 years after radiopeptide brachytherapy. Based on these observations, we also assessed the feasibility of local radiotherapy following extensive debulking, which was well tolerated. Targeted beta-particle irradiation based on diffusible small peptidic vectors appears to be a promising modality for the treatment of malignant gliomas.

Adult↗
PubMed2001

Intramedullary spinal cord tumours: a clinical outcome and radiological follow-up study.

PRINCIPLES: Intramedullary spinal cord tumours are rare. The long-term results depend on their varying natural histories and the surgical approach. Less extensive tumour resection avoids greater postoperative neurological impairment without a negative impact on postoperative outcome. METHODS: Twenty-seven patients who underwent a total of 34 surgical interventions (including 7 reoperations) were clinically and radiologically reinvestigated. Histology revealed 19 glial, 4 nonglial and 4 miscellaneous tumours. RESULTS: Postoperative long-term clinical follow-up (mean 62 months postoperatively) in 25 patients revealed functional improvement in 2 cases, stable conditions in 17 and deterioration in 6. Although there was residual tumour on MRI in 19 of the 22 patients reexamined, stable radiological studies were seen in 15 cases. Despite the high percentage of partial resections or biopsies, good long-term clinical results were found in 19 patients (70%). CONCLUSION: The long-term outcome depends on tumour biology and the type of surgery. For low-grade astrocytomas we propose partial resection without incurring the risk of major postoperative neurological deficits, with semi-annual and, after 5 years, annual follow-up. Despite the fact that ependymomas are amenable to complete surgical resection, this was achieved in only one of six cases in this series. Postoperative MRI follow-up of intramedullary tumours must be protracted, as most of these tumours are slow-growing. An increase in the extent and intensity of contrast enhancement of the tumours was defined as tumour recurrence or progressive tumour growth.

Adult↗
PubMed2001

17beta-Estradiol reduces cortical lesion size in the glutamate excitotoxicity model by enhancing extracellular lactate: a new neuroprotective pathway.

Estrogens play an important role in neuronal function and in protecting neurones in the cerebral cortex against pathological conditions. An in vivo model of glutamate excitotoxicity in which glutamate is applied to the cortex of rats through a microdialysis probe has been used to investigate the neuroprotective processes initiated by 17beta-estradiol. Rats were pre-treated with 17beta-estradiol (i.v.) before local application of 100 mM glutamate into the cortex through a microdialysis probe. Pre-treatment with 17beta-estradiol significantly reduced the size of the glutamate-induced cortical lesion. In the cortical microdialysates collected from the probe, a peak of lactate was observed immediately after glutamate application. After 17beta-estradiol pre-treatment this peak of lactate was significantly higher with estradiol than without 120 min after glutamate application, reaching 700% basal level at the end of measurement. The level of extracellular glucose was markedly decreased with and without 17beta-estradiol pre-treatment. Local blockage of neuronal lactate transporters with alpha-cyano-4-hydroxycinnamate (4-CIN) completely abolished the neuroprotective effect of 17beta-estradiol and induced a larger cortical lesion. An accumulation of extracellular lactate was observed after inhibition of the lactate transporters suggesting that transport of lactate into neurones is necessary for the neuroprotective effect of 17beta-estradiol. The anti-estrogen tamoxifen also abolished the neuroprotective effect of 17beta-estradiol on the lesion size and inhibited the production of lactate. These results suggest a new neuroprotective mechanism of 17beta-estradiol by activating glutamate-stimulated lactate production, which is estrogen receptor-dependent.

Animals↗
PubMed2001

Quantitative real-time PCR does not show selective targeting of p14(ARF) but concomitant inactivation of both p16(INK4A) and p14(ARF) in 105 human primary gliomas.

In many human cancers, the INK4A locus is frequently mutated by homozygous deletions. By alternative splicing this locus encodes two non-related tumor suppressor genes, p16(INK4A) and p14(ARF) (p19(ARF) in mice), which regulate cell cycle and cell survival in the retinoblastoma protein (pRb) and p53 pathways, respectively. In mice, the role of p16(INK4A) as the critical tumor suppressor gene at the INK4A locus was challenged when it was found that p19(ARF) only knock-out mice developed tumors, including gliomas. We have analysed the genetic status of the INK4A locus in 105 primary gliomas using both microsatellite mapping (MSM) and quantitative real-time PCR (QRT-PCR). Comparison of the results of the two methods revealed agreement in 67% of the tumors examined. In discordant cases, fluorescence in situ hybridization (FISH) analysis was always found to support QRT-PCR classification. Direct assessment of p14(ARF) exon 1beta, p16(INK4A) exon 1alpha and exon 2 by QRT-PCR revealed 43 (41%) homozygous and eight (7%) hemizygous deletions at the INK4A locus. In 49 (47%) gliomas, both alleles were retained. In addition, QRT-PCR, but not MSM, detected hyperploidy in five (5%) tumors. Deletion of p14(ARF) was always associated with co-deletion of p16(INK4A) and increased in frequency upon progression from low to high grade gliomas. Shorter survival was associated with homozygous deletions of INK4A in the subgroup of glioblastoma patients older than 50 years of age (P=0.025, Anova test single factor, alpha=0.05).

Chromosome Mapping↗
PubMed2001

Coagulopathy induced spinal intradural extramedullary haematoma: report of three cases and review of the literature.

In a retrospective review of patients operated for coagulopathy induced spinal intradural-extramedullary haematoma the literature regarding coagulopathy induced spinal haemorrhage is reviewed and the etiology of these rare spinal subdural and subarachnoid haemorrhages is discussed. Spinal intradural haematomas are usually related to trauma or a previous lumbar puncture. A review of the literature revealed only a handful cases of spinal intradural haemorrhages occurring secondary to an underlying haematological disorder or an iatrogenic coagulopathy. Coagulopathy induced spinal haemorrhage should be included in the differential diagnosis of acute paraparesis in patients with co-existent haematological disorders or undergoing anticoagulation therapy. Due to the often mixed subdural and subarachnoid bleeding patterns we have termed this entity spinal intradural-extramedullary haematoma.

Adult↗
PubMed2001

Microdialytical monitoring of uric and ascorbic acids in the brains of patients after severe brain injury and during neurovascular surgery.

OBJECTIVES: Microdialysis has been extensively used to monitor brain metabolism in the extracellular fluid of patients with severe head injury, to detect the onset of secondary ischaemic damage. The aim was to investigate whether concentrations of uric and ascorbic acids were altered in such patients. Both these compounds play a part in free radical metabolism, which is accelerated after ischaemia and brain injury. METHODS: Patients with aneurysm or bypass operations were monitored intraoperatively to assess concentrations in minimally disturbed tissue. Afterwards, 13 patients with severe head trauma were monitored for up to 13 days in the intensive care unit. RESULTS: Intraoperatively, concentrations of both ascorbic and uric acids were significantly higher in the bypass group than in patients with aneurysm, which might be attributed to chronic ischaemic conditions caused by the unilateral occlusion of the carotid artery. In the patients with trauma, mean values of uric acid, varying between 6 microM and 180 microM, did not correlate with type of injury (contusion or diffuse) or duration of monitoring time. Patients who died had significantly higher concentrations of uric acid than those with a good outcome. Ascorbic acid could be detected only intermittently, probably due to technical problems. Concentrations of these two compounds could not be correlated with clinical findings during the course of monitoring. CONCLUSIONS: Although uric and ascorbic acids are influenced by ischaemic conditions-for example, in bypass patients, neither compound is suitable for monitoring for free radical activity after severe head injury. Patients with a bad outcome tended to have higher concentrations of uric acid.

Adult↗
PubMed2001

Extracellular levels of glucose and lactate measured by quantitative microdialysis in the human brain.

The aim of this study was to use quantitative microdialysis to estimate the true extracellular concentrations of glucose and lactate in minimally disturbed human brain. These values are important as criteria for microdialytical monitoring in critical care patients and for determining therapy. Microdialysis procedures were carried out during tumor operations, the probe being inserted distant from the site of manipulation in minimally disturbed tissue. Two methods were used: 1. The zero net flux method of Lönnroth. 2. The low flow method (10 mm membrane length, flow rate 0.3 microliter min-1, high in vivo recovery). Both methods gave similar values of about 2000 microM for lactate and slightly less for glucose (1700 microM). Glucose levels correspond with those measured by other methods in humans, allowing for the fact that our patients were anesthetised. Extracellular glucose levels were positively correlated with blood glucose values measured before the operation, and with extracellular lactate. Results confirm that extracellular glucose is zero when blood glucose is about 2 mM.

Blood Glucose↗
PubMed2000

A four lumen screwing device for multiparametric brain monitoring.

We describe multiparametric monitoring in severe head trauma using a new screwing device. Our aim was to create a screw which would make the implantation of the probes and thus multiparametric monitoring easier. The new screw allows us to implant 3 probes (microdialysis, Paratrend and an intracranial pressure device) through one burr hole. The screw has four channels, the fourth being for ventricular drainage. We monitored 13 patients with severe head trauma (GCS = 3-8) for up to 7 days. Brain tissue pO2, pCO2, pH, and temperature were measured on-line with the Paratrend 7 machine. The microdialytic parameters glucose, lactate, pyruvate and glutamate were determined semi on-line with a CMA 600 enzymatic analyser. There were no complications in any of the patients that could be ascribed to the screw.

Adult↗
PubMed1999

The PTEN lipid phosphatase domain is not required to inhibit invasion of glioma cells.

The tumor suppressor PTEN negatively controls the phosphoinositide 3-kinase pathway for cell survival by dephosphorylating the phospholipid substrates phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. PTEN has been proposed to dephosphorylate focal adhesion kinase and is implicated in the regulation of cell spreading and motility. We analyzed the role of PTEN in invasion using the two highly infiltrative glioma cell lines U87MG (which lacks functional PTEN) and LN229 (wild-type PTEN). After constitutive overexpression of wild-type and phosphatase-deficient (C124S) PTEN, we found significant inhibition of invasion (50-70%) independent of the PTEN status of the cell and of the catalytic core domain of PTEN. Although wild-type but not mutant (C124S) PTEN decreased PKB/Akt phosphorylation and induced a stellate morphology in U87MG cells, an accompanying reduction of focal adhesion kinase phosphorylation was not seen. We conclude that phosphatase-independent domains of PTEN markedly reduced the invasive potential of glioma cells, defining a structural role for PTEN that regulates cell motility distinct of the PKB/Akt pathway.

Brain Neoplasms↗
PubMed1999

[Intermittent paraparesis as manifestation of a bilateral chronic subdural hematoma].

Chronic subdural haematomas are mainly related to slight or moderate head trauma with consecutive lesion of bridge or cortical veins and bleeding in the subdural space. Further predisposing factors are known impairment of coagulation (coagulopathies, treatment with anticoagulants, alcohol abuse), risk factors for degenerative disease of the arteries (diabetes mellitus, arterial hypertension), and development of pressure gradients (hydrocephalus, epileptic seizures, lumbar puncture, CSF drainage and cerebral atrophy). Chronic subdural haematomas appear bilaterally in 20 to 25% of cases. We report on a 69-year-old male with a 4-day history of intermittent, proximal, painless paraparesis (BMA grade M2-5) without a trigger event. Sensibility was normal in all qualities and vigilance was not disturbed. Computed tomography of the neurocranium revealed a bitemporally located chronic subdural haematoma with extension to parietal on both sides. Trepanation was performed over the tuber parietale and temporoparietally on both sides, with release of 150 ml fluid. The neurologic deficits regressed totally within 12 hours postoperatively. To the best of our knowledge, we are the first to describe the clinical paradox of intermittent, painless paraparesis with preserved sensibility and without disturbances of vigilance, as manifestation of a chronic subdural haematoma possibly leading to impairment of cerebral blood flow in the area of the middle cerebral artery. Small changes in systemic blood pressure lead to changes in cerebral perfusion pressure due to vessel compression by the haematoma, thus explaining the intermittent character of the clinical presentation.

Aged↗
PubMed1999

Premeatal and retromeatal cerebellopontine angle meningioma. Two distinct clinical entities.

OBJECTIVE: Meningiomas represent the second most common type of neoplasm of the cerebellopontine angle (cpa). Their relationship to critical neural or vascular structures of the cpa is variable and they present with different signs and symptoms. MATERIALS AND METHODS: A retrosigmoid craniotomy was performed in 31 cpa-meningiomas from January 1981 to February 1997. The mean age of the 25 women (81%) and the 6 men (19%) was 53 +/- 13 years. According to their location within the posterior fossa and with special reference to the internal auditory canal (IAC), they were classified in 17 cases (55%) as retromeatal (posterior to the iac) and in 14 cases (45%) as premeatal (anterior to the iac). RESULTS: The retromeatal group showed a significantly larger tumour size (21 +/- 15 vs 29 +/- 20 mm) and the diagnosis was made later (2.7 +/- 3.2 vs 1.1 +/- 0.9 years) compared to premeatally located meningiomas. Before the operation, a reduction of the facial nerve function (64% vs 0%) and hearing function (100% vs 25%) was present significantly more often in premeatal meningiomas. The clinical appearance of the retromeatal group was dominated by cerebellar symptoms (44% vs 0%). Both preoperative and postoperative impairment of facial nerve and auditory function prevailed in the premeatal group. CONCLUSION: The topological classification of CPA-meningiomas according to their location anterior or posterior to the ICA is important, because the clinical presentation, the surgical strategy to be applied, and the functional outcome of critical neural structures differ between the two subtypes. Our results provide substantial evidence for the paradoxical observation that premeatal meningiomas have a significantly worse postoperative functional outcome compared to retromeatal meningiomas although premeatal meningiomas become symptomatic earlier and at smaller sizes.

Adult↗
PubMed1999

Acute effects of an aminosteroid on microdialytically measured parameters after experimental middle cerebral artery occlusion in the rat.

The effects of the neuroprotective aminosteroid U74389G were monitored microdialytically in rat cortex during 4 h after permanent middle cerebral artery occlusion. Either U74389G or vehicle only was administered one hour before and 2 h after operation. The dialysate was analysed for on-line pH, ascorbic acid, uric acid, glucose and lactate. In aminosteroid treated animals the levels of ascorbic and uric acids were lower in dialysates after occlusion, total release of lactate was significantly reduced and on-line pH was significantly higher than in control animals. Lesion volume at 4 h, which was significantly reduced in treated animals, correlated positively with ascorbic acid release and on-line pH. Results suggest that neuroprotective effects of aminosteroids might be explained by: (a) preservation of intracellular levels of the radical scavenger ascorbic acid with possible concomitant reduction of glutamate release; and (b) reduced lactate release and increased pH which might influence oedema positively. Copyright 1999 Harcourt Publishers Ltd.

Journal Article↗
PubMed1999

Predictive value of cerebrospinal fluid (CSF) lactate level versus CSF/blood glucose ratio for the diagnosis of bacterial meningitis following neurosurgery.

The value of cerebrospinal fluid (CSF) lactate level and CSF/blood glucose ratio for the identification of bacterial meningitis following neurosurgery was assessed in a retrospective study. During a 3-year period, 73 patients fulfilled the inclusion criteria and could be grouped by preset criteria in one of three categories: proven bacterial meningitis (n = 12), presumed bacterial meningitis (n = 14), and nonbacterial meningeal syndrome (n = 47). Of 73 patients analyzed, 45% were treated with antibiotics and 33% with steroids at the time of first lumbar puncture. CSF lactate values (cutoff, 4 mmol/L), in comparison with CSF/blood glucose ratios (cutoff, 0.4), were associated with higher sensitivity (0.88 vs. 0.77), specificity (0.98 vs. 0.87), and positive (0.96 vs. 0.77) and negative (0.94 vs. 0.87) predictive values. In conclusion, determination of the CSF lactate value is a quick, sensitive, and specific test to identify patients with bacterial meningitis after neurosurgery.

Adult↗
PubMed1999

Operated low grade astrocytomas: a long term PET study on the effect of radiotherapy.

The role of postoperative radiotherapy in patients with low grade gliomas is not established yet. PET with 11C methionine (MET) and 18F fluorodeoxyglucose (FDG) was used to perform cross sectional comparisons as well as within patient follow up studies in 30 operated patients with fibrillary astrocytoma WHO II. Uptake of tracer by tumour was quantified by radioactivity concentration ratios in tumour over contralateral brain (T/C). Comparing patients who did (n=13) or did not (n=17) receive external radiotherapy subsequent to first tumour resection, no differences in MET and FDG T/C between both groups were found during a postoperative period of 94 months (when recurrence and malignant progression of low grade astrocytomas are expected). Malignant progression occurred at a similar rate in both patient groups at a mean (SD) postoperative interval of 46 (26) months. Irrespective of whether radiotherapy was applied or not, malignant tumour recurrences showed higher T/C values (MET: 1.70 (0.64), FDG: 0.98 (0.23)) than recurrences without signs of malignancy (MET: 1.21 (0.21), FDG: 0.82 (0.08)) (Mann-Whitney: MET p=0.086, FDG p=0.035). The data show a relative lack of radiotherapy administered immediately after first tumour resection. In the course of disease, patients with tumours undergoing malignant progression may be identified with PET tracer methods.

Adult↗
PubMed1999

Effect of radiotherapy on brain glucose metabolism in patients operated on for low grade astrocytoma.

OBJECTIVE: To assess the effect of postoperative radiotherapy on brain glucose metabolism (CMRGlu) of operated patients with low grade astrocytomas. METHODS: PET and 18F-fluorodeoxyglucose was used to measure absolute CMRGlu in patients with fibrillary astrocytoma (WHO II) of the frontal lobe, who did (n=7) or did not (n=12) receive radiotherapy subsequent to first debulking tumour resection. In addition, statistical parametric mapping (SPM95) was applied to assess the pattern of relative CMRGlu associated with the frontal tumour. Data were compared with 12 healthy controls. RESULTS: A global reduction of absolute CMRGlu was found when either patients with or without radiotherapy were compared with controls (ROI analysis). Brain areas of relative CMRGlu reduction were found in the brain ipsilateral and contralateral to the tumour, comparing both patient groups with controls by SPM ("tumour diaschisis effect"). Superimposed, absolute CMRGlu in the contralateral frontal, parietal, occipital cortex as well as in the white matter was on average 17% lower in patients receiving radiotherapy than in patients who did not. CONCLUSIONS: The data discriminate a tumour effect from a radiotherapy effect, and support the view of adverse effects of radiotherapy on brain not directly involved by tumour.

Adult↗